bluuebunny/crossref_metadata_2025 huggingface dataset:
Health Risk Assessment of Mercury Exposure from Fish Consumption in Munduruku Indigenous Communities in the Brazilian Amazon
Authors: Vasconcellos Ana Claudia Santiago de , Hallwass Gustavo , Bezerra Jaqueline Gato , Aciole Angélico Nonato Serrão , Meneses Heloisa Nascimento de Moura , Lima Marcelo de Oliveira , Jesus Iracina Maura de , Hacon Sandra de Souza , Basta Paulo Cesar
Published: July 2021

Fish serves as the principal source of animal protein for the indigenous people of the Amazon, ensuring their food and nutritional security. However, gold mining causes mercury (Hg) contamination in fish, and consequently increases health risks associated with fish consumption. The aim of this study was to assess the health risk attributed to the consumption of mercury-contaminated fish by Munduruku indigenous communities in the Middle-Tapajós Region. Different fish species were collected in the Sawré Muybu Indigenous Land to determine mercury levels. The health risk assessment was carried out according to the World Health Organization (WHO 2008) methodology and different scenarios were built for counterfactual analysis. Eighty-eight fish specimens from 17 species and four trophic levels were analyzed. Estimates of Hg ingestion indicated that the methylmercury daily intake exceeds the U.S. EPA (United States Environmental Protection Agency) (2000) reference dose from 3 to 25-fold, and up to 11 times the FAO (Food and Agriculture Organization)/WHO (2003) dose recommendation. In all situations analyzed, the risk ratio estimates were above 1.0, meaning that the investigated Munduruku communities are at serious risk of harm as a result of ingestion of mercury-contaminated fish. These results indicate that, at present, fish consumption is not safe for this Munduruku population. This hazardous situation threatens the survival of this indigenous population, their food security, and their culture.
Culturally Adaptive Governance—Building a New Framework for Equity in Aboriginal and Torres Strait Islander Health Research: Theoretical Basis, Ethics, Attributes and Evaluation
Authors: Duke Daniel L.M. , Prictor Megan , Ekinci Elif , Hachem Mariam , Burchill Luke J.
Published: July 2021

Indigenous health inequities persist in Australia due to a system of privilege and racism that has political, economic and social determinants, rather than simply genetic or behavioural causes. Research involving Aboriginal and Torres Strait Islander (‘Indigenous’) communities is routinely funded to understand and address these health inequities, yet current ethical and institutional conventions for Indigenous health research often fall short of community expectations. Typically, mainstream research projects are undertaken using traditional “top-down” approaches to governance that hold inherent tensions with other dominant governance styles and forms. This approach perpetuates long-held power imbalances between those leading the research and those being researched. As an alternative, Indigenous governance focuses on the importance of place, people, relationships and process for addressing power imbalances and achieving equitable outcomes. However, empowering principles of Indigenous governance in mainstream environments is a major challenge for research projects and teams working within organisations that are regulated by Western standards and conventions. This paper outlines the theoretical basis for a new Culturally Adaptive Governance Framework (CAGF) for empowering principles of Indigenous governance as a prerequisite for ethical conduct and practice in Indigenous health research. We suggest new orientations for mainstream research project governance, predicated on translating theoretical and practical attributes of real-world ethics, adaptive governance and critical allyship frameworks to Indigenous health research. The CAGF is being implemented in a national Indigenous multicenter trial evaluating the use of continuous blood glucose monitors as a new technology with the potential to improve diabetes care and treatment for Indigenous Australians—the FlashGM Study. The CAGF is a governance framework that identifies the realities of power, acknowledges the complexities of culture and emerging health technologies, and foregrounds the principle of equity for mainstream Indigenous health research.
Differences in Incidence of Acute Viral Hepatitis between Foreigners and Autochthonous Population in Italy
Authors: D’Angelo Franca , Ferrigno Luigina , Mele Annamaria , Alfonsi Valeria , Declich Silvia , De Ponte Giulia , Crateri Simonetta , Burgio Alessandra , Caminada Susanna , Tosti Maria ,   on behalf of The SEIEVA Collaborating Group
Published: July 2021

Background: In European countries, the prevalence of HBV and HCV in refugees and migrants tends to reflect the prevalence in their countries of origin. The aim of this study is to analyse acute viral hepatitis cases diagnosed in Italy among foreign citizens and to compare incidence rates in foreigners and Italians. Methods: We analysed the cases of each viral hepatitis type among foreigners. Standardised incidence rates were compared between natives and foreigners. Results: Between 2004 and 2019, 15,872 cases of acute viral hepatitis were notified by 10 Italian regions, 14.8% among foreign citizens. Until 2012, the percentage increased gradually, while a fluctuating trend set in from 2013 onwards; in 2019, 23.9% of cases were foreigners. Data from the SEIEVA surveillance show higher standardised incidence rates of hepatitis A and B among foreign citizens; no significant difference emerged between Italians and foreigners in terms of their hepatitis C incidence. Conclusions: foreign citizens have an increased incidence of hepatitis A and B. Regarding hepatitis A, vaccination is strongly recommended to foreigners travelling to their countries of origin. Screening tests for hepatitis B and C infection should be offered to newly arrived migrants from high prevalence countries, or having specific risk factors.
The Influence of Running and Dancing on the Occurrence and Progression of Premenstrual Disorders
Authors: Witkoś Joanna , Hartman-Petrycka Magdalena
Published: July 2021

Background: The aim of the study was to assess the influence of both physical activity, such as running and dancing, and the personal characteristics of the studied women on the occurrence and progression of premenstrual disorder (PMD). Methods: We surveyed 414 women aged 22–48 who were experiencing the menstrual cycle but not using hormonal contraception. There were two physically active groups, runners (N = 215) and Argentine tango dancers (N = 94), and there was one group not undertaking any physical activity—the control group (N = 104). The research was conducted using the researchers’ own questionnaire. Results: The number of days of PMD symptoms in the tango vs. runner vs. control groups are as follows: pre-bleeding (mean: 4.14 vs. 4.86 vs. 4.85; p = 0.024), after the onset of bleeding (mean: 1.76 vs. 2.39 vs. 2.16; p = 0.001), and in total (mean: 5.94 vs. 7.25 vs. 7.01; p < 0.001). The regression analysis results without grouping results are as follows: the number of days of symptoms before bleeding and menarche (B: −0.16; 95% CIs: from −0.29 to −0.04; p = 0.011), the total duration of symptoms and menarche (B: −0.17; 95% CIs: from −0.32 to −0.01; p = 0.036), lower abdominal pain and age (B: −0.05; 95% CIs: 0.92–0.98; p = 0.002), diarrhoea (B: −0.08; 95% CIs: 0.88–0.97; p < 0.001), tearfulness, depressive states and age (B: −0.06; 95% CIs: 0.91–0.97; p < 0.001), skin problems and age (B: −0.05; 95% CIs: 0.92–0.98; p = 0.004), joint pain and age (B: −0.09; 95% CIs: 0.86–0.96; p = 0.001), pain in the lumbar spine (B: −0.06, 95% CIs: 0.91–0.98; p = 0.001), water retention and BMI (B: 0.09; 95% CIs: 0.92–0.98; p = 0.007), and water retention and menarche (B: −0.19; 95% CIs: 0.73–0.94; p = 0.003). Information: generally there is one regression model, we have several here, we have a bit the description. Conclusions: Physical activity such as dancing (tango) shortens the duration of PMD symptoms but does not completely eliminate them. Running does not have as beneficial an effect on symptom relief as dancing. Current age, age when menstruation began (menarche), and BMI were revealed to be important factors influencing the symptoms of premenstrual disorders.
Spatial Disparity and Influencing Factors of Coupling Coordination Development of Economy–Environment–Tourism–Traffic: A Case Study in the Middle Reaches of Yangtze River Urban Agglomerations
Authors: Chen Qian , Bi Yuzhe , Li Jiangfeng
Published: July 2021

In the process of rapid development of economic globalization and regional integration, the importance of urban agglomeration has become increasingly prominent. It is not only the main carrier for countries and regions to participate in international competition, but also the main place to promote regional coordination and sustainable development. Coordinated economic, environmental, tourism and traffic development is very necessary for sustainable regional development. However, the existing literature lacks research on coupling coordination of the Economy–Environment–Tourism–Traffic (EETT) system in urban agglomeration. In this study, in order to fill this gap, we establish the index system from four dimensions of economy, environment, tourism and traffic, and select the influencing factors from the natural and human perspectives to exam the spatio-temporal changes and influencing factors in the coupling coordination of the EETT system using an integrated method in the Middle Reaches of Yangtze River Urban Agglomerations (MRYRUA), China. The results indicate that the coupling coordination degree of the EETT system transitioned from the uncoordinated period to the coordinated period, while it showed an increasing trend on the whole from 1995 to 2017. The spatial agglomeration effect has been positive since 2010, while “High–High” and “Low–High” agglomeration regions were transferred from the east to the south. Land used for urban construction as a percentage of the urban area and vegetation index has a great impact on the coupling coordination degree. These results provide important guidance for the formulation of integration and coordinated development policy in the MRYRUA, and then increase China’s international competitiveness by improving the contribution of urban agglomerations to GDP.
Nutrient Dense, Low-Cost Foods Can Improve the Affordability and Quality of the New Zealand Diet—A Substitution Modeling Study
Authors: Starck Carlene S. , Blumfield Michelle , Keighley Tim , Marshall Skye , Petocz Peter , Inan-Eroglu Elif , Abbott Kylie , Cassettari Tim , Ali Ajmol , Wham Carol , Kruger Rozanne , Kira Geoff , Fayet-Moore Flavia
Published: July 2021

The high prevalence of non-communicable disease in New Zealand (NZ) is driven in part by unhealthy diet selections, with food costs contributing to an increased risk for vulnerable population groups. This study aimed to: (i) identify the nutrient density-to-cost ratio of NZ foods; (ii) model the impact of substituting foods with a lower nutrient density-to-cost ratio with those with a higher nutrient density-to-cost ratio on diet quality and affordability in representative NZ population samples for low and medium socioeconomic status (SES) households by ethnicity; and (iii) evaluate food processing level. Foods were categorized, coded for processing level and discretionary status, analyzed for nutrient density and cost, and ranked by nutrient density-to-cost ratio. The top quartile of nutrient dense, low-cost foods were 56% unprocessed (vegetables, fruit, porridge, pasta, rice, nuts/seeds), 31% ultra-processed (vegetable dishes, fortified bread, breakfast cereals unfortified <15 g sugars/100 g and fortified 15–30 g sugars/100 g), 6% processed (fruit juice), and 6% culinary processed (oils). Using substitution modeling, diet quality improved by 59% and 71% for adults and children, respectively, and affordability increased by 20–24%, depending on ethnicity and SES. The NZ diet can be made healthier and more affordable when nutritious, low-cost foods are selected. Processing levels in the healthier, modeled diet suggest that some non-discretionary ultra-processed foods may provide a valuable source of low-cost nutrition for food insecure populations.
Deep Learning with Neuroimaging and Genomics in Alzheimer’s Disease
Authors: Lin Eugene , Lin Chieh-Hsin , Lane Hsien-Yuan
Published: July 2021

A growing body of evidence currently proposes that deep learning approaches can serve as an essential cornerstone for the diagnosis and prediction of Alzheimer’s disease (AD). In light of the latest advancements in neuroimaging and genomics, numerous deep learning models are being exploited to distinguish AD from normal controls and/or to distinguish AD from mild cognitive impairment in recent research studies. In this review, we focus on the latest developments for AD prediction using deep learning techniques in cooperation with the principles of neuroimaging and genomics. First, we narrate various investigations that make use of deep learning algorithms to establish AD prediction using genomics or neuroimaging data. Particularly, we delineate relevant integrative neuroimaging genomics investigations that leverage deep learning methods to forecast AD on the basis of incorporating both neuroimaging and genomics data. Moreover, we outline the limitations as regards to the recent AD investigations of deep learning with neuroimaging and genomics. Finally, we depict a discussion of challenges and directions for future research. The main novelty of this work is that we summarize the major points of these investigations and scrutinize the similarities and differences among these investigations.
Identification of miR-20a-5p as Robust Normalizer for Urine microRNA Studies in Renal Cell Carcinoma and a Profile of Dysregulated microRNAs
Authors: Oto Julia , Herranz Raquel , Plana Emma , Sánchez-González José Vicente , Pérez-Ardavín Javier , Hervás David , Fernández-Pardo Álvaro , Cana Fernando , Vera-Donoso César David , Martínez-Sarmiento Manuel , Medina Pilar
Published: July 2021

Renal cell carcinoma (RCC) is the third most frequent urinary malignancy and one of the most lethal. Current diagnostic and follow-up techniques are harmful and unspecific in low-grade tumors. Novel minimally invasive markers such as urine microRNAs (miRNAs) are under study. However, discrepancies arise among studies in part due to lack of consent regarding normalization. We aimed to identify the best miRNA normalizer for RCC studies performed in urine samples together with a miRNA profile with diagnostic value and another for follow-up. We evaluated the performance of 120 candidate miRNAs in the urine of 16 RCC patients and 16 healthy controls by RT-qPCR followed by a stability analysis with RefFinder. In this screening stage, miR-20a-5p arose as the most stably expressed miRNA in RCC and controls, with a good expression level. Its stability was validated in an independent cohort of 51 RCC patients and 32 controls. Using miR-20a-5p as normalizer, we adjusted and validated a diagnostic model for RCC with three miRNAs (miR-200a-3p, miR-34a-5p and miR-365a-3p) (AUC = 0.65; Confidence Interval 95% [0.51, 0.79], p = 0.043). let-7d-5p and miR-205-5p were also upregulated in patients compared to controls. Comparing RCC samples before surgery and fourteen weeks after, we identified let-7d-5p, miR-152-3p, miR-30c-5p, miR-362-3p and miR-30e-3p as potential follow-up profile for RCC. We identified validated targets of most miRNAs in the renal cell carcinoma pathway. This is the first study that identifies a robust normalizer for urine RCC miRNA studies, miR-20a-5p, which may allow the comparison of future studies among laboratories. Once confirmed in a larger independent cohort, the miRNAs profiles identified may improve the non-invasive diagnosis and follow-up of RCC.
Complex Analysis of Antioxidant Activity, Abscisic Acid Level, and Accumulation of Osmotica in Apple and Cherry In Vitro Cultures under Osmotic Stress
Authors: Jiroutova Petra , Kovalikova Zuzana , Toman Jakub , Dobrovolna Dominika , Andrys Rudolf
Published: July 2021

Plant response to osmotic stress is a complex issue and includes a wide range of physiological and biochemical processes. Extensive studies of known cultivars and their reaction to drought or salinity stress are very important for future breeding of new and tolerant cultivars. Our study focused on the antioxidant activity, accumulations of osmotica, and the content of abscisic acid in apple (cv. “Malinové holovouské”, “Fragrance”, “Rubinstep”, “Idared”, “Car Alexander”) and cherry (cv. “Regina”, “Napoleonova”, “Kaštánka”, “Sunburst”, “P-HL-C”) cultivated in vitro on media containing different levels of polyethylene glycol PEG-6000. Our results indicated that the studied genotypes responded differently to osmotic stress manifested as reduction in the leaf relative water content (RWC) and increment in the activities of antioxidant enzymes, proline, sugars, and abscisic acid content. Overall, cherry cultivars showed a smaller decrease in percentage RWC and enzymatic activities, but enhanced proline content compared to the apple plants cultivars. Cultivars “Rubinstep”, “Napoleonova”, and “Kaštánka” exhibited higher antioxidant capacity and accumulation of osmoprotectants like proline and sorbitol that can be associated with the drought-tolerance system.
Maternal Neutrophil Depletion Fails to Avert Systemic Lipopolysaccharide-Induced Early Pregnancy Defects in Mice
Authors: Panja Sourav , Benjamin John T. , Paria Bibhash C.
Published: July 2021

Maternal infection-induced early pregnancy complications arise from perturbation of the immune environment at the uterine early blastocyst implantation site (EBIS), yet the underlying mechanisms remain unclear. Here, we demonstrated in a mouse model that the progression of normal pregnancy from days 4 to 6 induced steady migration of leukocytes away from the uterine decidual stromal zone (DSZ) that surrounds the implanted blastocyst. Uterine macrophages were found to be CD206+ M2-polarized. While monocytes were nearly absent in the DSZ, DSZ cells were found to express monocyte marker protein Ly6C. Systemic endotoxic lipopolysaccharide (LPS) exposure on day 5 of pregnancy led to: (1) rapid (at 2 h) induction of neutrophil chemoattractants that promoted huge neutrophil infiltrations at the EBISs by 24 h; (2) rapid (at 2 h) elevation of mRNA levels of MyD88, but not Trif, modulated cytokines at the EBISs; and (3) dose-dependent EBIS defects by day 7 of pregnancy. Yet, elimination of maternal neutrophils using anti-Ly6G antibody prior to LPS exposure failed to avert LPS-induced EBIS defects allowing us to suggest that activation of Tlr4-MyD88 dependent inflammatory pathway is involved in LPS-induced defects at EBISs. Thus, blocking the activation of the Tlr4-MyD88 signaling pathway may be an interesting approach to prevent infection-induced pathology at EBISs.
Atrazine Inhalation Causes Neuroinflammation, Apoptosis and Accelerating Brain Aging
Authors: Genovese Tiziana , Siracusa Rosalba , Fusco Roberta , D’Amico Ramona , Impellizzeri Daniela , Peritore Alessio Filippo , Crupi Rosalia , Gugliandolo Enrico , Morabito Rossana , Cuzzocrea Salvatore , Trovato Salinaro Angela , Cordaro Marika , Di Paola Rosanna
Published: July 2021

Background: exposure to environmental contaminants has been linked to an increased risk of neurological diseases and poor outcomes. Chemical name of Atrazine (ATR) is 6-chloro-N-ethyl-N′-(1-methylethyl)-1,3,5-triazine-2,4-diamine, and it is the most commonly used broad-spectrum herbicide in agricultural crops. Several studies have demonstrated that ATR has the potential to be harmful to the brain’s neuronal circuits. Until today nobody has explored the effect of ATR inhalation on young and aged mice. Methods: young and aged mice were subject to 25 mg of ATR in a vehicle made with saline and 10% of Dimethyl sulfoxide (DMSO) every day for 28 days. At the end of experiment different behavioral test were made and brain was collected. Results: exposure to ATR induced the same response in terms of behavioral alterations and motor and memory impairment in mice but in aged group was more marked. Additionally, in both young and aged mice ATR inhalations induced oxidative stress with impairment in physiological antioxidant response, lipid peroxidation, nuclear factor kappa-light-chain-enhancer of activated B cells (nf-κb) pathways activation with consequences of pro-inflammatory cytokines release and apoptosis. However, the older group was shown to be more sensitive to ATR inhalation. Conclusions: our results showed that aged mice were more susceptible compared to young mice to air pollutants exposure, put in place a minor physiologically response was seen when exposed to it.
The Presynaptic Scaffold Protein Bassoon in Forebrain Excitatory Neurons Mediates Hippocampal Circuit Maturation: Potential Involvement of TrkB Signalling
Authors: Annamneedi Anil , del Angel Miguel , Gundelfinger Eckart D. , Stork Oliver , Çalışkan Gürsel
Published: July 2021

A presynaptic active zone organizer protein Bassoon orchestrates numerous important functions at the presynaptic active zone. We previously showed that the absence of Bassoon exclusively in forebrain glutamatergic presynapses (BsnEmx1cKO) in mice leads to developmental disturbances in dentate gyrus (DG) affecting synaptic excitability, morphology, neurogenesis and related behaviour during adulthood. Here, we demonstrate that hyperexcitability of the medial perforant path-to-DG (MPP-DG) pathway in BsnEmx1cKO mice emerges during adolescence and is sustained during adulthood. We further provide evidence for a potential involvement of tropomyosin-related kinase B (TrkB), the high-affinity receptor for brain-derived neurotrophic factor (BDNF), mediated signalling. We detect elevated TrkB protein levels in the dorsal DG of adult mice (~3–5 months-old) but not in adolescent (~4–5 weeks-old) mice. Electrophysiological analysis reveals increased field-excitatory-postsynaptic-potentials (fEPSPs) in the DG of the adult, but not in adolescent BsnEmx1cKO mice. In line with an increased TrkB expression during adulthood in BsnEmx1cKO, blockade of TrkB normalizes the increased synaptic excitability in the DG during adulthood, while no such effect was observed in adolescence. Accordingly, neurogenesis, which has previously been found to be increased in adult BsnEmx1cKO mice, was unaffected at adolescent age. Our results suggest that Bassoon plays a crucial role in the TrkB-dependent postnatal maturation of the hippocampus.
Chronological Age Affects MSC Senescence In Vitro—A Systematic Review
Authors: Kapetanos Konstantinos , Asimakopoulos Dimitrios , Christodoulou Neophytos , Vogt Antonia , Khan Wasim
Published: July 2021

The use of mesenchymal stromal cells (MSCs) in regenerative medicine and tissue engineering is well established, given their properties of self-renewal and differentiation. However, several studies have shown that these properties diminish with age, and understanding the pathways involved are important to provide regenerative therapies in an ageing population. In this PRISMA systematic review, we investigated the effects of chronological donor ageing on the senescence of MSCs. We identified 3023 studies after searching four databases including PubMed, Web of Science, Cochrane, and Medline. Nine studies met the inclusion and exclusion criteria and were included in the final analyses. These studies showed an increase in the expression of p21, p53, p16, ROS, and NF-κB with chronological age. This implies an activated DNA damage response (DDR), as well as increased levels of stress and inflammation in the MSCs of older donors. Additionally, highlighting the effects of an activated DDR in cells from older donors, a decrease in the expression of proliferative markers including Ki67, MAPK pathway elements, and Wnt/β-catenin pathway elements was observed. Furthermore, we found an increase in the levels of SA-β-galactosidase, a specific marker of cellular senescence. Together, these findings support an association between chronological age and MSC senescence. The precise threshold for chronological age where the reported changes become significant is yet to be defined and should form the basis for further scientific investigations. The outcomes of this review should direct further investigations into reversing the biological effects of chronological age on the MSC senescence phenotype.
The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses
Authors: Demyanenko Svetlana , Sharifulina Svetlana
Published: July 2021

Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.
Targeted Therapies in Rare Brain Tumours
Authors: Bruno Francesco , Pellerino Alessia , Bertero Luca , Soffietti Riccardo , Rudà Roberta
Published: July 2021

Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.
Protein Arginine Methyltransferase 1 Is Essential for the Meiosis of Male Germ Cells
Authors: Waseem Sahar , Kumar Sudeep , Lee Kanghoon , Yoon Byoung-Ha , Kim Mirang , Kim Hail , Lee Keesook
Published: July 2021

Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells; however, its function in vivo is not well understood due to its early embryonic lethality in null mice exhibiting spontaneous DNA damage, cell cycle delays, and defects in check point activation. Here, we generated germ cell-specific Prmt1 knock-out (KO) mice to evaluate the function of PRMT1 in spermatogenesis. Our findings demonstrate that PRMT1 is vital for male fertility in mice. Spermatogenesis in Prmt1 KO mice was arrested at the zygotene-like stage of the first meiotic division due to an elevated number of DNA double-strand breaks (DSBs). There was a loss of methylation in meiotic recombination 11 (MRE11), the key endonuclease in MRE11/RAD50/NBS 1 (MRN) complex, resulting in the accumulation of SPO11 protein in DSBs. The ATM-mediated negative feedback control over SPO11 was lost and, consequently, the repair pathway of DSBs was highly affected in PRMT1 deficient male germ cells. Our findings provide a novel insight into the role of PRMT1-mediated asymmetric demethylation in mouse spermatogenesis.
Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A3 Receptor Subtype
Authors: Coppi Elisabetta , Cherchi Federica , Lucarini Elena , Ghelardini Carla , Pedata Felicita , Jacobson Kenneth A. , Di Cesare Mannelli Lorenzo , Pugliese Anna Maria , Salvemini Daniela
Published: July 2021

Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.
A Proteomic Study Suggests Stress Granules as New Potential Actors in Radiation-Induced Bystander Effects
Authors: Tudor Mihaela , Gilbert Antoine , Lepleux Charlotte , Temelie Mihaela , Hem Sonia , Armengaud Jean , Brotin Emilie , Haghdoost Siamak , Savu Diana , Chevalier François
Published: July 2021

Besides the direct effects of radiations, indirect effects are observed within the surrounding non-irradiated area; irradiated cells relay stress signals in this close proximity, inducing the so-called radiation-induced bystander effect. These signals received by neighboring unirradiated cells induce specific responses similar with those of direct irradiated cells. To understand the cellular response of bystander cells, we performed a 2D gel-based proteomic study of the chondrocytes receiving the conditioned medium of low-dose irradiated chondrosarcoma cells. The conditioned medium was directly analyzed by mass spectrometry in order to identify candidate bystander factors involved in the signal transmission. The proteomic analysis of the bystander chondrocytes highlighted 20 proteins spots that were significantly modified at low dose, implicating several cellular mechanisms, such as oxidative stress responses, cellular motility, and exosomes pathways. In addition, the secretomic analysis revealed that the abundance of 40 proteins in the conditioned medium of 0.1 Gy irradiated chondrosarcoma cells was significantly modified, as compared with the conditioned medium of non-irradiated cells. A large cluster of proteins involved in stress granules and several proteins involved in the cellular response to DNA damage stimuli were increased in the 0.1 Gy condition. Several of these candidates and cellular mechanisms were confirmed by functional analysis, such as 8-oxodG quantification, western blot, and wound-healing migration tests. Taken together, these results shed new lights on the complexity of the radiation-induced bystander effects and the large variety of the cellular and molecular mechanisms involved, including the identification of a new potential actor, namely the stress granules.
Differential Expression of the Host Lipid Regulators ANGPTL-3 and ANGPTL-4 in HCV Infection and Treatment
Authors: Valiakou Vaia , Eliadis Petros , Karamichali Eirini , Tsitsilonis Ourania , Koskinas John , Georgopoulou Urania , Foka Pelagia
Published: July 2021

Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct-acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin-like protein-3 (ANGPTL-3) and angiopoietin-like protein-4 (ANGPTL-4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT-qPCR to investigate ANGPTL-3 and ANGPTL-4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long-term HCV infection in vitro, before and after DAA treatment. ANGPTL-3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL-4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL-3 mRNA was down-regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL-3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL-4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor- β (TGF-β). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL-3 as a contributor to post-treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.
The Protective Function and Modification of Secondary Metabolite Accumulation in Response to Light Stress in Dracocephalum forrestii Shoots
Authors: Weremczuk-Jeżyna Izabela , Hnatuszko-Konka Katarzyna , Lebelt Liwia , Grzegorczyk-Karolak Izabela
Published: July 2021

The aim of this work was to determine the effect of stress conditions caused by different light sources, i.e., blue LED (λ = 430 nm), red LED (λ = 670 nm), blue and red LED (70%:30%) and white LED (430–670 nm) on the growth and morphology of cultivated in vitro Dracocephalum forrestii shoot culture. It also examines the effects on bioactive phenolic compound production and photosynthetic pigment content, as well as on antioxidant enzyme activity (CAT, SOD, POD) and antioxidant properties. The most beneficial proliferation effect was observed under white LEDs (7.1 ± 2.1 shoots per explant). The white and blue lights stimulated the highest fresh weight gain, while red light induced the highest dry weight gain. The total phenolic acid content ranged from 13.824 ± 1.181 to 20.018 ± 801 mg g DW−1 depending on light conditions. The highest content of rosmarinic acid was found in the control shoots (cultivated under fluorescent lamps), followed by culture grown under red light. All LED treatments, especially red and blue, increased salvianolic acid B content, and blue increased apigenin p-coumarylrhamnoside biosynthesis. The greatest ferric reduction activity was observed in shoots cultivated under red light, followed by blue; this is associated with the presence of the highest total phenol content, especially phenolic acids. Similarly, the highest DPPH radical scavenging potential was observed under red light followed by blue. This study proves that LEDs have emerged as significant support for directed in vitro propagation, taking advantage of specific stress responses on various light spectra. This study also showed how stress induced by different LED light spectra increases in Dracocephalum forrestii the synthesis of pharmacologically-active compounds. Hence, light stress may turn out to be a simpler alternative to metabolic engineering for improving the production of secondary metabolites of therapeutic value.
Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing
Authors: Barvitenko Nadezhda , Aslam Muhammad , Lawen Alfons , Saldanha Carlota , Skverchinskaya Elisaveta , Uras Giuseppe , Manca Alessia , Pantaleo Antonella
Published: July 2021

Changes in plasma membrane curvature and intracellular ionic strength are two key features of cell volume perturbations. In this hypothesis we present a model of the responsible molecular apparatus which is assembled of two molecular motors [non-muscle myosin II (NMMII) and protrusive actin polymerization], a spring [a complex between the plasma membrane (PM) and the submembrane actin-based cytoskeleton (smACSK) which behaves like a viscoelastic solid] and the associated signaling proteins. We hypothesize that this apparatus senses changes in both the plasma membrane curvature and the ionic strength and in turn activates signaling pathways responsible for regulatory volume increase (RVI) and regulatory volume decrease (RVD). During cell volume changes hydrostatic pressure (HP) changes drive alterations in the cell membrane curvature. HP difference has opposite directions in swelling versus shrinkage, thus allowing distinction between them. By analogy with actomyosin contractility that appears to sense stiffness of the extracellular matrix we propose that NMMII and actin polymerization can actively probe the transmembrane gradient in HP. Furthermore, NMMII and protein-protein interactions in the actin cortex are sensitive to ionic strength. Emerging data on direct binding to and regulating activities of transmembrane mechanosensors by NMMII and actin cortex provide routes for signal transduction from transmembrane mechanosensors to cell volume regulatory mechanisms.
Secretome and Tunneling Nanotubes: A Multilevel Network for Long Range Intercellular Communication between Endothelial Cells and Distant Cells
Authors: Charreau Béatrice
Published: July 2021

As a cellular interface between the blood and tissues, the endothelial cell (EC) monolayer is involved in the control of key functions including vascular tone, permeability and homeostasis, leucocyte trafficking and hemostasis. EC regulatory functions require long-distance communications between ECs, circulating hematopoietic cells and other vascular cells for efficient adjusting thrombosis, angiogenesis, inflammation, infection and immunity. This intercellular crosstalk operates through the extracellular space and is orchestrated in part by the secretory pathway and the exocytosis of Weibel Palade Bodies (WPBs), secretory granules and extracellular vesicles (EVs). WPBs and secretory granules allow both immediate release and regulated exocytosis of messengers such as cytokines, chemokines, extracellular membrane proteins, coagulation or growth factors. The ectodomain shedding of transmembrane protein further provide the release of both receptor and ligands with key regulatory activities on target cells. Thin tubular membranous channels termed tunneling nanotubes (TNTs) may also connect EC with distant cells. EVs, in particular exosomes, and TNTs may contain and transfer different biomolecules (e.g., signaling mediators, proteins, lipids, and microRNAs) or pathogens and have emerged as a major triggers of horizontal intercellular transfer of information.
An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity
Authors: Gómez-Zorita Saioa , Milton-Laskibar Iñaki , García-Arellano Laura , González Marcela , Portillo María P.
Published: July 2021

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.
Decellularised Human Umbilical Artery as a Vascular Graft Elicits Minimal Pro-Inflammatory Host Response Ex Vivo and In Vivo
Authors: Ahlmann Alexander Høgsted , Fang Shu , Mortensen Sussi Bagge , Andersen Line Weis , Pedersen Pernille Gejl , Callesen Johanne Juel , Bak Sara Thornby , Lambertsen Kate Lykke , Andersen Ditte Caroline
Published: July 2021

Small diameter (<6 mm) vessel grafts still pose a challenge for scientists worldwide. Decellularised umbilical artery (dUA) remains promising as small diameter tissue engineered vascular graft (TEVG), yet their immunogenicity remains unknown. Herein, we evaluated the host immune responses, with a focus on the innate part, towards human dUA implantation in mice, and confirmed our findings in an ex vivo allogeneic human setup. Overall, we did not observe any differences in the number of circulating white blood cells nor the number of monocytes among three groups of mice (1) dUA patch; (2) Sham; and (3) Mock throughout the study (day −7 to 28). Likewise, we found no difference in systemic inflammatory and anti-inflammatory cytokine levels between groups. However, a massive local remodelling response with M2 macrophages were observed in the dUA at day 28, whereas M1 macrophages were less frequent. Moreover, human monocytes from allogeneic individuals were differentiated into macrophages and exposed to lyophilised dUA to maximize an eventual M1 response. Yet, dUA did not elicit any immediate M1 response as determined by the absence of CCR7 and CXCL10. Together this suggests that human dUA elicits a minimal pro-inflammatory response further supporting its use as a TEVG in an allogeneic setup.
Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia
Authors: Rybnikova Elena , Nalivaeva Natalia
Published: July 2021

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.
Activation of Peripheral Blood Mononuclear Cells and Leptin Secretion: New Potential Role of Interleukin-2 and High Mobility Group Box (HMGB)1
Authors: Coppola Andrea , Capuani Barbara , Pacifici Francesca , Pastore Donatella , Arriga Roberto , Bellia Alfonso , Andreadi Aikaterini , Di Daniele Nicola , Lauro Renato , Della-Morte David , Sconocchia Giuseppe , Lauro Davide
Published: July 2021

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1β from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.
Knockdown of PEX16 Induces Autophagic Degradation of Peroxisomes
Authors: Wei Xiaofan , Maharjan Yunash , Dorotea Debra , Dutta Raghbendra-Kumar , Kim Donghyun , Kim Hyunsoo , Mu Yizhu , Park Channy , Park Raekil
Published: July 2021

Peroxisome abundance is regulated by homeostasis between the peroxisomal biogenesis and degradation processes. Peroxin 16 (PEX16) is a peroxisomal protein involved in trafficking membrane proteins for de novo peroxisome biogenesis. The present study demonstrates that PEX16 also modulates peroxisome abundance through pexophagic degradation. PEX16 knockdown in human retinal pigment epithelial-1 cells decreased peroxisome abundance and function, represented by reductions in the expression of peroxisome membrane protein ABCD3 and the levels of cholesterol and plasmalogens, respectively. The activation of pexophagy under PEX16 knockdown was shown by (i) abrogated peroxisome loss under PEX16 knockdown in autophagy-deficient ATG5 knockout cell lines, and (ii) increased autophagy flux and co-localization of p62—an autophagy adaptor protein—with ABCD3 in the presence of the autophagy inhibitor chloroquine. However, the levels of cholesterol and plasmalogens did not recover despite the restoration of peroxisome abundance following chloroquine treatment. Thus, PEX16 is indispensable for maintaining peroxisome homeostasis by regulating not only the commonly known biogenesis pathway but also the autophagic degradation of peroxisomes.