bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep and Awakening Quality during COVID-19 Confinement: Complexity and Relevance for Health and Behavior
Authors: Paiva Teresa , Reis Cátia , Feliciano Amélia , Canas-Simião Hugo , Machado Maria Augusta , Gaspar Tânia , Tomé Gina , Branquinho Cátia , Silva Maria Raquel , Ramiro Lúcia , Gaspar Susana , Bentes Carla , Sampaio Francisco , Pinho Lara , Pereira Conceição , Carreiro Alexandra , Moreira Susana , Luzeiro Isabel , Pimentel Joana , Videira Gabriela , Fonseca Júlio , Bernarda Ana , Vaz Castro Joana , Rebocho Sofia , Almondes Katie , Canhão Helena , Matos Margarida Gaspar
Published: March 2021

Objective: The aim of this study was to evaluate sleep and awakening quality (SQ and AQ) during COVID-19 in a large and diversified population in order to identify significant associations and risks in terms of demography, health and health-related behaviors, sleep variables, mental health, and attitudes. Methods/Results:Online surveys were used for data collection, received from 5479 individuals from the general population, sleep disorder patients, and COVID-involved (medical doctors (MDs) and nurses) and COVID-affected professionals (teachers, psychologists, and dentists). SQ and AQ were worse in adults, females, and high-education subjects. Feeling worse, having economic problems, depression, anxiety, irritability, and a high Calamity Experience Check List (CECL) score during COVID were significantly associated with poor SQ and AQ. Shorter sleep duration, increased latency, poor nutrition, low physical activity, increased mobile and social network use, more negative and less positive attitudes and behaviors were associated with poor AQ. Conclusions: The SQ logistic regression showed gender, morbidities, CECL, and awakenings as relevant, whereas, for AQ, relevant variables further included age and physical activity. Aiming to have a high stress compliance, each individual should sleep well, have important control of their mood, practice positive behaviors while dismissing negative behaviors and attitudes, practice exercise, have adequate nutrition, and beware of technologies and dependences.
Posture and Health: Are the Biomechanical Postural Evaluation and the Postural Evaluation Questionnaire Comparable to and Predictive of the Digitized Biometrics Examination?
Authors: Barassi Giovanni , Di Simone Edoardo , Galasso Piero , Cristiani Salvatore , Supplizi Marco , Kontochristos Leonidas , Colarusso Simona , Visciano Christian Pasquale , Marano Pietro , Antonella Di Iulio , Giancola Orazio
Published: March 2021

Background: Postural tone alterations are expressions of myofascial and, therefore, of structural, visceral, and emotional disorders. To prevent these disorders, this study proposes a quantitative investigation method which administers a postural evaluation questionnaire and a postural biomechanical evaluation to 100 healthy subjects. Methods: The reliability of the method is studied by comparing both assessments with digitized biometrics. In addition, 50 subjects undergo the biomechanical evaluation form twice, by four different operators, to study the intraoperative repeatability. Results: The results show a satisfactory overlap between the results obtained with the postural evaluation questionnaire and the postural biomechanical evaluation compared to computerized biometrics. Furthermore, intraoperative repeatability in the use of the biomechanical evaluation form is demonstrated thanks to a minimal margin of error. Conclusions: This experience suggests the importance of undertaking this path in both the curative and the preventive sphere on a large scale and on different types of people who easily, and even unknowingly, may face dysfunctional syndromes, not only structural and myofascial but also consequently of the entire body’s homeostasis.
Numerical Modeling of Groundwater Pollution by Chlorpyrifos, Bromacil and Terbuthylazine. Application to the Buñol-Cheste Aquifer (Spain)
Authors: Pérez-Indoval Ricardo , Rodrigo-Ilarri Javier , Cassiraga Eduardo , Rodrigo-Clavero María-Elena
Published: March 2021

Chlorpyrifos, Bromacil and Terbuthylazine are commonly used as insecticides and herbicides to control weeds and prevent non-desirable growth of algae, fungi and bacteria in many agricultural applications. Despite their highly negative effects on human health, environmental modeling of these pesticides in the vadose zone until they reach groundwater is still not being conducted on a regular basis. This work shows results obtained by version 5.08 of the Pesticide Root Zone Model (PRZM5) numerical model to simulate the fate and transport of Chlorpyrifos, Bromacil and Terbuthylazine between 2006 and 2018 inside the Buñol-Cheste aquifer in Spain. The model uses a whole set of parameters to solve a modified version of the mass transport equation considering the combined effect of advection, dispersion and reactive transport processes. The simulation process was designed for a set of twelve scenarios considering four application doses for each pesticide. Results show that the maximum concentration value for every scenario exceeds the current Spanish Maximum Concentration Limit (0.1 μg/L). Numerical simulations were able to reproduce concentration observations over time despite the limited amount of available data.
A Scoping Review of the Health of African Immigrant and Refugee Children
Authors: Salami Bukola , Fernandez-Sanchez Higinio , Fouche Christa , Evans Catrin , Sibeko Lindiwe , Tulli Mia , Bulaong Ashley , Kwankye Stephen Owusu , Ani-Amponsah Mary , Okeke-Ihejirika Philomina , Gommaa Hayat , Agbemenu Kafuli , Ndikom Chizoma Millicent , Richter Solina
Published: March 2021

Migration is a growing phenomenon around the world, including within the African continent. Many migrants, especially African children, face challenges related to health and social inclusion and can face increased health risks. A systematic scoping review of available literature on the health of African migrant children across the globe was conducted to offer insight into these health risks. The review was conducted over a 15-month period from January 2019 to April 2020, yielding 6602 articles once duplicates were removed. This search included electronic databases, reference lists of articles reviewed, and searches of libraries of relevant organisations. A total of 187 studies met the inclusion criteria, of which 159 were quantitative, 22 were qualitative, and 6 used mixed methods. The findings reveal decreased health in this population in areas of nutrition, infectious diseases, mental health, birth outcomes, sexual and reproductive health, physical and developmental health, parasitic infections, oral health, respiratory health, preventative health, endocrine disorders, health care services, and haematological conditions. The findings offer insights into factors influencing the health of African immigrant and refugee children. Further studies, especially qualitative studies, are needed to determine barriers to service access after migration and to investigate other underexplored and overlooked health concerns of African migrant children, including pneumonia and child maltreatment.
Environmental Heavy Metal Contamination from Electronic Waste (E-Waste) Recycling Activities Worldwide: A Systematic Review from 2005 to 2017
Authors: Houessionon M. G. Karel , Ouendo Edgard-Marius D. , Bouland Catherine , Takyi Sylvia A. , Kedote Nonvignon Marius , Fayomi Benjamin , Fobil Julius N. , Basu Niladri
Published: March 2021

The recycling of electronic waste (e-waste) contaminates ecosystems with metals, though a compilation of data from across sites worldwide is lacking, without which evidence-based comparisons and conclusions cannot be realized. As such, here, a systematic review of the literature was conducted to identify peer-reviewed studies concerning e-waste sites (published between 2005 and 2017) that reported on the concentration of heavy metals (Cd, Hg, As, Pb and Cr) in soil, water and sediment. From 3063 papers identified, 59 studies from 11 countries meeting predefined criteria were included. Reported metal concentrations were summarized, and a narrative synthesis was performed. This review summarized 8286 measurements of the aforementioned metals in soils (5836), water (1347) and sediment (1103). More than 70% of the studies were conducted in Asia. In nearly all cases, the average metal concentrations in a particular medium from a given site were above guideline values; suggesting soils, water and sediment at, or near, e-waste recycling sites are contaminated. Across all media, concentrations of Pb were generally highest, followed by Cr, As, Cd and Hg. The synthesized information demonstrates that e-waste sites worldwide are contaminated with metals, that geographic data gaps exist, that the quality of most studies can be improved and that action is needed to help reduce such levels to protect human health and the environment.
The Economic Costs of Childhood Disability: A Literature Review
Authors: Shahat Ahmed Ramadan Shokry , Greco Giulia
Published: March 2021

Background: This literature review investigates the economic costs of childhood disability analysing methodologies used and summarizing the burden worldwide comparing developed and developing countries. Methods: Four electronic databases were searched. Studies were categorised according to country, perspective, methods of costing, disability category, and time horizon. Annual costs were converted to 2019 current US dollars then compared to the country’s per capita current health expenditure (CHE) and gross domestic product (GDP). Results: Of 2468 references identified, 20 were included in the review. Annual burden of childhood disability ranged ≈$450–69,500 worldwide. Childhood disability imposes a heavy economic burden on families, health systems, and societies. The reason for the wide range of costs is the variability in perspective, costs included, methods, and disability type. Conclusion: The annual societal costs for one disabled child could be up to the country’s GDP per capita. The burden is heavier on households in developing countries as most of the costs are paid out-of-pocket leading to impoverishment of the whole family. Efforts should be directed to avoid preventable childhood disabilities and to support disabled children and their households to make them more independent and increase their productivity. More studies from developing countries are needed.
Assessment of Workplace Social Encounters: Social Profiles, Burnout, and Engagement
Authors: Leiter Michael P.
Published: March 2021

Employed people (N = 826) completed questionnaires including the Social Encounters Scale that assessed civility, incivility, and intimidation from supervisors, coworkers, and respondents on identical frequency scale. Factor analyses, correlations, and profile analysis addressed the first research question by demonstrating the benefits of assessing various dimensions of workplace social dynamics on a common rating scale. A subsample (N = 275 completed a second survey, confirming consistency over time. To address the second research question a Latent Profile Analysis (LPA) identified five social profiles: Civil, Low Contact, Uncivil Coworkers, Uncivil Supervisor, and Uncivil. These profiles were associated with distinct perceptions of the work environment, addressing the third research question. To address the fourth research question, crosstabulation with a profile structure based on the Maslach Burnout Scale demonstrated close links of workplace social culture with psychological connections with work.
Zero-Risk Interpretation in the Level of Preventive Action Method Implementation for Health and Safety in Construction Sites
Authors: Carpio-de los Pinos Antonio José , González-García María de las Nieves , Pentelhão Ligia Cristina , Baptista J. Santos
Published: March 2021

Risk assessment is a legal obligation for all companies in most countries worldwide. It aims to control the quality of working conditions and avoid externalizing the consequences of accidents and resulting costs to society. This work discusses the need for an adequate interpretation of the zero-risk concept from a technical-preventive perspective to assess occupational risks in construction sites. A critical analysis of several risk assessment methodologies was carried out, focusing on the evaluation criteria of little or no-risk situations. The verification of the results was made through a case study. The perception of health and safety risks by workers is very different from that of the evaluators. Often, when workers identify a situation as low-risk or even zero-risk, the evaluator assesses the same context as maximum risk. Given the workers’ and the evaluators’ responses, the Preventive Action Method establishes a new parameter, the Environment Congruence. This parameter is based on the perception of the preventive environment and gives more importance to the evaluators’ decision. When preventive action is optimal, the risk is low in all preventive observation settings. In conclusion, this study justifies the non-nullity of the risk and the difficulty of assessing zero-risk in construction sites. Therefore, evaluations with qualitative and quantitative non-risk approaches should be discarded.
Effect of Work–Family Conflict, Psychological Job Demand, and Job Control on the Health Status of Nurses
Authors: Pien Li-Chung , Cheng Wan-Ju , Chou Kuei-Ru , Lin Li-Chiu
Published: March 2021

Work–family conflicts (WFCs) are common in the healthcare sector and pose significant health risks to healthcare workers. This study examined the effect of WFCs on the health status and nurses’ leaving intentions in Taiwan. A self-administered questionnaire was used to survey 200 female nurses’ experiences of WFC from a regional hospital. Data on psychosocial work conditions, including work shifts, job control, psychological job demands, and workplace justice, were collected. Health conditions were measured using the Beck Depression Inventory-II and self-rated health. Leaving intentions were measured using a self-developed questionnaire. The participants’ average work experience was 6.79 (Standard Deviation (SD) = 5.26) years, their highest educational level was university, and work shifts were mostly night and rotating shifts. Approximately 75.5% of nurses perceived high levels of WFCs. Leaving intentions were correlated with WFCs (r = 0.350, p < 0.01) and psychological work demands (r = 0.377, p < 0.01). After adjusting for age, educational level, and work characteristics, high levels of WFCs were associated with poor self-rated health, and depression, but not associated with high leaving intentions. Nurses’ experiences of high levels of WFCs greatly affected their health status.
Association between Work-Related Trauma Exposure and Posttraumatic Stress Symptoms among Child Welfare Workers in Japan: A Cross-Sectional Study
Authors: Kataoka Mayumi , Nishi Daisuke
Published: March 2021

Child welfare workers often experience work-related traumatic events and may be at risk of post-traumatic stress disorder (PTSD), which can hinder early interventions for child abuse. This study examined the association between each single work-related traumatic event experienced by child welfare workers and the cumulative number of traumatic event types with PTSD symptoms. A checklist of traumatic events was used to investigate work-related traumatic events. The PTSD checklist for DSM-5 (PCL-5) was used to screen for PTSD symptoms. Two multivariate analyses were performed. A total of 140 workers were included in the analyses. In the first multivariate analysis, the event, “Witnessed a parent violently beating, hitting, kicking, or otherwise injuring a child or the other parent during work” (β = 11.96; 95% CI, 2.11–21.80; p < 0.05) and resilience (β = −0.60; 95% CI, −0.84 to −0.36; p < 0.01) were significantly associated with PTSD symptoms, as was resilience in the second multivariate analysis (β = −0.60; 95% CI, −0.84 to −0.36; p < 0.01). The association between the cumulative number of event types and PTSD symptoms was not significant, but it was stronger when the cumulative number was four or more. The findings suggest the importance of reducing child welfare worker exposure to traumatic events.
The Effect of Multiprobiotics on Memory and Attention in Fibromyalgia: A Pilot Randomized Controlled Trial
Authors: Cardona Diana , Roman Pablo , Cañadas Fernando , Sánchez-Labraca Nuria
Published: March 2021

Fibromyalgia syndrome (FMS) is a chronic, generalized and diffuse pain disorder accompanied by cognitive deficits such as forgetfulness, concentration difficulties, loss of vocabulary and mental slowness, among others. In recent years, FMS has been associated with altered intestinal microbiota, suggesting that modulating gut microbiota (for example, through probiotics) could be an effective therapeutic treatment. Thus, the aim of the present study was to continue exploring the role of probiotics in cognitive processes in patients with FMS. A pilot randomized controlled trial was conducted in 31 patients diagnosed with FMS to compare the effects of a multispecies probiotic versus a placebo on cognitive variables (memory and attention) after eight weeks. Results showed that treatment with a multispecies probiotic produced an improvement in attention by reducing errors on an attention task, but it had no effect on memory. More specifically, a tendency to reduce errors of omission (Go trials) during the Go/No-Go Task was observed after treatment. These findings, along with our previous results in impulsivity, underline the relevance of using probiotics as a therapeutic option in FMS, although more research with a larger sample size is required.
Influence of Depression and Anxiety on Hemodialysis Patients: The Value of Multidisciplinary Care
Authors: Delgado-Domínguez Carlos J. , Sanz-Gómez Sergio , López-Herradón Ana , Díaz Espejo Beatriz , Lamas González Olaya , de los Santos Roig Macarena , Berdud Godoy Isabel , Rincón Bello Abraham , Ramos Sánchez Rosa
Published: March 2021

Affective disorders promote poorer outcomes in hemodialysis patients. According to the presence or not of depression/anxiety in these patients, aims were to analyze differences in sociodemographic, clinical and/or psychological factors and to identify predictors. One hundred eighty-six hemodialysis patients were classified based on their depression/anxiety status. Basal characteristics showed differences between groups where mainly male sex (Depression: OR 0.2; Anxiety: OR 0.3) albumin (Depression: OR 0.1; Anxiety: OR 0.2) and calcium levels (Depression: OR 0.5; Anxiety: OR 0.4), impaired quality of life (Depression: OR 1.4; Anxiety: OR 1.2) and psychological inflexibility (Depression: OR 1.3; Anxiety: OR 1.2) were associated (all p < 0.01) to these mental conditions. Multivariate models showed that worse quality of life (OR 1.3; p < 0.001) predicted depression while marital status (with a partner; OR 0.3; p = 0.025) and albumin levels (OR 0.1; p = 0.027) were protective factors. Depression represented a risk factor for anxiety (OR 1.2; p = 0.001), although calcium levels (OR 0.5; p = 0.039) would protect this state. Interestingly, psychological inflexibility predicted both disorders (Depression: OR 1.2, p < 0.001 and Anxiety: OR 1.1; p = 0.002). Results highlight the relevance of well-trained multidisciplinary hemodialysis units to control the influence of these factors on the presence of depression/anxiety, and thus, their impact on the patients’ outcomes.
A Participatory Intervention to Improve the Psychosocial Work Environment and Mental Health in Human Service Organisations. A Mixed Methods Evaluation Study
Authors: Cedstrand Emma , Nyberg Anna , Sanchez-Bengtsson Sara , Alderling Magnus , Augustsson Hanna , Bodin Theo , Mölsted Alvesson Helle , Johansson Gun
Published: March 2021

Work-related stress is a global problem causing suffering and economic costs. In Sweden, employees in human service occupations are overrepresented among persons on sick leave due to mental health problems such as stress-related disorders. The psychosocial work environment is one contributing factor for this problem, making it urgent to identify effective methods to decrease stress at the workplace. The aim of the study is to evaluate a participatory intervention to improve the psychosocial work environment and mental health using an embedded mixed methods design. The study is a controlled trial with a parallel process evaluation exploring fidelity and participants’ reactions to the intervention activities, experiences of learning and changes in behaviours and work routines. We collected data through documentation, interviews and three waves of questionnaires. Our results show small changes in behaviours and work routines and no positive effects of the intervention on the psychosocial work environment nor health outcomes. One explanation is end-users’ perceived lack of involvement over the process causing the intervention to be seen as a burden. Another explanation is that the intervention activities were perceived targeting the wrong organisational level. A representative participation over both content and process can be an effective strategy to change psychosocial working conditions and mental health.
Statistical Advances in Epidemiology and Public Health
Authors: Matranga Domenica , Bono Filippa , Maniscalco Laura
Published: March 2021

The key role of statistical modeling in epidemiology and public health is unquestionable [...]
Successful Partnerships: Exploring the Potential of Immunogenic Signals Triggered by TMZ, CX-4945, and Combined Treatment in GL261 Glioblastoma Cells
Authors: Villamañan Lucía , Martínez-Escardó Laura , Arús Carles , Yuste Victor J. , Candiota Ana P.
Published: March 2021

Background: The relevance of the cancer immune cycle in therapy response implies that successful treatment may trigger the exposure or the release of immunogenic signals. Previous results with the preclinical GL261 glioblastoma (GB) showed that combination treatment of temozolomide (TMZ) + CX-4945 (protein kinase CK2 inhibitor) outperformed single treatments, provided an immune-friendly schedule was followed. Our purpose was to study possible immunogenic signals released in vitro by GB cells. Methods: GL261 GB cells were treated with TMZ and CX-4945 at different concentrations (25 µM–4 mM) and time frames (12–72 h). Cell viability was measured with Trypan Blue and propidium iodide. Calreticulin exposure was assessed with immunofluorescence, and ATP release was measured with bioluminescence. Results: TMZ showed cytostatic rather than cytotoxic effects, while CX-4945 showed remarkable cytotoxic effects already at low concentrations. Calreticulin exposure after 24 h was detected with TMZ treatment, as well as TMZ/CX-4945 low concentration combined treatment. ATP release was significantly higher with CX-4945, especially at high concentrations, as well as with TMZ/CX-4945. Conclusions: combined treatment may produce the simultaneous release of two potent immunogenic signals, which can explain the outperformance over single treatments in vivo. A word of caution may be raised since in vitro conditions are not able to mimic pharmacokinetics observed in vivo fully.
The Inflammatory Profile of Obesity and the Role on Pulmonary Bacterial and Viral Infections
Authors: Hornung Franziska , Rogal Julia , Loskill Peter , Löffler Bettina , Deinhardt-Emmer Stefanie
Published: March 2021

Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function that can be attributed to mechanical dysfunctions. Moreover, the alterations of adipocyte-derived signal mediators strongly influence the regulation of inflammation, resulting in chronic low-grade inflammation. Our review summarizes the known effects regarding pulmonary bacterial and viral infections. For this, we discuss model systems that allow mechanistic investigation of the interplay between obesity and lung infections. Overall, obesity gives rise to a higher susceptibility to infectious pathogens, but the pathogenetic process is not clearly defined. Whereas, viral infections often show a more severe course in obese patients, the same patients seem to have a survival benefit during bacterial infections. In particular, we summarize the main mechanical impairments in the pulmonary tract caused by obesity. Moreover, we outline the main secretory changes within the expanded adipose tissue mass, resulting in chronic low-grade inflammation. Finally, we connect these altered host factors to the influence of obesity on the development of lung infection by summarizing observations from clinical and experimental data.
Gene Transactivation and Transrepression in MYC-Driven Cancers
Authors: Scafuro Marika , Capasso Lucia , Carafa Vincenzo , Altucci Lucia , Nebbioso Angela
Published: March 2021

MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
pH-Responsive Self-Assembly of Designer Aromatic Peptide Amphiphiles and Enzymatic Post-Modification of Assembled Structures
Authors: Wakabayashi Rie , Higuchi Ayato , Obayashi Hiroki , Goto Masahiro , Kamiya Noriho
Published: March 2021

Supramolecular fibrous materials in biological systems play important structural and functional roles, and therefore, there is a growing interest in synthetic materials that mimic such fibrils, especially those bearing enzymatic reactivity. In this study, we investigated the self-assembly and enzymatic post-modification of short aromatic peptide amphiphiles (PAs), Fmoc-LnQG (n = 2 or 3), which contain an LQG recognition unit for microbial transglutaminase (MTG). These aromatic PAs self-assemble into fibrous structures via π-π stacking interactions between the Fmoc groups and hydrogen bonds between the peptides. The intermolecular interactions and morphologies of the assemblies were influenced by the solution pH because of the change in the ionization states of the C-terminal carboxy group of the peptides. Moreover, MTG-catalyzed post-modification of a small fluorescent molecule bearing an amine group also showed pH dependency, where the enzymatic reaction rate was increased at higher pH, which may be because of the higher nucleophilicity of the amine group and the electrostatic interaction between MTG and the self-assembled Fmoc-LnQG. Finally, the accumulation of the fluorescent molecule on these assembled materials was directly observed by confocal fluorescence images. Our study provides a method to accumulate functional molecules on supramolecular structures enzymatically with the morphology control.
Cardiac Oxidative Signaling and Physiological Hypertrophy in the Na/K-ATPase α1s/sα2s/s Mouse Model of High Affinity for Cardiotonic Steroids
Authors: Marck Pauline V. , Pessoa Marco T. , Xu Yunhui , Kutz Laura C. , Collins Dominic M. , Yan Yanling , King Cierra , Wang Xiaoliang , Duan Qiming , Cai Liquan , Xie Jeffrey X. , Lingrel Jerry B. , Xie Zijian , Tian Jiang , Pierre Sandrine V.
Published: March 2021

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1r/rα2s/s mouse failed to do so in the α1s/sα2s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.
Feedback Regulation of O-GlcNAc Transferase through Translation Control to Maintain Intracellular O-GlcNAc Homeostasis
Authors: Lin Chia-Hung , Liao Chen-Chung , Chen Mei-Yu , Chou Teh-Ying
Published: March 2021

Protein O-GlcNAcylation is a dynamic post-translational modification involving the attachment of N-acetylglucosamine (GlcNAc) to the hydroxyl groups of Ser/Thr residues on numerous nucleocytoplasmic proteins. Two enzymes are responsible for O-GlcNAc cycling on substrate proteins: O-GlcNAc transferase (OGT) catalyzes the addition while O-GlcNAcase (OGA) helps the removal of GlcNAc. O-GlcNAcylation modifies protein functions; therefore, dysregulation of O-GlcNAcylation affects cell physiology and contributes to pathogenesis. To maintain homeostasis of cellular O-GlcNAcylation, there exists feedback regulation of OGT and OGA expression responding to fluctuations of O-GlcNAc levels; yet, little is known about the molecular mechanisms involved. In this study, we investigated the O-GlcNAc-feedback regulation of OGT and OGA expression in lung cancer cells. Results suggest that, upon alterations in O-GlcNAcylation, the regulation of OGA expression occurs at the mRNA level and likely involves epigenetic mechanisms, while modulation of OGT expression is through translation control. Further analyses revealed that the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) contributes to the downregulation of OGT induced by hyper-O-GlcNAcylation; the S5A/S6A O-GlcNAcylation-site mutant of 4E-BP1 cannot support this regulation, suggesting an important role of O-GlcNAcylation. The results provide additional insight into the molecular mechanisms through which cells may fine-tune intracellular O-GlcNAc levels to maintain homeostasis.
Sphingosine-1-Phosphate Receptor Type 4 (S1P4) Is Differentially Regulated in Peritoneal B1 B Cells upon TLR4 Stimulation and Facilitates the Egress of Peritoneal B1a B Cells and Subsequent Accumulation of Splenic IRA B Cells under Inflammatory Conditions
Authors: Riese Janik , Gromann Alina , Lührs Felix , Kleinwort Annabel , Schulze Tobias
Published: March 2021

Background: Gram-negative infections of the peritoneal cavity result in profound modifications of peritoneal B cell populations and induce the migration of peritoneal B cells to distant secondary lymphoid organs. However, mechanisms controlling the egress of peritoneal B cells from the peritoneal cavity and their subsequent trafficking remain incompletely understood. Sphingosine-1-phosphate (S1P)-mediated signaling controls migratory processes in numerous immune cells. The present work investigates the role of S1P-mediated signaling in peritoneal B cell trafficking under inflammatory conditions. Methods: Differential S1P receptor expression after peritoneal B cell activation was assessed semi‑quantitatively using RT-PCR in vitro. The functional implications of differential S1P1 and S1P4 expression were assessed by transwell migration in vitro, by adoptive peritoneal B cell transfer in a model of sterile lipopolysaccharide (LPS)‑induced peritonitis and in the polymicrobial colon ascendens stent peritonitis (CASP) model. Results: The two sphingosine-1-phosphate receptors (S1PRs) expressed in peritoneal B cell subsets S1P1 and S1P4 are differentially regulated upon stimulation with the TLR4 agonist LPS, but not upon PMA/ionomycin or B cell receptor (BCR) crosslinking. S1P4 deficiency affects both the trafficking of activated peritoneal B cells to secondary lymphoid organs and the positioning of these cells within the functional compartments of the targeted organ. S1P4 deficiency in LPS-activated peritoneal B cells results in significantly reduced numbers of splenic innate response activator B cells. Conclusions: The S1P-S1PR system is implicated in the trafficking of LPS-activated peritoneal B cells. Given the protective role of peritoneal B1a B cells in peritoneal sepsis, further experiments to investigate the impact of S1P4-mediated signaling on the severity and mortality of peritoneal sepsis are warranted.
Cardioinotropic Effects in Subchronic Intoxication of Rats with Lead and/or Cadmium Oxide Nanoparticles
Authors: Klinova Svetlana V. , Katsnelson Boris A. , Minigalieva Ilzira A. , Gerzen Oksana P. , Balakin Alexander A. , Lisin Ruslan V. , Butova Ksenia A. , Nabiev Salavat R. , Lookin Oleg N. , Katsnelson Leonid B. , Privalova Larisa I. , Kuznetsov Daniil A. , Shur Vladimir Ya. , Shishkina Ekaterina V. , Makeev Oleg H. , Valamina Irene E. , Panov Vladimir G. , Sutunkova Marina P. , Nikitina Larisa V. , Protsenko Yuri L.
Published: March 2021

Subchronic intoxication was induced in outbred male rats by repeated intraperitoneal injections with lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles (NPs) 3 times a week during 6 weeks for the purpose of examining its effects on the contractile characteristics of isolated right ventricle trabeculae and papillary muscles in isometric and afterload contractions. Isolated and combined intoxication with these NPs was observed to reduce the mechanical work produced by both types of myocardial preparation. Using the in vitro motility assay, we showed that the sliding velocity of regulated thin filaments drops under both isolated and combined intoxication with CdO–NP and PbO–NP. These results correlate with a shift in the expression of myosin heavy chain (MHC) isoforms towards slowly cycling β–MHC. The type of CdO–NP + PbO–NP combined cardiotoxicity depends on the effect of the toxic impact, the extent of this effect, the ratio of toxicant doses, and the degree of stretching of cardiomyocytes and muscle type studied. Some indices of combined Pb–NP and CdO–NP cardiotoxicity and general toxicity (genotoxicity included) became fully or partly normalized if intoxication developed against background administration of a bioprotective complex.
Characterization of Potency of the P2Y13 Receptor Agonists: A Meta-Analysis
Authors: Dsouza Chrisanne , Komarova Svetlana V
Published: March 2021

P2Y13 is an ADP-stimulated G-protein coupled receptor implicated in many physiological processes, including neurotransmission, metabolism, pain, and bone homeostasis. Quantitative understanding of P2Y13 activation dynamics is important for translational studies. We systematically identified PubMed annotated studies that characterized concentration-dependence of P2Y13 responses to natural and synthetic agonists. Since the comparison of the efficacy (maximum response) is difficult for studies performed in different systems, we normalized the data and conducted a meta-analysis of EC50 (concentration at half-maximum response) and Hill coefficient (slope) of P2Y13-mediated responses to different agonists. For signaling events induced by heterologously expressed P2Y13, EC50 of ADP-like agonists was 17.2 nM (95% CI: 7.7–38.5), with Hills coefficient of 4.4 (95% CI: 3.3–5.4), while ATP-like agonists had EC50 of 0.45 μM (95% CI: 0.06–3.15). For functional responses of endogenously expressed P2Y13, EC50 of ADP-like agonists was 1.76 μM (95% CI: 0.3–10.06). The EC50 of ADP-like agonists was lower for the brain P2Y13 than the blood P2Y13. ADP-like agonists were also more potent for human P2Y13 compared to rodent P2Y13. Thus, P2Y13 appears to be the most ADP-sensitive receptor characterized to date. The detailed understanding of tissue- and species-related differences in the P2Y13 response to ADP will improve the selectivity and specificity of future pharmacological compounds.
Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology
Authors: Bofarid Sala , Hosman Anna E. , Mager Johannes J. , Snijder Repke J. , Post Marco C.
Published: March 2021

In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.
Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia
Authors: Soontarapornchai Kutilda , Cai Charles L. , Ahmad Taimur , Aranda Jacob V. , Hand Ivan , Beharry Kay D.
Published: March 2021

(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine.
BRAF Gene and Melanoma: Back to the Future
Authors: Ottaviano Margaret , Giunta Emilio , Tortora Marianna , Curvietto Marcello , Attademo Laura , Bosso Davide , Cardalesi Cinzia , Rosanova Mario , De Placido Pietro , Pietroluongo Erica , Riccio Vittorio , Mucci Brigitta , Parola Sara , Vitale Maria , Palmieri Giovannella , Daniele Bruno , Simeone Ester ,   on behalf of SCITO YOUTH
Published: March 2021

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.
Long Noncoding RNAs—Crucial Players Organizing the Landscape of the Neuronal Nucleus
Authors: Sas-Nowosielska Hanna , Magalska Adriana
Published: March 2021

The ability to regulate chromatin organization is particularly important in neurons, which dynamically respond to external stimuli. Accumulating evidence shows that lncRNAs play important architectural roles in organizing different nuclear domains like inactive chromosome X, splicing speckles, paraspeckles, and Gomafu nuclear bodies. LncRNAs are abundantly expressed in the nervous system where they may play important roles in compartmentalization of the cell nucleus. In this review we will describe the architectural role of lncRNAs in the nuclei of neuronal cells.
Molecular Characterization of the Extracellular Domain of Human Junctional Adhesion Proteins
Authors: Mendoza Christopher , Nagidi Sai Harsha , Mizrachi Dario
Published: March 2021

The junction adhesion molecule (JAM) family of proteins play central roles in the tight junction (TJ) structure and function. In contrast to claudins (CLDN) and occludin (OCLN), the other membrane proteins of the TJ, whose structure is that of a 4α-helix bundle, JAMs are members of the immunoglobulin superfamily. The JAM family is composed of four members: A, B, C and 4. The crystal structure of the extracellular domain of JAM-A continues to be used as a template to model the secondary and tertiary structure of the other members of the family. In this article, we have expressed the extracellular domains of JAMs fused with maltose-binding protein (MBP). This strategy enabled the work presented here, since JAM-B, JAM-C and JAM4 are more difficult targets due to their more hydrophobic nature. Our results indicate that each member of the JAM family has a unique tertiary structure in spite of having similar secondary structures. Surface plasmon resonance (SPR) revealed that heterotypic interactions among JAM family members can be greatly favored compared to homotypic interactions. We employ the well characterized epithelial cadherin (E-CAD) as a means to evaluate the adhesive properties of JAMs. We present strong evidence that suggests that homotypic or heterotypic interactions among JAMs are stronger than that of E-CADs.
Patient-Derived Organoids as a Model for Cancer Drug Discovery
Authors: Rae Colin , Amato Francesco , Braconi Chiara
Published: March 2021

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell–cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue–tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.
PGC-1s in the Spotlight with Parkinson’s Disease
Authors: Piccinin Elena , Sardanelli Anna Maria , Seibel Peter , Moschetta Antonio , Cocco Tiziana , Villani Gaetano
Published: March 2021

Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.