bluuebunny/crossref_metadata_2025 huggingface dataset:
Residents’ Physical Activities in Home Isolation and Its Relationship with Health Values and Well-Being: A Cross-Sectional Survey during the COVID-19 Social Quarantine
Authors: Zuo Yifan , Zhang Mu , Han Jiayu , Chen Kevin W. , Ren Zhanbing
Published: June 2021

The objective of the present study was to examine the associations between residents’ physical activity, health values, and well-being during isolation. On the basis of the physical activity rating scale, health values scale, subjective well-being scale, and the satisfaction with life scale, we collected 505 valid questionnaires online from 31 provinces, municipalities, and autonomous regions in China. A series of multiple linear regression models were established to study the relationship between variables, and the bootstrap confidence interval was selected to test the mediating effect. The results showed that during the period of isolation, physical activity directly (b = 0.463, p < 0.001) or indirectly (b = 0.358, p < 0.001) had a positive impact on residents’ well-being through the mediating effect of health values. There was a positive correlation between physical activity and health values (b = 0.710, p < 0.001), while health values had a direct positive association on well-being (b = 0.504, p < 0.001). In addition, a moderate amount of physical activity was found to be more associated with the well-being of residents during home isolation compared to small and large amounts of physical activity. This study shows the importance of residents’ physical activities in home isolation. Moderate exercise at home and regular physical activity are beneficial to our physical and mental health, especially in terms of improving overall well-being.
Healthcare Resource Utilization for Chronic Rhinosinusitis in Older Adults
Authors: Jang David W. , Lee Hui-Jie , Huang Ryan J. , Cheng Jeffrey , Abi Hachem Ralph , Scales Chuck D.
Published: June 2021

Objectives: Chronic rhinosinusitis (CRS) is a common and costly health problem in the United States. While often associated with younger adults, CRS can affect the elderly. As the aging population increases in the United States, the cost burden of CRS in older adults is important to assess. The objective of this study is to characterize healthcare resource utilization (HCRU) and healthcare expenditure (HCE) for CRS in this population. Methods: Patients meeting criteria for CRS with three years of continuous data were identified on IBM® Marketscan Research Databases over a five-year period (2013–2017). Medication utilization, outpatient visits, surgery, and expenditures related to CRS were assessed for older adults (>65) and compared with other age groups. As a secondary analysis, multivariable generalized linear models were utilized to compare HCE while adjusting for baseline medication utilization. Results: A total of 238,825 patients met the inclusion criteria, of which 20,927 were older adults. Older adults had the highest overall prevalence of nasal polyps (10%) and asthma (16%) among adult groups. Surgery rate was lower than other adult groups, but medication utilization was the highest. Mean overall HCE at two years was highest in older adults (USD 2545 vs. 2298 in young adults). However, HCE was highest for the young adult group after adjusting for baseline medication usage. Conclusion: Older adults had a higher rate of CRS-related co-morbidities as well as the highest CRS-related medication utilization and unadjusted two-year HCE. Although the reasons for this are unclear, possibilities include greater disease severity and preference for medical versus surgical management. HCE for CRS is expected to increase as the aging population grows.
Cost Effectiveness of ACEIs/ARBs versus Amlodipine Monotherapies: A Single-Center Retrospective Chart Review
Authors: AlRuthia Yazed , Alotaibi Fahad , Jamal Amr , Sales Ibrahim , Alwhaibi Monira , Alqahtani Nawaf , AlNajrany Sina M. , Almalki Khalid , Alsaigh Abdulaziz , Mansy Wael
Published: June 2021

The aim of this retrospective chart review study was to examine the cost effectiveness of angiotensin-converting enzyme inhibitors (ACEIs); angiotensin receptor blockers (ARBs); and dihydropyridine calcium channel blockers (CCBs) such as amlodipine, monotherapies in the management of essential hypertension among adult patients (≥18 years) without cancer, cardiovascular disease, and chronic kidney disease in the primary care clinics of a university-affiliated tertiary care hospital. Patients were followed up for at least 12 months from the initiation of therapy. Propensity score bin bootstrapping with 10,000 replications was conducted to generate the 95% confidence intervals (CI) for both treatment outcome (e.g., reduction of the systolic (SBP) and diastolic blood pressures (DBP) in mmHG) and the cost (e.g., costs of drugs, clinic visits, and labs in Saudi riyals (SAR)). Among the 153 included patients who met the inclusion criteria, 111 patients were on ACEIs/ARBs, while 44 patients were on amlodipine. On the basis of the bootstrap distribution, we found that the use of ACEIs/ARBs was associated with an incremental reduction of SBP of up to 4.46 mmHg but with an incremental cost of up to SAR 116.39 (USD 31.04), which results in an incremental cost effectiveness ratio (ICER) of SAR 26.09 (USD 6.95) per 1 mmHg reduction with 55.26% level of confidence. With regard to DBP, ACEIs/ARBs were associated with an incremental reduction of DBP of up to 5.35 mmHg and an incremental cost of up to SAR 144.96 (USD 38.66), which results in an ICER of SAR 27.09 (USD 7.23) per 1 mmHg reduction with 68.10% level of confidence. However, ACEIs/ARBs were less effective and costlier than amlodipine in reducing SBP and DBP with 44.74% and 31.89% levels of confidence, respectively. The findings of this study indicate that the use of ACEI or ARB as a monotherapy seems to be more effective than amlodipine monotherapy in the management of essential hypertension in primary care settings with minimal incremental cost.
Cutaneous Manifestations in SARS-CoV-2 Infection—A Series of Cases from the Largest Infectious Diseases Hospital in Western Romania
Authors: Laza Ruxandra , Musta Virgil Filaret , Nicolescu Narcisa Daniela , Marinescu Adelina Raluca , Mocanu Alexandra , Vilceanu Laura , Paczeyka Roxana , Cut Talida Georgiana , Lazureanu Voichita Elena
Published: June 2021

(1) Background: SARS-CoV-2 infection, which appeared as an isolated epidemic outbreak in December 2019, proved to be so contagious that, within 3 months, the WHO declared COVID-19 a pandemic. For one year (pre-vaccination period), the virus acted unhindered and was highly contagious, with a predominantly respiratory-oriented aggression. Although this lung damage, responsible for the more than 3,090,025 deaths, has provided sufficient data to facilitate the understanding of pathogenic mechanisms, other observation data, which meet the quality of emerging clinical aspects, such as rashes, remain without well-defined etiopathogenic support or a well-contoured clinical framework. (2) Methods and Results: We followed the occurrence of cutaneous manifestations in patients hospitalized during the second and third outbreak of SARS-CoV-2 in the main clinics of infectious diseases of our county, Timis, and recorded laboratory investigations and clinical evolution for five suggestive cases. (3) Conclusions: The presented cases, added to many other present and future clinical observations, will allow for better knowledge and understanding of SARS-CoV-2 infection, a requirement that has become a global priority for the entire medical and scientific community.
Investigation of the Impact of Dental Care via Composite Resin Restoration among Children with Attention Deficit Hyperactivity Disorder: A Registry-Based Nested Case–Control Study
Authors: Hu Chien-Jen , Yu Hui-Chieh , Chang Yu-Chao
Published: June 2021

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric conditions. Many studies have shown that exposure to low-dose bisphenol-A (BPA) can contribute to ADHD. The relationship between ADHD and composite resin is still unclear. We designed a nested case–control study to investigate the relationship between ADHD and composite resin restorations among children from the Taiwan’s National Health Insurance Research Database. We included 85,503 people whose birth years were between 1998 and 2005 and who received resin restoration from January 2000 to December 2008. A 1:2 matched control sample without ADHD was randomly selected from the database by propensity score matching based on birth year and sex. We identified 4984 individuals as ADHD patients. The average diagnostic age of ADHD was 7.45 years old. The patients who received composite resin restorations had higher risk of ADHD than those who had never received them (aOR (adjusted odds ratio) = 1.25; 95% CI (confidence interval) = 1.13–1.38). Males had a higher risk of ADHD (aOR = 1.29; 95% CI = 1.14–1.43). Taken together, this nested case–control study demonstrated a positive association between ADHD and dental care via composite resin restoration in Taiwanese children. Prospective clinical studies of the relationship between ADHD and composite resin are warranted.
Virus-Negative Necrotizing Coronary Vasculitis with Aneurysm Formation in Human SARS-CoV-2 Infection
Authors: Frustaci Andrea , Francone Marco , Verardo Romina , Capobianchi Maria Rosaria , Chimenti Cristina
Published: June 2021

We report a case of myopericarditis associated to SARS-CoV-2 infection with necrotizing coronary vasculitis of intramural vessels, giving rise to biventricular apical microaneurysms and to electrical instability. Negativity of myocardial polymerase chain reaction for the most common cardiotropic viruses and for SARS-CoV-2 suggested an immune-mediated myocardial and pericardial inflammatory disease. High dose (1 mg/Kg daily) prednisone and anti-viral (Remdesivir, IDA Business, Carrigtohill, County Cork, T45 DP77, Ireland) therapy led to resolution of cardiac inflammation and ventricular arrhythmias. Morpho-molecular characterization of endomyocardial tissue may improve the outcome in subjects with SARS-CoV-2-associated myopericarditis and coronary vasculitis.
Use of Pulsed-Field Gel Electrophoresis to Determine the Source of Methicillin-Resistant Staphylococcus aureus Bacteremia
Authors: Yeung Eugene Y. H. , Gorn Ivan
Published: June 2021

Pulsed-field gel electrophoresis (PFGE) has historically been considered the gold standard in fingerprinting bacterial strains in epidemiological studies and outbreak investigations; little is known regarding its use in individual clinical cases. The current study detailed two clinical cases in which PFGE helped to determine the source of their methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Patient A was found to have MRSA bacteremia after trauma in her pelvic area. MRSA was also found in her groin but not in her nostril and rectum. PFGE was performed that showed variable bands of her MRSA isolates from blood and groin, suggestive of different strains of MRSA. Her MRSA bacteremia was determined to be unrelated to her pelvic trauma. Patient B was found to have MRSA bacteremia after colonoscopy. MRSA was also found in his nostril and rectum. PFGE was performed that showed variable bands of his MRSA isolates from blood and rectum but identical bands of MRSA isolates from his blood and nostril. His MRSA bacteremia was determined to be unrelated to his colonoscopy procedure. The current study demonstrates the use of PFGE to rule out the source of bacteremia in individual clinical cases.
Childhood Trauma and Psychological Distress: A Serial Mediation Model among Chinese Adolescents
Authors: Zhang Lin , Ma Xueyao , Yu Xianglian , Ye Meizhu , Li Na , Lu Shan , Wang Jiayi
Published: June 2021

The consequence of childhood trauma may last for a long time. The purpose of the present study was to examine the effect of childhood trauma on general distress among Chinese adolescents and explore the potential mediating roles of social support and family functioning in the childhood trauma-general distress linkage. A total of 2139 valid questionnaires were collected from two high schools in southeast China. Participants were asked to complete the questionnaires measuring childhood trauma, social support, family functioning, and general distress. Pathway analysis was conducted by using SPSS AMOS 24.0 and PROCESS Macro for SPSS 3.5. Results showed that childhood trauma was positively associated with general distress among Chinese adolescents. Social support and family functioning independently and serially mediated the linkage of childhood trauma and general distress. These findings confirmed and complemented the ecological system theory of human development and the multisystem developmental framework for resilience. Furthermore, these findings indicated that the mental and emotional problems of adolescents who had childhood trauma were not merely issues of adolescents themselves, but concerns of the whole system and environment.
Ten Thousand-Fold Higher than Acceptable Bacterial Loads Detected in Kenyan Hospital Environments: Targeted Approaches to Reduce Contamination Levels
Authors: Odoyo Erick , Matano Daniel , Georges Martin , Tiria Fredrick , Wahome Samuel , Kyany’a Cecilia , Musila Lillian
Published: June 2021

Microbial monitoring of hospital surfaces can help identify target areas for improved infection prevention and control (IPCs). This study aimed to determine the levels and variations in the bacterial contamination of high-touch surfaces in five Kenyan hospitals and identify the contributing modifiable risk factors. A total of 559 high-touch surfaces in four departments identified as high risk of hospital-acquired infections were sampled and examined for bacterial levels of contamination using standard bacteriological culture methods. Bacteria were detected in 536/559 (95.9%) surfaces. The median bacterial load on all sampled surfaces was 6.0 × 104 CFU/cm2 (interquartile range (IQR); 8.0 × 103–1.0 × 106). Only 55/559 (9.8%) of the sampled surfaces had acceptable bacterial loads, <5 CFU/cm². Cleaning practices, such as daily washing of patient sheets, incident rate ratio (IRR) = 0.10 [95% CI: 0.04–0.24], providing hand wash stations, IRR = 0.25 [95% CI: 0.02–0.30], having running water, IRR = 0.19 [95% CI: 0.08–0.47] and soap for handwashing IRR = 0.21 [95% CI: 0.12–0.39] each significantly lowered bacterial loads. Transporting dirty linen in a designated container, IRR = 72.11 [95% CI: 20.22–257.14], increased bacterial loads. The study hospitals can best reduce the bacterial loads by improving waste-handling protocols, cleaning high-touch surfaces five times a day and providing soap at the handwash stations.
Regional Features of Long-Term Exposure to PM2.5 Air Quality over Asia under SSP Scenarios Based on CMIP6 Models
Authors: Shim Sungbo , Sung Hyunmin , Kwon Sanghoon , Kim Jisun , Lee Jaehee , Sun Minah , Song Jaeyoung , Ha Jongchul , Byun Younghwa , Kim Yeonhee , Turnock Steven T. , Stevenson David S. , Allen Robert J. , O’Connor Fiona M. , Teixeira Joao C. , Williams Jonny , Johnson Ben , Keeble James , Mulcahy Jane , Zeng Guang
Published: June 2021

This study investigates changes in fine particulate matter (PM2.5) concentration and air-quality index (AQI) in Asia using nine different Coupled Model Inter-Comparison Project 6 (CMIP6) climate model ensembles from historical and future scenarios under shared socioeconomic pathways (SSPs). The results indicated that the estimated present-day PM2.5 concentrations were comparable to satellite-derived data. Overall, the PM2.5 concentrations of the analyzed regions exceeded the WHO air-quality guidelines, particularly in East Asia and South Asia. In future SSP scenarios that consider the implementation of significant air-quality controls (SSP1-2.6, SSP5-8.5) and medium air-quality controls (SSP2-4.5), the annual PM2.5 levels were predicted to substantially reduce (by 46% to around 66% of the present-day levels) in East Asia, resulting in a significant improvement in the AQI values in the mid-future. Conversely, weak air pollution controls considered in the SSP3-7.0 scenario resulted in poor AQI values in China and India. Moreover, a predicted increase in the percentage of aged populations (>65 years) in these regions, coupled with high AQI values, may increase the risk of premature deaths in the future. This study also examined the regional impact of PM2.5 mitigations on downward shortwave energy and surface air temperature. Our results revealed that, although significant air pollution controls can reduce long-term exposure to PM2.5, it may also contribute to the warming of near- and mid-future climates.
Changes in Domestic Energy and Water Usage during the UK COVID-19 Lockdown Using High-Resolution Temporal Data
Authors: Menneer Tamaryn , Qi Zening , Taylor Timothy , Paterson Cheryl , Tu Gengyang , Elliott Lewis R. , Morrissey Karyn , Mueller Markus
Published: June 2021

In response to the COVID-19 outbreak, the UK Government provided public health advice to stay at home from 16 March 2020, followed by instruction to stay at home (full lockdown) from 24 March 2020. We use data with high temporal resolution from utility sensors installed in 280 homes across social housing in Cornwall, UK, to test for changes in domestic electricity, gas and water usage in response to government guidance. Gas usage increased by 20% following advice to stay at home, the week before full lockdown, although no difference was seen during full lockdown itself. During full lockdown, morning electricity usage shifted to later in the day, decreasing at 6 a.m. and increasing at midday. These changes in energy were echoed in water usage, with a 17% increase and a one-hour delay in peak morning usage. Changes were consistent with people getting up later, spending more time at home and washing more during full lockdown. Evidence for these changes was also observed in later lockdowns, but not between lockdowns. Our findings suggest more compliance with an enforced stay-at-home message than with advice. We discuss implications for socioeconomically disadvantaged households given the indication of inability to achieve increased energy needs during the pandemic.
Test–Retest Reliability of Functional Electromechanical Dynamometer on Five Sit-to-Stand Measures in Healthy Young Adults
Authors: Jerez-Mayorga Daniel , Huerta-Ojeda Álvaro , Chirosa-Ríos Luis , Guede-Rojas Francisco , Guzmán-Guzmán Iris , Intelangelo Leonardo , Miranda-Fuentes Claudia , Delgado-Floody Pedro
Published: June 2021

Background: The purpose of this study was to determine the reliability for the strength and movement velocity of the concentric phase from the five Sit-to-Stand (5STS), using three incremental loads measured by a functional electromechanical dynamometer (FEMD) in healthy young adults. Methods: The average and peak strength and velocity values of sixteen healthy adults (mean ± standard deviation (SD): age = 22.81 ± 2.13 years) were recorded at 5, 10 and 15 kg. To evaluate the reliability of FEMD, the intraclass correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV) were obtained. Results: Reliability was high for the 10 kg (CV range: 3.70–4.18%, ICC range: 0.95–0.98) and 15 kg conditions (CV range: 1.64–3.02%, ICC: 0.99) at average and peak strength, and reliability was high for the 5 kg (CV range: 1.71–2.84%, ICC range: 0.96–0.99), 10 kg (CV range: 0.74–1.84%, ICC range: 0.99–1.00) and 15 kg conditions (CV range: 0.79–3.11%, ICC range: 0.99–1.00) at average and peak velocity. Conclusions: The findings of this study demonstrate that FEMD is a reliable instrument to measure the average and peak strength and velocity values during the five STS in healthy young adults.
Postmenopausal Symptoms and Their Correlates among Saudi Women Attending Different Primary Health Centers
Authors: Abdel-Salam Doaa M. , Mohamed Rehab A. , Alruwaili Rawan R. , Alhablani Farah S. , Aldaghmi Raghad M. , ALghassab Raghad E.
Published: June 2021

(1) Background and objectives: Due to increasing life expectancy, more than one-third of women’s life can be spent in the postmenopausal period. In this period, women have different somatic, psychological, and urogenital symptoms. The present study was done to evaluate postmenopausal symptoms and their correlations among Saudi women attending different primary health centers. (2) Methods: adopting a cross-sectional study was done among 845 postmenopausal women attending different primary health centers. The menopause rating scale (MRS) was utilized to investigate the prevalence and severity of different menopausal manifestations. Data collection was done using a structured anonymous questionnaire disseminated during face-to-face interviews. Analysis of data was done utilizing the SPSS program, version 24. (3) Results: The total MRS score was 15.68 ± 6.85. The mean score of the subscales were: 5.56 ± 2.78 for the somatic domain, 6.04 ± 2.89 for the psychological domain, and 4.08 ± 2.32 for the urogenital domain. Joint and muscle pain (25.2%) and sleep problems (18.6%) were the most prevalent severe/very severe somatic symptoms. The most severe/very severe symptoms of the psychological domain were mental and physical exhaustion (20.2%) and depressed mode (19.2%), while that of the urogenital domain were sexual problems (20.1%) and bladder problems (16.3%). Significant predictors of the subscales of MRS were sociodemographic characteristics such as age, residence, marital status, educational level, and occupation. Furthermore, history of chronic diseases, parity, and menopause duration were significant predictors of the subscales of MRS. (4) Conclusion: women in the present study experience different postmenopausal symptoms. Health care providers should consider this crucial stage of women’s life to help elderly women manage these different postmenopausal manifestations.
Lights and Shadows of Microbiota Modulation and Cardiovascular Risk in HIV Patients
Authors: Villoslada-Blanco Pablo , Pérez-Matute Patricia , Oteo José A.
Published: June 2021

Human immunodeficiency virus (HIV) infection is associated with premature aging and the development of aging-related comorbidities, such as cardiovascular disease (CVD). Gut microbiota (GM) disturbance is involved in these comorbidities and there is currently interest in strategies focused on modulating GM composition and/or functionality. Scientific evidence based on well-designed clinical trials is needed to support the use of prebiotics, probiotics, symbiotics, and fecal transplantation (FT) to modify the GM and reduce the incidence of CVD in HIV-infected patients. We reviewed the data obtained from three clinical trials focused on prebiotics, 25 trials using probiotics, six using symbiotics, and four using FT. None of the trials investigated whether these compounds could reduce CVD in HIV patients. The huge variability observed in the type of compound as well as the dose and duration of administration makes it difficult to adopt general recommendations and raise serious questions about their application in clinical practice.
Air Pollution and COVID-19: A Possible Dangerous Synergy for Male Fertility
Authors: Montano Luigi , Donato Francesco , Bianco Pietro Massimiliano , Lettieri Gennaro , Guglielmino Antonino , Motta Oriana , Bonapace Ian Marc , Piscopo Marina
Published: June 2021

Several studies indicate that semen quality has strongly declined in the last decades worldwide. Air pollution represents a significant co-factor with the COVID-19 impact and has negative effects on the male reproductive system, through pro-oxidant, inflammatory and immune-dysregulating mechanisms. It has recently been reported that chronic exposure to PM2.5 causes overexpression of the alveolar ACE2 receptor, the entry route of SARS-CoV-2 into the organism shared by the lungs and testis where expression is highest in the body. In the testis, the ACE2/Ang-(1–7)/MasR pathway plays an important role in the regulation of spermatogenesis and an indirect mechanism of testicular damage could be due to the blockade of the ACE2 receptor by SARS-CoV-2. This prevents the conversion of specific angiotensins, and their excess causes inflammation with the overproduction of cytokines. PM2.5-induced overexpression of the alveolar ACE2 receptor, in turn, could increase local viral load in patients exposed to pollutants, producing ACE2 receptor depletion and compromising host defenses. By presenting an overall view of epidemiological data and molecular mechanisms, this manuscript aims to interpret the possible synergistic effects of both air pollution and COVID-19 on male reproductive function, warning that the spread of SARS-CoV-2 in the fertile years may represent a significant threat to global reproductive health. All of this should be of great concern, especially for men of the age of maximum reproductive capacity, and an important topic of debate for policy makers. Altered environmental conditions, together with the direct and indirect short- and long-term effects of viral infection could cause a worsening of semen quality with important consequences for male fertility, especially in those areas with higher environmental impact.
A Longitudinal Study of Episodic and Semantic Autobiographical Memory in aMCI and Alzheimer’s Disease Patients
Authors: Meléndez Juan C. , Pitarque Alfonso , Delhom Iraida , Real Elena , Abella Mireia , Satorres Encarnación
Published: June 2021

Background: The main objective of this study was to analyze the evolution of autobiographical memory (both episodic and semantic) in patients with mild cognitive impairment, patients with Alzheimer’s disease, and a healthy control group. We compared these groups at two time points: first, at baseline, and in a follow-up after 18 months. Method: Twenty-six healthy older adults, 17 patients with mild amnestic cognitive impairment, and 16 patients with Alzheimer’s disease, matched on age and educational level, were evaluated at both time points with the Autobiographical Memory Interview. Results: The results showed significant longitudinal deterioration in episodic and semantic autobiographical memory in patients with mild cognitive impairment and in patients with Alzheimer’s disease, but not in healthy older adults. Conclusions: The deterioration of episodic and semantic autobiographical memory in AD is confirmed; however, although the episodic was impaired in aMCI, a pattern that evolved toward deterioration over a period of eighteen months was observed for the semantic autobiographical memory.
Flavonoids in Skin Senescence Prevention and Treatment
Authors: Domaszewska-Szostek Anna , Puzianowska-Kuźnicka Monika , Kuryłowicz Alina
Published: June 2021

Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging.
The Roles of the IGF Axis in the Regulation of the Metabolism: Interaction and Difference between Insulin Receptor Signaling and IGF-I Receptor Signaling
Authors: Okuyama Tomoko , Kyohara Mayu , Terauchi Yasuo , Shirakawa Jun
Published: June 2021

It has been well established that insulin-like growth factors (IGFs) mainly mediate long-term actions in cell fates, whereas insulin predominantly exerts its role on metabolic activity. Indeed, insulin mediates multiple anabolic biological activities in glucose and amino acid transport, lipid and protein synthesis, the induction of glycogen, the inhibition of gluconeogenesis, lipolysis, and protein degradation. The interactions and differences between insulin receptor signaling and IGF-I receptor signaling in the metabolism and the cell fates are quite complicated. Because of the overlapping actions of IGF-I singling with insulin signaling, it has been difficult to distinguish the role of both signaling mechanisms on the metabolism. Furthermore, comprehensive information on the IGF-I function in respective tissues remains insufficient. Therefore, we need to clarify the precise roles of IGF-I signaling on the metabolism separate from those of insulin signaling. This review focuses on the metabolic roles of IGFs in the respective tissues, especially in terms of comparison with those of insulin, by overviewing the metabolic phenotypes of tissue-specific IGF-I and insulin receptor knockout mice, as well as those in mice treated with the dual insulin receptor/IGF-I receptor inhibitor OSI-906.
RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain
Authors: Harbin Nicholas H. , Bramlett Sara N. , Montanez-Miranda Carolina , Terzioglu Gizem , Hepler John R.
Published: June 2021

The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.
Gemcitabine-Based Chemoradiotherapy Enhanced by a PARP Inhibitor in Pancreatic Cancer Cell Lines
Authors: Waissi Waisse , Amé Jean-Christophe , Mura Carole , Noël Georges , Burckel Hélène
Published: June 2021

Pancreatic ductal adenocarcinoma is a devastating disease with a 5-year overall survival of 9% for all stages. Gemcitabine-based chemoradiotherapy for locally advanced pancreatic cancer is highly toxic. We conducted an in vitro study to determine whether poly(ADP-ribose) polymerase-1 inhibition radiosensitized gemcitabine-based chemotherapy. Human pancreatic cancer cell lines, MIA PaCa-2, AsPC-1, BxPC-3 and PANC-1 were treated with gemcitabine (10 nM) and/or olaparib (1 µM). Low-LET gamma single dose of 2, 5 and 10 Gy radiations were carried out. Clonogenic assay, PAR immunoblotting, cell cycle distribution, γH2Ax, necrotic and autophagic cell death quantifications were performed. Treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines, particularly at high dose per fraction A non-cytotoxic concentration of gemcitabine radiosensitized cells, but less than olaparib. Interestingly, olaparib significantly enhanced gemcitabine-based radiosensitization in PDAC cell lines with synergistic effect in BxPC-3 cell line. All cell lines were radiosensitized by the combination of gemcitabine and olaparib, through an increase of unrepaired double-strand, a G2 phase block and cell death. Radiosensitization was increased with high dose of radiation. The combination of olaparib with gemcitabine-based chemoradiotherapy could lead to an enhancement of local control in vivo and an improvement in disease-free survival.
Behavioral Phenotyping in a Murine Model of GBA1-Associated Parkinson Disease
Authors: Do Jenny , Perez Gani , Berhe Bahafta , Tayebi Nahid , Sidransky Ellen
Published: June 2021

Mutations in GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled GBA1-associated PD by crossing gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether gba+/−//SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of gba+/−//SNCAA53T (n = 8), SNCAA53T (n = 9), gba+/− (n = 10) and wildtype (n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old gba+/−//SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between gba+/−//SNCAA53T and SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.
Molecular and Electrophysiological Role of Diabetes-Associated Circulating Inflammatory Factors in Cardiac Arrhythmia Remodeling in a Metabolic-Induced Model of Type 2 Diabetic Rat
Authors: Zayas-Arrabal Julian , Alquiza Amaia , Tuncay Erkan , Turan Belma , Gallego Monica , Casis Oscar
Published: June 2021

Background: Diabetic patients have prolonged cardiac repolarization and higher risk of arrhythmia. Besides, diabetes activates the innate immune system, resulting in higher levels of plasmatic cytokines, which are described to prolong ventricular repolarization. Methods: We characterize a metabolic model of type 2 diabetes (T2D) with prolonged cardiac repolarization. Sprague-Dawley rats were fed on a high-fat diet (45% Kcal from fat) for 6 weeks, and a low dose of streptozotozin intraperitoneally injected at week 2. Body weight and fasting blood glucose were measured and electrocardiograms of conscious animals were recorded weekly. Plasmatic lipid profile, insulin, cytokines, and arrhythmia susceptibility were determined at the end of the experimental period. Outward K+ currents and action potentials were recorded in isolated ventricular myocytes by patch-clamp. Results: T2D animals showed insulin resistance, hyperglycemia, and elevated levels of plasma cholesterol, triglycerides, TNFα, and IL-1b. They also developed bradycardia and prolonged QTc-interval duration that resulted in increased susceptibility to severe ventricular tachycardia under cardiac challenge. Action potential duration (APD) was prolonged in control cardiomyocytes incubated 24 h with plasma isolated from diabetic rats. However, adding TNFα and IL-1b receptor blockers to the serum of diabetic animals prevented the increased APD. Conclusions: The elevation of the circulating levels of TNFα and IL-1b are responsible for impaired ventricular repolarization and higher susceptibility to cardiac arrhythmia in our metabolic model of T2D.
The Odorant-Binding Proteins of the Spider Mite Tetranychus urticae
Authors: Zhu Jiao , Renzone Giovanni , Arena Simona , Dani Francesca Romana , Paulsen Harald , Knoll Wolfgang , Cambillau Christian , Scaloni Andrea , Pelosi Paolo
Published: June 2021

Spider mites are one of the major agricultural pests, feeding on a large variety of plants. As a contribution to understanding chemical communication in these arthropods, we have characterized a recently discovered class of odorant-binding proteins (OBPs) in Tetranychus urticae. As in other species of Chelicerata, the four OBPs of T. urticae contain six conserved cysteines paired in a pattern (C1–C6, C2–C3, C4–C5) differing from that of insect counterparts (C1–C3, C2–C5, C4–C6). Proteomic analysis uncovered a second family of OBPs, including twelve members that are likely to be unique to T. urticae. A three-dimensional model of TurtOBP1, built on the recent X-ray structure of Varroa destructor OBP1, shows protein folding different from that of insect OBPs, although with some common features. Ligand-binding experiments indicated some affinity to coniferyl aldehyde, but specific ligands may still need to be found among very large molecules, as suggested by the size of the binding pocket.
Curcumin Suppresses TGF-β1-Induced Myofibroblast Differentiation and Attenuates Angiogenic Activity of Orbital Fibroblasts
Authors: Yu Wei-Kuang , Hwang Wei-Lun , Wang Yi-Chuan , Tsai Chieh-Chih , Wei Yau-Huei
Published: June 2021

Orbital fibrosis, a hallmark of tissue remodeling in Graves’ ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor β1 (TGF-β1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-β1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-β1 for 24 h. The effects of curcumin on TGF-β1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-β1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-β1. Curcumin, at the concentration of 5 μg/mL, suppressed 5 ng/mL TGF-β1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-β1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.
The Roles Played by Long Non-Coding RNAs in Glioma Resistance
Authors: Chae Yeonsoo , Roh Jungwook , Kim Wanyeon
Published: June 2021

Glioma originates in the central nervous system and is classified based on both histological features and molecular genetic characteristics. Long non-coding RNAs (lncRNAs) are longer than 200 nucleotides and are known to regulate tumorigenesis and tumor progression, and even confer therapeutic resistance to glioma cells. Since oncogenic lncRNAs have been frequently upregulated to promote cell proliferation, migration, and invasion in glioma cells, while tumor-suppressive lncRNAs responsible for the inhibition of apoptosis and decrease in therapeutic sensitivity in glioma cells have been generally downregulated, the dysregulation of lncRNAs affects many features of glioma patients, and the expression profiles associated with these lncRNAs are needed to diagnose the disease stage and to determine suitable therapeutic strategies. Accumulating studies show that the orchestrations of oncogenic lncRNAs and tumor-suppressive lncRNAs in glioma cells result in signaling pathways that influence the pathogenesis and progression of glioma. Furthermore, several lncRNAs are related to the regulation of therapeutic sensitivity in existing anticancer therapies, including radiotherapy, chemotherapy and immunotherapy. Consequently, we undertook this review to improve the understanding of signaling pathways influenced by lncRNAs in glioma and how lncRNAs affect therapeutic resistance.
Computational Modeling of Spinal Locomotor Circuitry in the Age of Molecular Genetics
Authors: Ausborn Jessica , Shevtsova Natalia A. , Danner Simon M.
Published: June 2021

Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computational modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior.
Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis
Authors: Rozier Pauline , Maumus Marie , Bony Claire , Maria Alexandre Thibault Jacques , Sabatier Florence , Jorgensen Christian , Guilpain Philippe , Noël Danièle
Published: June 2021

Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGFβ1-induced model of human myofibroblasts (Tβ-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that Tβ-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on Tβ-Fb and SSc-Fb, but only when pre-stimulated with TGFβ1. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that Tβ-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGFβ1-induced pro-fibrotic environment may alter the function of ASCs.
5-HT3 Signaling Alters Development of Sacral Neural Crest Derivatives That Innervate the Lower Urinary Tract
Authors: Ritter K. Elaine , Buehler Dennis P. , Asher Stephanie B. , Deal Karen K. , Zhao Shilin , Guo Yan , Southard-Smith E Michelle
Published: June 2021

The autonomic nervous system derives from the neural crest (NC) and supplies motor innervation to the smooth muscle of visceral organs, including the lower urinary tract (LUT). During fetal development, sacral NC cells colonize the urogenital sinus to form pelvic ganglia (PG) flanking the bladder neck. The coordinated activity of PG neurons is required for normal urination; however, little is known about the development of PG neuronal diversity. To discover candidate genes involved in PG neurogenesis, the transcriptome profiling of sacral NC and developing PG was performed, and we identified the enrichment of the type 3 serotonin receptor (5-HT3, encoded by Htr3a and Htr3b). We determined that Htr3a is one of the first serotonin receptor genes that is up-regulated in sacral NC progenitors and is maintained in differentiating PG neurons. In vitro cultures showed that the disruption of 5-HT3 signaling alters the differentiation outcomes of sacral NC cells, while the stimulation of 5-HT3 in explanted fetal pelvic ganglia severely diminished neurite arbor outgrowth. Overall, this study provides a valuable resource for the analysis of signaling pathways in PG development, identifies 5-HT3 as a novel regulator of NC lineage diversification and neuronal maturation in the peripheral nervous system, and indicates that the perturbation of 5-HT3 signaling in gestation has the potential to alter bladder function later in life.
RETRACTED: Thymoquinone and Curcumin Defeat Aging-Associated Oxidative Alterations Induced by D-Galactose in Rats’ Brain and Heart
Authors: El-Far Ali , Elewa Yaser , Abdelfattah Elsayeda-Zeinab , Alsenosy Abdel-Wahab , Atta Mustafa , Abou-Zeid Khalid , Al Jaouni Soad , Mousa Shaker , Noreldin Ahmed
Published: June 2021

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.