bluuebunny/crossref_metadata_2025 huggingface dataset:
Travel Time for Dental Care Services Based on Patient Preference in South Korea
Authors: Cho Han-A , Kim Bo-Ra , Shin Hosung
Published: February 2022

This study analyzed patient preferences using travel time from residence to dental institution when selecting dental care services. We used data from the Korean Health Panel from 2008 to 2017 and analyzed each dental service episode. Since the distribution of travel time was skewed to the left, median travel time was analyzed. The association of travel time with services was analyzed via the population-averaged generalized estimating equation (GEE) with the Poisson family. The median of the average travel time per episode was longer for non-National Health Insurance (NHI)-covered services and shorter for NHI-covered services. The first quintile of low-income subjects traveled the longest for all services and utilized dental care the most. In the GEE analysis, travel time was approximately three times longer for implant treatment and gold inlay/resin fillings and >2 times longer for orthodontic care than for NHI-covered services. Patients residing in rural counties traveled for longer than residents of large cities. Income was statistically significant; however, the coefficient was close to zero. Travel time was related to the type of service and reflected patient preference. This was more prominent for expensive non-NHI-covered services than for NHI-covered services. The findings suggest patients’ subjective preferences for dental clinic selection are expressed as rational deliberation considering each individual’s situation.
Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients
Authors: Wu Ting Yu , Khorramshahi Taura , Taylor Lindsey A. , Bansal Nikita S. , Rodriguez Betsy , Rey Irma R.
Published: February 2022

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a known complex, multi-organ system disorder with a sudden or subacute onset. ME/CFS occurs most commonly among women between 30 and 50 years of age. The current diagnostic criteria of ME/CFS, as defined by the Centers for Disease Control and Prevention, includes: profound fatigue and post-exertional malaise (>6 mo) unrelieved by rest, persistent cognitive impairment or orthostatic intolerance, and chronic unrefreshing sleep. Despite reported associations between ME/CFS onset and exposure to infectious agents (viral, bacterial, or fungal), the pathophysiology of ME/CFS remains unknown. In this prevalence study, we investigated the rates of Aspergillus-derived toxin levels, Aflatoxin (AF), Ochratoxin A (OTA), and Gliotoxin (GT), in the urinalysis of 236 ME/CFS patients with a history of chronic exposure to mold (i.e., from water-damaged buildings). Among ME/CFS patients reporting chronic exposure to mold, we found evidence of exposure in 92.4 percent of patients, with OTA being the most prevalent mycotoxin. Mold distributions (OTA, AF, and GT) in the urinalysis all demonstrated right skewness, while the distribution of age of ME/CFS patients diagnosed showed no deviation from normality. This study aims to provide preliminary, epidemiological evidence among ME/CFS patients who were diagnosed in South Florida with a history of exposure to mycotoxins. Based on these findings, we proposed how future control studies should approach investigating the association between chronic mold exposure and the diagnosis of ME/CFS.
Impact of Socioeconomic Environment on Home Social Care Service Demand and Dependent Users
Authors: Badell Daniel , de Armas Jesica , Julià Albert
Published: February 2022

An aging population and rising life expectancy lead to an increased demand for social services to care for dependent users, among other factors. In Barcelona, home social care (HSC) services are a key agent in meeting this demand. However, demand is not evenly distributed among neighborhoods, and we hypothesized that this can be explained by the user’s social environment. In this work, we describe the user’s environment at a macroscopic level by the socioeconomic features of the neighborhood. This research aimed to gain a deeper understanding of the dependent user’s socioeconomic environment and service needs. We applied descriptive analytics techniques to explore possible patterns linking HSC demand and other features. These methods include principal components analysis (PCA) and hierarchical clustering. The main analysis was made from the obtained boxplots, after these techniques were applied. We found that economic and disability factors, through users’ mean net rent and degree of disability features, are related to the demand for home social care services. This relation is even clearer for the home-based social care services. These findings can be useful to distribute the services among areas by considering more features than the volume of users/population. Moreover, it can become helpful in future steps to develop a management tool to optimize HSC scheduling and staff assignment to improve the cost and quality of service. For future research, we believe that additional and more precise characteristics could provide deeper insights into HSC service demand.
Walking Environment and Obesity: A Gender-Specific Association Study in Shanghai
Authors: Gao Hei , Xu Zike , Chen Yu , Lu Yutian , Lin Jian
Published: February 2022

Walking environment is commonly cited as an element that reduces the risk of obesity. Many literatures have shown that the impact of walking environment on the incidence rate of obesity may vary across gender, but few studies have conducted in-depth investigations. The present study aimed to provide empirical evidence for a cross-sectional association between the built community environment and the incidence of obesity among male and female residents. Thus, we collected height and weight level of 1355 residents and constructed seven walking environment indicators around 54 communities. Also, BMI was calculated and categorized to define overweight and obesity. We used generalized estimation equation to evaluate the gender-specific association between walking environment on obesity based on a diverse population sample. The study showed that female residents who lived in neighborhoods with higher road sky view index (p = 0.033; OR = 0.002 [95% CI = 0.001–0.619]) and increased intersection density (p = 0.009; OR = 0.979 [95% CI = 0.963–0.995]) showed lower risk of increased BMI, but the advantage does not successfully radiate significant obesity consequences. In addition, the increased density of bus stops can also reduce the risk of obesity in women groups (p = 0.035; OR = 0.910 [95% CI = 0.836–0.990]). These findings suggest that women were more sensitive and were more likely to make different behavioral choices and physiological responses due to distinct walking environments. This provides useful evidence for future obesity prevention and urban planning.
A Multivariate Analysis of Depression Prevalence in Psoriasis Patients: A Cohort Study
Authors: Fabrazzo Michele , Romano Francesca , Arrigo Marzia , Puca Rosa Valentina , Fuschillo Antonietta , De Santis Valeria , Sampogna Gaia , Giordano Giulia Maria , Catapano Francesco , Lo Schiavo Ada
Published: February 2022

The literature reported higher depression rates in psoriasis patients compared to the general population. Our study aimed to verify whether variability in depression prevalence was due to using different diagnostic tools. We also aimed to determine whether dysfunctional coping strategies might increase the depression burden. We assessed psoriasis severity by the Psoriasis Area Severity Index (PASI) and PSOdisk. We analyzed mental alterations of 120 outpatients by Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), Symptom Checklist-90-Revised (SCL-90-R), plus coping strategies and quality of life by Coping Orientation to Problems Experienced (COPE) Inventory and 36-Item Short Form Health Survey (SF-36). We divided our cohort into five subgroups from minimal to severe psoriasis using the PSOdisk total score. Depression prevalence varied according to the assessment criteria for specificity, frequency, and severity. Different mood disorders other than major depression emerged when we used DSM-IV-TR criteria. Correlation analysis of the criteria we used to diagnose depression or depressed mood indicated that a dysfunctional coping strategy was highly and positively correlated only in patients of the severe subgroup. Differently, a negative correlation emerged between the SF-36 Mental Summary Component (MSC) and behavioral disengagement, thus suggesting that psychopathological distress might induce patients with a marked/severe psoriasis to adopt dysfunctional coping strategies. Dermatologists are fundamental in detecting comorbid depression, referring psoriasis patients to mental health specialists to achieve adequate treatments, and preventing suicide risk.
The Influence of the Pharmacists’ Training on the Quality and Comprehensiveness of Professional Advice Given in the Field of Inhalation Techniques in Community Pharmacies in Poland
Authors: Waszyk-Nowaczyk Magdalena , Guzenda Weronika , Targosz Patrycja , Byliniak Michał , Plewka Beata , Dąbrowiecki Piotr , Michalak Michał , Bąbol Aneta , Szapel Karol , Bielas Marzena , Żabiński Jerzy
Published: February 2022

Background: Following the example of other countries, it is very important to educate patients on the correct use of inhalers by properly trained healthcare professionals, including pharmacists. Objectives: The aim of the study was to assess the quality and comprehensiveness of professional advice given by pharmacists on the use of inhalers, which was determined by the pharmacists’ level of training. Methods: The study was conducted from June 2019 to March 2020. 150 pharmacists from Poznan and Warsaw (Poland) were involved. Before the study began, the professional education of 240 pharmacists was conducted in Warsaw to implement standard operating procedures. The study used the model of a mystery shopper. Results: The conversation with a trained pharmacist lasted on average 5.5 min, with an untrained one—3.0 min (p < 0.0001). Placebo inhalers were used more often by trained pharmacists during patients’ education (p < 0.0001). Moreover, 10.3% of untrained pharmacists did not provide any education. Additionally, untrained employees’ quality of advice was assessed on an average of 3.5 points, while trained ones—7.6 points (p < 0.0001). Conclusions: This study has shown that there is a need for professional training among pharmacists in Poland, which translates into better patient education in the field of inhalation techniques.
Physician-Customized Strategies for Reducing Outpatient Waiting Time in South Korea Using Queueing Theory and Probabilistic Metamodels
Authors: Lee Hanbit , Choi Eun Kyoung , Min Kyung A. , Bae Eunjeong , Lee Hooyun , Lee Jongsoo
Published: February 2022

The time a patient spends waiting to be seen by a healthcare professional is an important determinant of patient satisfaction in outpatient care. Hence, it is crucial to identify parameters that affect the waiting time and optimize it accordingly. First, statistical analysis was used to validate the effective parameters. However, no parameters were found to have significant effects with respect to the entire outpatient department or to each department. Therefore, we studied the improvement of patient waiting times by analyzing and optimizing effective parameters for each physician. Queueing theory was used to calculate the probability that patients would wait for more than 30 min for a consultation session. Using this result, we built metamodels for each physician, formulated an effective method to optimize the problem, and found a solution to minimize waiting time using a non-dominated sorting genetic algorithm (NSGA-II). On average, we obtained a 30% decrease in the probability that patients would wait for a long period. This study shows the importance of customized improvement strategies for each physician.
The Association between Diabetes and Human T-Cell Leukaemia Virus Type-1 (HTLV-1) with Strongyloides stercoralis: Results of a Community-Based, Cross-Sectional Survey in Central Australia
Authors: Talukder Mohammad Radwanur , Pham Hai , Woodman Richard , Wilson Kim , Taylor Kerry , Kaldor John , Einsiedel Lloyd
Published: February 2022

In central Australia, an area that is endemic for the human T-cell leukaemia virus type-1 (HTLV-1), the prevalence of Strongyloides stercoralis and its association with other health conditions are unknown. A cross-sectional community-based survey was conducted in seven remote Aboriginal communities in central Australia, from 2014 to 2018. All residents aged ≥10 years were invited to complete a health survey and to provide blood for Strongyloides serology, HTLV-1 serology and HTLV-1 proviral load (PVL). Risk factors for Strongyloides seropositivity and associations with specific health conditions including diabetes and HTLV-1 were determined using logistic regression. Overall Strongyloides seroprevalence was 27% (156/576) (children, 22% (9/40); adults (≥15 years), 27% (147/536), varied widely between communities (5–42%) and was not associated with an increased risk of gastrointestinal, respiratory or dermatological symptoms. Increasing age, lower HTLV-1 PVL (<1000 copies per 105 peripheral blood leucocytes) compared to the HTLV-1 uninfected group and community of residence were significant risk factors for Strongyloides seropositivity in an adjusted model. A modest reduction in the odds of diabetes among Strongyloides seropositive participants was found (aOR 0.58, 95% CI 0.35, 1.00; p = 0.049); however, this was lost when body mass index was included in the adjusted model (aOR 0.48, 95% CI 0.48, 1.47; p = 0.542). Strongyloides seropositivity had no relationship with anaemia. Exploring social and environmental practices in communities with low Strongyloides seroprevalence may provide useful lessons for similar settings.
ARNI in HFrEF—One-Centre Experience in the Era before the 2021 ESC HF Recommendations
Authors: Niemiec Rafał , Morawska Irmina , Stec Maria , Kuczmik Wiktoria , Swinarew Andrzej S. , Stanula Arkadiusz , Mizia-Stec Katarzyna
Published: February 2022

Background: Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor (ARNI), has demonstrated a survival benefit and reduces heart failure hospitalization in patients with heart failure with reduced left ventricular ejection fraction (HFrEF); however, our experience in this field is limited. This study aimed to summarize a real clinical practice of the use of ARNI in HFrEF patients hospitalized due to HFrEF in the era before the 2021 ESC HF recommendations, as well as assess their clinical outcome with regard to ARNI administration. Methods and Materials: Overall, 613 patients with HFrEF hospitalized in 2018–2020 were enrolled into a retrospective one-centre cross-sectional analysis. The study population was categorized into patients receiving (82/13.4%) and not-receiving (531/82.6%) ARNI. Clinical outcomes defined as rehospitalization, number of rehospitalizations, time to the first rehospitalization and death from any cause were analysed in the 1–2 year follow-up in the ARNI and non-ARNI groups, matched as to age and LVEF. Results: Clinical characteristics revealed the following differences between ARNI and non-ARNI groups: A higher percentage of cardiovascular implantable electronic devices (CIED) (p = 0.014) and defibrillators with cardiac resynchronization therapy (CRT-D) (p = 0.038), higher frequency of atrial fibrillation (p = 0.002) and history of stroke (p = 0.024) were in the ARNI group. The percentage of patients with HFrEF NYHA III/IV presented an increasing trend to be higher in the ARNI (64.1%) as compared to the non-ARNI group (51.5%, p = 0.154). Incidence of rehospitalization, number of rehospitalizations and time to the first rehospitalization were comparable between the groups. There were no differences between the numbers of deaths of any cause in the ARNI (28%) and non-ARNI (28%) groups. The independent negative predictor of death in the whole population of ARNI and non-ARNI groups was the coexistence of coronary artery disease (CAD) (beta= −0.924, HR 0.806, p = 0.011). Conclusions: Our current positive experience in ARNI therapy is limited to extremely severe patients with HFrEF. Regardless of the more advanced HF and HF comorbidities, the patients treated with ARNI presented similar mortality and rehospitalizations as the patients treated by standard therapy.
The Mediating Effect of Nature Restorativeness, Stress Level, and Nature Connectedness in the Association between Nature Exposure and Quality of Life
Authors: Baceviciene Migle , Jankauskiene Rasa
Published: February 2022

This study aimed to test the mediating effects of nature restorativeness, stress, and nature connectedness in the association between nature exposure and quality of life (QoL). Urban and rural Lithuanian inhabitants (n = 924; 73.6% were women), mean age of 40.0 ± 12.4 years (age range of 18–79) participated in the study. In total, 31% of the respondents lived in rural areas. Study participants completed an online survey form with measures on sociodemographic factors, nature proximity, nature exposure, nature connectedness, and nature restorativeness, stress, and QoL assessed by the abbreviated version of the World Health Organization’s Quality of Life Questionnaire’s (WHOQOL-BREF). Path analysis was conducted to test the mediating effects of nature restorativeness, stress, and nature connectedness in the model of nature exposure and QoL. Nature exposure was directly associated with a greater QoL (β = 0.14; B = 2.60; SE = 0.57; p < 0.001) and mediated the association between nature proximity and QoL. Nature restorativeness and lower stress levels were mediators between nature exposure and QoL. Nature connectedness was a mediator between nature exposure and QoL. A path model was invariant across genders and the urban and rural place of residence groups: patterns of loadings of the pathways were found to be similar. Nature restorativeness (β = 0.10–0.12; p < 0.01) had a positive effect on the psychological, physical, social, and environmental domains of QoL. Connectedness to nature positively predicted psychological (β = 0.079; p < 0.05) and environmental (β = 0.082; p < 0.05) domains of QoL. Enhancing nature exposure and nature connectedness might help strengthen QoL in urban and rural inhabitants.
When Bodybuilding Goes Wrong—Bilateral Renal Artery Thrombosis in a Long-Term Misuser of Anabolic Steroids Treated with AngioJet Rheolytic Thrombectomy
Authors: Lemiński Artur , Kubis Markiian , Kaczmarek Krystian , Gołąb Adam , Kazimierczak Arkadiusz , Kotfis Katarzyna , Słojewski Marcin
Published: February 2022

Bilateral renal infarction is an extremely rare condition with only few cases reported in the literature. We present a case of bilateral renal infarction affecting an otherwise healthy 34 year old bodybuilder chronically misusing testosterone and stanozolol. The patient presented with severe flank pain mimicking renal colic and biochemical features of acute kidney injury. Diagnostic workup revealed thrombosis affecting both renal arteries. Subsequently, the patient underwent a percutaneous rheolytic thrombectomy with AngioJet catheter, along with catheter-directed thrombolysis. Right-sided retroperitoneal hematoma developed as an early complication, mandating surgical exploration and nephrectomy due to kidney rupture and the unstable condition of the patient. Intensive care and continuous renal replacement therapy were instigated until a gradual improvement of the patient status and a return of kidney function was achieved. No abnormalities were found in the cardiological and hematological evaluation. We believe this is a first report of bilateral renal infarction associated with anabolic steroid misuse in an otherwise healthy individual, and a first report of AngioJet thrombectomy in bilateral thrombosis of renal arteries. It stresses the importance of a thorough diagnostic workup of colic patients and emphasizes the need for sports medicine to reach out to amateur athletes with education on the harms of doping.
Simulating the Spatial Heterogeneity of Housing Prices in Wuhan, China, by Regionally Geographically Weighted Regression
Authors: Wang Zengzheng , Zhao Yangyang , Zhang Fuhao
Published: February 2022

Geographically weighted regression (GWR) is an effective method for detecting spatial non-stationary features based on the hypothesis of proximity correlation. In reality, especially in the social and economic fields, research objects not only have spatial non-stationary characteristics, but also spatial discrete heterogeneity characteristics. Therefore, how to improve the accuracy of GWR estimation in this case is worth studying. In this paper, a regionally geographically weighted regression (RGWR) is proposed. Using incoming dummy variables, the zoning discrimination is added to the spatial kernel function of GWR, the spatial kernel function is modified, the spatial weight is optimized, and the influence of “near heterogeneous” observation points is reduced. In this paper, the residential sale price in Wuhan City is taken as an example in the analysis of three aspects: model performance, fitting effect and influencing factors. The results show that the introduction of a zoning dummy variables can significantly improve the model accuracy of a fixed bandwidth and adaptive bandwidth. Under a fixed bandwidth, compared with the GWR model, RGWR increases R2 and R2adj from 0.6776 and 0.6732 to 0.777 and 0.7746, respectively, and the Akaike information criterion, corrected (AICc) standard decreases by 37.4006 compared with GWR, which proves the effectiveness of the method.
Calcium-Dependent Cytosolic Phospholipase A2α as Key Factor in Calcification of Subdermally Implanted Aortic Valve Leaflets
Authors: Bonetti Antonella , Contin Magali , Tonon Federica , Marchini Maurizio , Ortolani Fulvia
Published: February 2022

Calcium-dependent cytosolic phospholipase A2α (cPLA2α) had been previously found to be overexpressed by aortic valve interstitial cells (AVICs) subjected to in vitro calcific induction. Here, cPLA2α expression was immunohistochemically assayed in porcine aortic valve leaflets (iAVLs) that had undergone accelerated calcification subsequent to 2- to 28-day-long implantation in rat subcutis. A time-dependent increase in cPLA2α-positive AVICs paralleled mineralization progression depending on dramatic cell membrane degeneration with the release of hydroxyapatite-nucleating acidic lipid material, as revealed by immunogold particles decorating organelle membranes in 2d-iAVLs, as well as membrane-derived lipid byproducts in 7d- to 28d-iAVLs. Additional positivity was detected for (i) pro-inflammatory IL-6, mostly exhibited by rat peri-implant cells surrounding 14d- and 28d-iAVLs; (ii) calcium-binding osteopontin, with time-dependent increase and no ossification occurrence; (iii) anti-calcific fetuin-A, mostly restricted to blood plasma within vessels irrorating the connective envelopes of 28d-iAVLs; (iv) early apoptosis marker annexin-V, limited to sporadic AVICs in all iAVLs. No positivity was found for either apoptosis executioner cleaved caspase-3 or autophagy marker MAP1. In conclusion, cPLA2α appears to be a factor characterizing AVL calcification concurrently with a distinct still uncoded cell death form also in an animal model, as well as a putative target for the prevention and treatment of calcific valve diseases.
Comprehensive Review Regarding Mercury Poisoning and Its Complex Involvement in Alzheimer’s Disease
Authors: Paduraru Emanuela , Iacob Diana , Rarinca Viorica , Rusu Angelica , Jijie Roxana , Ilie Ovidiu-Dumitru , Ciobica Alin , Nicoara Mircea , Doroftei Bogdan
Published: February 2022

Mercury (Hg) is considered one of the most widespread toxic environmental pollutants, which seems to have multiple effects on organisms even at low concentrations. It has a critical role in many health problems with harmful consequences, with Hg primarily targeting the brain and its components, such as the central nervous system (CNS). Hg exposure was associated with numerous CNS disorders that frequently trigger Alzheimer’s disease (AD). Patients with AD have higher concentrations of Hg in blood and brain tissue. This paper aims to emphasize a correlation between Hg and AD based on the known literature in the occupational field. The outcome shows that all these concerning elements could get attributed to Hg. However, recent studies did not investigate the molecular level of Hg exposure in AD. The present review highlights the interactions between Hg and AD in neuronal degenerations, apoptosis, autophagy, oxidative stress (OS), mitochondrial malfunctions, gastrointestinal (GI) microflora, infertility and altering gene expression.
How to Cope with the Challenges of Environmental Stresses in the Era of Global Climate Change: An Update on ROS Stave off in Plants
Authors: Singh Archana , Mehta Sahil , Yadav Sunita , Nagar Garima , Ghosh Rajgourab , Roy Amit , Chakraborty Amrita , Singh Indrakant K.
Published: February 2022

With the advent of human civilization and anthropogenic activities in the shade of urbanization and global climate change, plants are exposed to a complex set of abiotic stresses. These stresses affect plants’ growth, development, and yield and cause enormous crop losses worldwide. In this alarming scenario of global climate conditions, plants respond to such stresses through a highly balanced and finely tuned interaction between signaling molecules. The abiotic stresses initiate the quick release of reactive oxygen species (ROS) as toxic by-products of altered aerobic metabolism during different stress conditions at the cellular level. ROS includes both free oxygen radicals {superoxide (O2•−) and hydroxyl (OH−)} as well as non-radicals [hydrogen peroxide (H2O2) and singlet oxygen (1O2)]. ROS can be generated and scavenged in different cell organelles and cytoplasm depending on the type of stimulus. At high concentrations, ROS cause lipid peroxidation, DNA damage, protein oxidation, and necrosis, but at low to moderate concentrations, they play a crucial role as secondary messengers in intracellular signaling cascades. Because of their concentration-dependent dual role, a huge number of molecules tightly control the level of ROS in cells. The plants have evolved antioxidants and scavenging machinery equipped with different enzymes to maintain the equilibrium between the production and detoxification of ROS generated during stress. In this present article, we have focused on current insights on generation and scavenging of ROS during abiotic stresses. Moreover, the article will act as a knowledge base for new and pivotal studies on ROS generation and scavenging.
Knockout of Tobacco Homologs of Arabidopsis Multi-Antibiotic Resistance 1 Gene Confers a Limited Resistance to Aminoglycoside Antibiotics
Authors: Rahman Hafizur , Fukushima Chika , Kaya Hidetaka , Yaeno Takashi , Kobayashi Kappei
Published: February 2022

To explore a possible recessive selective marker for future DNA-free genome editing by direct delivery of a CRISPR/Cas9-single guide RNA (sgRNA) ribonucleoprotein complex, we knocked out homologs of the ArabidopsisMulti-Antibiotic Resistance 1 (MAR1)/RTS3 gene, mutations of which confer aminoglycoside resistance, in tobacco plants by an efficient Agrobacterium-mediated gene transfer. A Cas9 gene was introduced into Nicotiana tabacum and Nicotiana sylvestris together with an sgRNA gene for one of three different target sequences designed to perfectly match sequences in both S- and T-genome copies of N. tabacumMAR1 homologs (NtMAR1hs). All three sgRNAs directed the introduction of InDels into NtMAR1hs, as demonstrated by CAPS and amplicon sequencing analyses, albeit with varying efficiency. Leaves of regenerated transformant shoots were evaluated for aminoglycoside resistance on shoot-induction media containing different aminoglycoside antibiotics. All transformants tested were as sensitive to those antibiotics as non-transformed control plants, regardless of the mutation rates in NtMAR1hs. The NtMAR1hs–knockout seedlings of the T1 generation showed limited aminoglycoside resistance but failed to form shoots when cultured on shoot-induction media containing kanamycin. The results suggest that, like Arabidopsis MAR1, NtMAR1hs have a role in plants’ sensitivity to aminoglycoside antibiotics, and that tobacco has some additional functional homologs.
Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment
Authors: Ntagwabira Fabio , Trujillo Madison , McElroy Taylor , Brown Taurean , Simmons Pilar , Sykes Delawerence , Allen Antiño R.
Published: February 2022

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.
Severe Acute Hepatic Dysfunction Induced by Ammonium Acetate Treatment Results in Choroid Plexus Swelling and Ventricle Enlargement in the Brain
Authors: Nakadate Kazuhiko , Kamata Sumito
Published: February 2022

Hepatic encephalopathy is a major cause of liver failure. However, the pathophysiological role of ventricle enlargement in brain edema remains unclear. Here, we used an acute hepatic encephalopathy mouse model to examine the sequential pathological changes in the brain associated with this condition. We collected tissue samples from experimental animals treated with ammonium acetate at 3 and 24 h post-injection. Despite the normalization of the animal’s ammonia levels, samples taken at 24 h after injection exhibited distinct enlargement of lateral ventricles. The choroid plexus samples obtained at 3 h post-ammonium acetate treatment indicated enlargement; however, this swelling was reduced at the later timepoint. The aquaporin-1 proteins that regulate the choroid plexus were localized both in the apical membrane and the cytoplasm of the epithelia in the control; however, they translocated to the apical membranes of the epithelia in response to ammonia treatment. Therefore, severe acute hepatic encephalopathy induced by ammonium acetate administration caused enlargement of the ventricles, through swelling of the choroid plexus and aquaporin-1 transport and aggregation within the apical membranes.
The Effects of Stress and Diet on the “Brain–Gut” and “Gut–Brain” Pathways in Animal Models of Stress and Depression
Authors: Herselman Mauritz F. , Bailey Sheree , Bobrovskaya Larisa
Published: February 2022

Compelling evidence is building for the involvement of the complex, bidirectional communication axis between the gastrointestinal tract and the brain in neuropsychiatric disorders such as depression. With depression projected to be the number one health concern by 2030 and its pathophysiology yet to be fully elucidated, a comprehensive understanding of the interactions between environmental factors, such as stress and diet, with the neurobiology of depression is needed. In this review, the latest research on the effects of stress on the bidirectional connections between the brain and the gut across the most widely used animal models of stress and depression is summarised, followed by comparisons of the diversity and composition of the gut microbiota across animal models of stress and depression with possible implications for the gut–brain axis and the impact of dietary changes on these. The composition of the gut microbiota was consistently altered across the animal models investigated, although differences between each of the studies and models existed. Chronic stressors appeared to have negative effects on both brain and gut health, while supplementation with prebiotics and/or probiotics show promise in alleviating depression pathophysiology.
Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy
Authors: Bourg Nathalie , Vu Hong Ai , Lostal William , Jaber Abbass , Guerchet Nicolas , Tanniou Guillaume , Bordier Fanny , Bertil-Froidevaux Emilie , Georger Christophe , Daniele Nathalie , Richard Isabelle , Israeli David
Published: February 2022

Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin.
Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia
Authors: Sidhom Emad , O’Brien John T. , Butcher Adrian J. , Smith Heather L. , Mallucci Giovanna R. , Underwood Benjamin R.
Published: February 2022

Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world’s population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed—particularly any that can slow down the disease’s progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents—in particular the licensed antidepressant trazodone—and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.
Tceal5 and Tceal7 Function in C2C12 Myogenic Differentiation via Exosomes in Fetal Bovine Serum
Authors: Sawada Aika , Yamamoto Takuya , Sato Takahiko
Published: February 2022

The proliferation and differentiation of skeletal muscle cells are usually controlled by serum components. Myogenic differentiation is induced by a reduction of serum components in vitro. It has been recently reported that serum contains not only various growth factors with specific actions on the proliferation and differentiation of myogenic cells, but also exogenous exosomes, the function of which is poorly understood in myogenesis. We have found that exosomes in fetal bovine serum are capable of exerting an inhibitive effect on the differentiation of C2C12 myogenic cells in vitro. In this process of inhibition, the downregulation of Tceal5 and Tceal7 genes was observed. Expression of these genes is specifically increased in direct proportion to myogenic differentiation. Loss- or gain- of function studies with Tceal5 and Tceal7 indicated that they have the potential to regulate myogenic differentiation via exosomes in fetal bovine serum.
The Thermal Stability of the Collagen Triple Helix Is Tuned According to the Environmental Temperature
Authors: Fujii Kazunori K. , Taga Yuki , Takagi Yusuke K. , Masuda Ryo , Hattori Shunji , Koide Takaki
Published: February 2022

Triple helix formation of procollagen occurs in the endoplasmic reticulum (ER) where the single-stranded α-chains of procollagen undergo extensive post-translational modifications. The modifications include prolyl 4- and 3-hydroxylations, lysyl hydroxylation, and following glycosylations. The modifications, especially prolyl 4-hydroxylation, enhance the thermal stability of the procollagen triple helix. Procollagen molecules are transported to the Golgi and secreted from the cell, after the triple helix is formed in the ER. In this study, we investigated the relationship between the thermal stability of the collagen triple helix and environmental temperature. We analyzed the number of collagen post-translational modifications and thermal melting temperature and α-chain composition of secreted type I collagen in zebrafish embryonic fibroblasts (ZF4) cultured at various temperatures (18, 23, 28, and 33 °C). The results revealed that thermal stability and other properties of collagen were almost constant when ZF4 cells were cultured below 28 °C. By contrast, at a higher temperature (33 °C), an increase in the number of post-translational modifications and a change in α-chain composition of type I collagen were observed; hence, the collagen acquired higher thermal stability. The results indicate that the thermal stability of collagen could be autonomously tuned according to the environmental temperature in poikilotherms.
IBtkα Activates the β-Catenin-Dependent Transcription of MYC through Ubiquitylation and Proteasomal Degradation of GSK3β in Cancerous B Cells
Authors: Vecchio Eleonora , Nisticò Nancy , Golino Gaetanina , Iaccino Enrico , Maisano Domenico , Mimmi Selena , Aloisio Annamaria , Renna Maurizio , Avagliano Angelica , Arcucci Alessandro , Fiume Giuseppe , Quinto Ileana
Published: February 2022

The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of Ibtk in MYC-dependent B-lymphomagenesis observed in Eμ-myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and MYC. We show that IBtkα, albeit indirectly, activates the β-catenin-dependent transcription of the MYC gene. Of course, IBtkα associates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β-catenin, a substrate of GSK3β, and results in the transcriptional activation of the MYC and CCND1 target genes of β-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt’s lymphoma cells, IBtkα silencing triggered the downregulation of both MYC mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry-based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma.
Targeted Suppression of Lipoprotein Receptor LSR in Astrocytes Leads to Olfactory and Memory Deficits in Mice
Authors: El Hajj Aseel , Herzine Ameziane , Calcagno Gaetano , Désor Frédéric , Djelti Fathia , Bombail Vincent , Denis Isabelle , Oster Thierry , Malaplate Catherine , Vigier Maxime , Kaminski Sandra , Pauron Lynn , Corbier Catherine , Yen Frances T. , Lanhers Marie-Claire , Claudepierre Thomas
Published: February 2022

Perturbations of cholesterol metabolism have been linked to neurodegenerative diseases. Glia–neuron crosstalk is essential to achieve a tight regulation of brain cholesterol trafficking. Adequate cholesterol supply from glia via apolipoprotein E-containing lipoproteins ensures neuronal development and function. The lipolysis-stimulated lipoprotein receptor (LSR), plays an important role in brain cholesterol homeostasis. Aged heterozygote Lsr+/− mice show altered brain cholesterol distribution and increased susceptibility to amyloid stress. Since LSR expression is higher in astroglia as compared to neurons, we sought to determine if astroglial LSR deficiency could lead to cognitive defects similar to those of Alzheimer’s disease (AD). Cre recombinase was activated in adult Glast-CreERT/lsrfl/fl mice by tamoxifen to induce astroglial Lsr deletion. Behavioral phenotyping of young and old astroglial Lsr KO animals revealed hyperactivity during the nocturnal period, deficits in olfactory function affecting social memory and causing possible apathy, as well as visual memory and short-term working memory problems, and deficits similar to those reported in neurodegenerative diseases, such as AD. Furthermore, GFAP staining revealed astroglial activation in the olfactory bulb. Therefore, astroglial LSR is important for working, spatial, and social memory related to sensory input, and represents a novel pathway for the study of brain aging and neurodegeneration.
Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support
Authors: Parikh Mihir , Shah Saumya , Basu Ratnadeep , Famulski Konrad S. , Kim Daniel , Mullen John C. , Halloran Philip F. , Oudit Gavin Y.
Published: February 2022

Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner.
Uncovering a Hub Signaling Pathway of Antimicrobial-Antifungal-Anticancer Peptides’ Axis on Short Cationic Peptides via Network Pharmacology Study
Authors: Oh Ki-Kwang , Adnan Md. , Cho Dong-Ha
Published: February 2022

Short cationic peptides (SCPs) with therapeutic efficacy of antimicrobial peptides (AMPs), antifungal peptides (AFPs), and anticancer peptides (ACPs) are known as an enhancement of the host defense system. Here, we investigated the uppermost peptide(s), hub signaling pathway(s), and their associated target(s) through network pharmacology. Firstly, we selected SCPs with positive amino acid residues on N- and C- terminals under 500 Dalton via RStudio. Secondly, the overlapping targets between the bacteria-responsive targets (TTD and OMIM) and AMPs’ targets were visualized by VENNY 2.1. Thirdly, the overlapping targets between AFPs’ targets and fungal-responsive targets were exhibited by VENNY 2.1. Fourthly, the overlapping targets between cancer-related targets (TTD and OMIM) and fungal-responsive targets were displayed by VENNY 2.1. Finally, a molecular docking study (MDS) was carried out to discover the most potent peptides on a hub signaling pathway. A total of 1833 SCPs were identified, and AMPs’, AFPs’, and ACPs’ filtration suggested that 197 peptides (30 targets), 81 peptides (6 targets), and 59 peptides (4 targets) were connected, respectively. The AMPs―AFPs―ACPs’ axis indicated that 27 peptides (2 targets) were associated. Each hub signaling pathway for the enhancement of the host defense system was “Inactivation of Rap1 signaling pathway on AMPs”, “Activation of Notch signaling pathway on AMPs―AFPs’ axis”, and “Inactivation of HIF-1 signaling pathway on AMPs―AFPs―ACPs’ axis”. The most potent peptides were assessed via MDS; finally, HPIK on STAT3 and HVTK on NOS2 and on HIF-1 signaling pathway were the most stable complexes. Furthermore, the two peptides had better affinity scores than standard inhibitors (Stattic, 1400 W). Overall, the most potent SCPs for the human defense system were HPIK on STAT3 and HVTK on NOS2, which might inactivate the HIF-1 signaling pathway.
Oxidative Stress Enhances the TGF-β2-RhoA-MRTF-A/B Axis in Cells Entering Endothelial-Mesenchymal Transition
Authors: Sobierajska Katarzyna , Wawro Marta E. , Niewiarowska Jolanta
Published: February 2022

Around 45% of deaths in the EU and the US are due to fibrotic diseases. Although myofibroblasts are detected in various fibrotic tissues, they are mostly transdifferentiated from endothelial cells during the endothelial-mesenchymal transition (EndMT) induced by tumor growth factor-beta (TGF-β) family members. Growing evidence indicates that oxidative stress might enhance the sensitivity and the effects of TGF-β stimulation; however, the molecular mechanisms involved in the coordination of oxidative stress and TGF-β inductions remain poorly understood. Our findings indicate for the first time that oxidative stress enhances mesenchymal trans-differentiation of human microvascular endothelial cells (HMEC-1 cells) and that the oxidative stress-dependent TGF-β2-RhoA/Rac1-MRTF-A axis is critical for the induction of later stages of EndMT. This additive effect was manifested in TGF-β1-stimulated and Snail-overexpressed cells, where it caused higher cell elongation and faster migration on collagen I layers. Additionally, Western blot assay indicated the presence of alterations in cell contraction and EndMT markers. We conclude that complex anti-fibrotic therapies based on the inhibition of MRTF activities and oxidative stress might be an attractive target for fibrosis treatment.