bluuebunny/crossref_metadata_2025 huggingface dataset:
Suicide Models and Treatment Models Are Separate Entities. What Does It Mean for Clinical Suicide Prevention?
Authors: Michel Konrad
Published: May 2021

Theoretical models of suicide are based on risk factors associated with suicide, such as psychiatric pathology, genetics, epigenetics, functional brain disorders, and impaired decision making. In current clinical practice, the predominant risk model is the medical model, which posits that treating suicide risk is primarily a matter of treating psychiatric disorders. However, even comprehensive risk factor models cannot overcome the basic problem that, by their nature, they cannot accommodate the suicidal person’s psychological experience of suicidality. Risk factor models do not translate into effective treatment models. Suicide risk is highly personal and fluid, and is related to individual vulnerabilities and to person-specific events triggering suicidal thoughts and actions. Clinicians need treatment models that are meaningful to suicidal patients. Understanding the single person’s suicidality requires a patient-centered approach. Therapeutic interventions that effectively reduce the risk of suicidal behavior have been developed from general principles of psychotherapy. Therapy process factors associated with effective therapies are working alliance, validation of the individual patient’s thoughts and feelings, active treatment engagement. Psychological therapies need patients who are active participants in a collaborative working relationship between therapist and patient. The goal must be to jointly develop a meaningful understanding of the suicidal crisis. In view of the limited personal resources in health care systems it is important that effective therapies are brief and effective. Future research must aim to improve our understanding of the factors involved in effective therapies in order to optimize treatments for individuals at risk. This may also include the integration of biological risk factors in psychological treatment models.
Exploring the Relationship between Despotic Leadership and Job Satisfaction: The Role of Self Efficacy and Leader–Member Exchange
Authors: Zhou Xiang , Rasool Samma Faiz , Yang Jing , Asghar Muhammad Zaheer
Published: May 2021

This study explores the effects of despotic leadership (DL) on employee job satisfaction (JS) using self-efficacy (SE) as a mediating variable and leader–member exchange (LMX) as a moderated variable. Building on the social learning and social exchange theory, our research proposes a research model. In this model, despotic leadership affects employee job satisfaction both directly and indirectly through self-efficacy and leader–member exchange. We used a questionnaire survey analysis approach to collect data. Data were collected from the employees of small- and medium-sized enterprises (SMEs) located in Guangdong Province, P.R. China. A pilot test of 20 participants with similar demographics as the final sample was performed to test the usability of the questionnaire. We distributed 500 questionnaires among the target population. In total, 230 usable questionnaires were returned, resulting in a response rate of 53%. To estimate the proposed relationships in the theoretical framework, we used SPSS and AMOS. The results of this study confirmed that despotic leadership has a negative impact on employee job satisfaction. Moreover, the outcomes of this study indicate that self-efficacy has a mediating effect between despotic leadership and employee job satisfaction. Similarly, the results also confirm that LMX has a moderating effect between despotic leadership and employee self-efficacy. Therefore, we conclude that the community is understanding of the mechanism of despotic leadership, identify the mechanism to effectively deal with its negative effects, broaden the relevant research on the antecedent variable of self-efficacy, and provide practical enlightenment enterprises to retain and employ people.
The Utilization of National Tobacco Cessation Services among Female Smokers and the Need for a Gender-Responsive Approach
Authors: Lee Ahnna , Lee Kang-Sook , Lee Dahyeon , Ahn Hyeju , Lee Hyun-Kyung , Kim Hyekyeong , Lee Jakyoung , Seo Hong-Gwan
Published: May 2021

Despite the steadily increasing prevalence of female smoking, gender-responsive tobacco cessation services have not been widely provided worldwide. The purpose of this study is to identify factors associated with the use of tobacco cessation services among female tobacco product users in Korea from a national perspective. We performed a logistic regression analysis using data from 663 female smokers; 11.0% of female smokers had used government-supported smoking cessation services. A logistic regression model showed a statistically significant association between the utilization of smoking cessation services and a history of pregnancy and childbirth, depression, current use of heated tobacco products and multiple tobacco products, parental smoking status and receiving advice to quit. With regard to the motivation ruler, those in their 50s reported a higher importance than those in their 20s. Weight gain concerns when quitting smoking were the lowest among the participants aged 19–29. The need to develop gender-specific smoking cessation programs is the highest among the participants aged 39–49 and the lowest among those aged 19–29. This study suggests several factors related to the utilization of national health services among female smokers. Further studies considering gender-specific needs for the development of gender-responsive tobacco cessation support are needed.
When Natural Hazards Intersect with Public Health: A Preliminary Exploration of the Impact of Bushfires and the COVID-19 Pandemic on Australian Coastal Drowning Fatalities
Authors: Lawes Jasmin C , Strasiotto Luke , Daw Shane , Peden Amy E
Published: May 2021

Natural hazards combined with the COVID-19 pandemic have had significant global impacts to the community and the environment. This study explores the impact of the Australian 2019/20 bushfires followed by the COVID-19 pandemic on unintentional coastal drowning fatalities. Fatality data were collated using triangulation methodology. Percentage change in coastal drowning fatalities between 2019/20 financial year (FY) and the 15FY annual average (2004/5–2018/19) were calculated for the dominant bushfire period (August 2019–February 2020 inclusive) and COVID-19 restrictions in place for 2019/20FY (March–June 2020 inclusive). Relative risk (RR; with 95% confidence intervals [CI]) of coastal drowning was calculated against the average for overall, bushfire and COVID-19 periods, using coastal participation data as the denominator, weighted for the predicted decrease in the use of outdoor coastal areas due to these widespread events. Coastal drowning fatalities increased in 2019/20FY by 9% overall (bushfires: 6%; COVID-19: 9%). Swimming/wading drowning fatalities increased during the bushfire period (RR = 2.02; 95% CI: 1.13–3.63), while boating and personal watercraft (PWC)-related fatalities increased during both the bushfire (RR = 2.92; 95% CI: 1.41–6.05) and COVID-19 period (RR = 3.86; 95% CI: 1.64–9.11). Rock fishing fatalities also increased across both the bushfire (RR = 4.19; 95% CI: 1.45–12.07; p = 0.008) and COVID-19 (RR = 3.8;95% CI: 1.24–11.62; p = 0.027) periods. Findings indicate the activity patterns leading to coastal drowning fatalities changed despite significant public health events impacting freedom of movement and thus opportunity for coastal participation. Understanding, and preparing for, the impacts of natural hazards on drowning risk is vital for future preventive efforts.
Displacement, Violence, and Mental Health: Evidence from Rohingya Adolescents in Cox’s Bazar, Bangladesh
Authors: O’Connor Katherine , Seager Jennifer
Published: May 2021

The Rohingya have endured generations of trauma through displacement and targeted violence in Myanmar. Hundreds of thousands have been forced out of the country, with a large proportion settling in refugee camps in Cox’s Bazar, Bangladesh. This study examines the impacts of exposure to trauma on mental health outcomes among Rohingya adolescents living in Bangladesh. Post-traumatic stress disorder (PTSD) and depression are examined as outcomes. The main explanatory variable is a measure of exposure to trauma at two levels of proximity (experiencing and witnessing). Resilience is investigated as a potential effect modifier. Experiencing and witnessing traumatic events are positively and significantly associated with PTSD and depression. However, this effect is only seen for PTSD as a continuous measure, reflecting high rates of low-level PTSD in this population. Resilience is found to reduce the effects of trauma on depression, indicating an effect modification of this relationship.
Environmental Conditions of Dance Rooms and Its Impact on Dance Conservatories Teachers’ Health (An Andalusian Study)
Authors: Redel-Macías María Dolores , del Rio Carmen , Arezes Pedro , Aparicio-Martínez Pilar , Cubero-Atienza Antonio José
Published: May 2021

Dance teachers have to be in long hours dancing. That entails repetitive movements, loud live music, and as well as forcing their voices. These demands can implicate severe health problems and other kind of illness as discomfort, stress, etc. However, the Spanish Ministry of Health only recognize as professional disease for this line of work, the vocal nodules. For this reason, this research studies the health problems in dance teachers in Andalusia, correlating the results of a survey carried out in different conservatories from Andalusia with measurement of noise emissions levels, assessment of noise exposure, and assessment of thermal environment in the classes measuring the thermal environment variables. To the authors’ knowledge, this is the first study where the influence of several sounds, such as tapping, castanets, and live music, on the health of dance teachers, musicians, and singers during flamenco classes has been researched. Results showed a correlation between some diseases, such as stress and the high level of sound in the classes. The sound levels were well above those established by European regulations reaching values higher than 85 dB(A) as equivalent continuous sound levels during the class time. This European regulation is stablished for an 8 h/day period, five days per week. The thermal environments are no adequate for this activity, mainly for high temperatures in Cordoba during summer. To improve the current working conditions, some recommendations were given to reduce the number of class hours and establish rest shifts, provide more information on health risks, or renovate the floor of some classrooms.
Spatial Uncertainty in Modeling Inhalation Exposure to Volatile Organic Compounds in Response to the Application of Consumer Spray Products
Authors: Jung Yerin , Kim Yoonsub , Seol Hwi-Soo , Lee Jong-Hyeon , Kwon Jung-Hwan
Published: May 2021

(1) Background: Mathematical exposure modeling of volatile organic compounds (VOCs) in consumer spray products mostly assumes instantaneous mixing in a room. This well-mixed assumption may result in the uncertainty of exposure estimation in terms of spatial resolution. As the inhalation exposure to chemicals from consumer spray products may depend on the spatial heterogeneity, the degree of uncertainty of a well-mixed assumption should be evaluated under specific exposure scenarios. (2) Methods: A room for simulation was divided into eight compartments to simulate inhalation exposure to an ethanol trigger and a propellant product. Real-time measurements of the atmospheric concentration in a room-sized chamber by proton transfer reaction mass spectrometry were compared with mathematical modeling to evaluate the non-homogeneous distribution of chemicals after their application. (3) Results: The well-mixed model overestimated short-term exposure, particularly under the trigger spray scenario. The uncertainty regarding the different chemical proportions in the trigger did not significantly vary in this study. (4) Conclusions: Inhalation exposure to aerosol generating sprays should consider the spatial uncertainty in terms of the estimation of short-term exposure.
Impact of COVID-19 Home Confinement in Children’s Refractive Errors
Authors: Alvarez-Peregrina Cristina , Martinez-Perez Clara , Villa-Collar Cesar , Andreu-Vázquez Cristina , Ruiz-Pomeda Alicia , Sánchez-Tena Miguel Ángel
Published: May 2021

Background: Myopia is a public health problem, with estimations that 50% of the world population will be myopic by 2050. Some environmental factors, such as time spent outdoors, doing near work, and using digital devices, influence the development of myopia in children. Home confinement in Spain has increased these risk factors, so this study aims to investigate the impact of home confinement during the COVID-19 outbreak in the vision of school-aged children; Methods: A cross-sectional study in children between 5 and 7 years old that completed a visual screening and a questionnaire about their lifestyles at opticians in Spain in September and October of 2019 and 2020. Statistical analysis to compare lifestyles pre and post confinement, and vision in 2020 versus a similar cohort examined at the same opticians in 2019, was conducted; Results: Spanish children spent less time outdoors and more time doing near work in 2020 than in 2019 (p ≤ 0.001). There was a significant decrease of the spherical equivalent (mean ± standard deviation; 0.66 ± 2.03 D in 2019 vs. 0.48 ± 1.81 D in 2020; p ≤ 0.001); Conclusions: Lifestyles of Spanish children changed during the home confinement at the beginning of 2020. Together with changes in their lifestyles, spherical equivalents have decreased, which implies higher figures of myopia for children aged between 5 and 7.
Block2vec: An Approach for Identifying Urban Functional Regions by Integrating Sentence Embedding Model and Points of Interest
Authors: Sun Zhihao , Jiao Hongzan , Wu Hao , Peng Zhenghong , Liu Lingbo
Published: May 2021

Urban functional regions are essential information in parsing urban spatial structure. The rapid and accurate identification of urban functional regions is important for improving urban planning and management. Thanks to its low cost and fast data update characteristics, the Point of Interest (POI) is one of the most common types of open access data. It mainly identifies urban functional regions by analyzing the potential correlation between POI data and the regions. Even though this is an important manifestation of the functional region, the spatial correlation between regions is rarely considered in previous studies. In order to extract the spatial semantic information among regions, a new model, called the Block2vec, is proposed by using the idea of the Skip-gram framework. The Block2vec model maps the spatial correlation between the POIs, as well as the regions, to a high-dimensional vector, in which classification of urban functional regions can be better performed. The results from cluster analysis showed that the high-dimensional vector extracted can well distinguish the regions with different functions. The random forests classification result (Overall accuracy = 0.7186, Kappa = 0.6429) illustrated the effectiveness of the proposed method. This study also verified the potential of the sentence embedding model in the semantic information extraction of POIs.
Recombinant γY278H Fibrinogen Showed Normal Secretion from CHO Cells, but a Corresponding Heterozygous Patient Showed Hypofibrinogenemia
Authors: Kamijo Tomu , Kaido Takahiro , Yoda Masahiro , Arai Shinpei , Yamauchi Kazuyoshi , Okumura Nobuo
Published: May 2021

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and conducted further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines, including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely, recombinant fibrinogen production was not reduced but the patients’ plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca2+ and “D:D” interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen was secreted normally from the patient’s hepatocytes but then underwent accelerated degradation by plasmin in the circulation.
The Selective Histone Deacetylase Inhibitor MI192 Enhances the Osteogenic Differentiation Efficacy of Human Dental Pulp Stromal Cells
Authors: Man Kenny , Lawlor Liam , Jiang Lin-Hua , Yang Xuebin B.
Published: May 2021

The use of human dental pulp stromal cells (hDPSCs) has gained increasing attention as an alternative stem cell source for bone tissue engineering. The modification of the cells’ epigenetics has been found to play an important role in regulating differentiation, with the inhibition of histone deacetylases 3 (HDAC3) being linked to increased osteogenic differentiation. This study aimed to induce epigenetic reprogramming using the HDAC2 and 3 selective inhibitor, MI192 to promote hDPSCs osteogenic capacity for bone regeneration. MI192 treatment caused a time–dose-dependent change in hDPSC morphology and reduction in viability. Additionally, MI192 successfully augmented hDPSC epigenetic functionality, which resulted in increased histone acetylation and cell cycle arrest at the G2/M phase. MI192 pre-treatment exhibited a dose-dependent effect on hDPSCs alkaline phosphatase activity. Quantitative PCR and In-Cell Western further demonstrated that MI192 pre-treatment significantly upregulated hDPSCs osteoblast-related gene and protein expression (alkaline phosphatase, bone morphogenic protein 2, type I collagen and osteocalcin) during osteogenic differentiation. Importantly, MI192 pre-treatment significantly increased hDPSCs extracellular matrix collagen production and mineralisation. As such, for the first time, our findings show that epigenetic reprogramming with the HDAC2 and 3 selective inhibitor MI192 accelerates the osteogenic differentiation of hDPSCs, demonstrating the considerable utility of this MSCs engineering approach for bone augmentation strategies.
Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue
Authors: Wawrzkiewicz-Jałowiecka Agata , Lalik Anna , Soveral Graça
Published: May 2021

The gonadal steroids, including androgens, estrogens and progestogens, are involved in the control of body fat distribution in humans. Nevertheless, not only the size and localization of the fat depots depend on the sex steroids levels, but they can also highly affect the functioning of adipose tissue. Namely, the gonadocorticoids can directly influence insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. They may also alter energy balance and glucose homeostasis in adipocytes in an indirect way, e.g., by changing the expression level of aquaglyceroporins. This work presents the recent advances in understanding the molecular mechanism of how the gonadal steroids influence the functioning of adipose tissue leading to a set of detrimental metabolic consequences. Special attention is given here to highlighting the sexual dimorphism of adipocyte functioning in terms of health and disease. Particularly, we discuss the molecular background of metabolic disturbances occurring in consequence of hormonal imbalance which is characteristic of some common endocrinopathies such as the polycystic ovary syndrome. From this perspective, we highlight the potential drug targets and the active substances which can be used in personalized sex-specific management of metabolic diseases, in accord with the patient’s hormonal status.
Daily Lifestyle and Cutaneous Malignancies
Authors: Sawada Yu , Nakamura Motonobu
Published: May 2021

Daily lifestyle is a fundamental part of human life and its influence accumulates daily in the human body. We observe that a good daily lifestyle has a beneficial impact on our health; however, the actual effects of individual daily lifestyle factors on human skin diseases, especially skin cancers, have not been summarized. In this review, we focused on the influence of daily lifestyle on the development of skin cancer and described the detailed molecular mechanisms of the development or regulation of cutaneous malignancies. Several daily lifestyle factors, such as circadian rhythm disruption, smoking, alcohol, fatty acids, dietary fiber, obesity, and ultraviolet light, are known to be associated with the risk of cutaneous malignancies, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Although the influence of some daily lifestyles on the risk of skin cancers is controversial, this review provides us a better understanding of the relationship between daily lifestyle factors and skin cancers.
Roles of Lipids in the Permeability Barriers of Skin and Oral Mucosa
Authors: Wertz Philip W.
Published: May 2021

PubMed searches reveal much literature regarding lipids in barrier function of skin and less literature on lipids in barrier function of the oral mucosa. In terrestrial mammals, birds, and reptiles, the skin’s permeability barrier is provided by ceramides, fatty acids, and cholesterol in the outermost layers of the epidermis, the stratum corneum. This layer consists of about 10–20 layers of cornified cells embedded in a lipid matrix. It effectively prevents loss of water and electrolytes from the underlying tissue, and it limits the penetration of potentially harmful substances from the environment. In the oral cavity, the regions of the gingiva and hard palate are covered by keratinized epithelia that much resemble the epidermis. The oral stratum corneum contains a lipid mixture similar to that in the epidermal stratum corneum but in lower amounts and is accordingly more permeable. The superficial regions of the nonkeratinized oral epithelia also provide a permeability barrier. These epithelial regions do contain ceramides, cholesterol, and free fatty acids, which may underlie barrier function. The oral epithelial permeability barriers primarily protect the underlying tissue by preventing the penetration of potentially toxic substances, including microbial products. Transdermal drug delivery, buccal absorption, and lipid-related disease are discussed.
Dual RNA-Sequencing Analysis of Resistant (Pinus pinea) and Susceptible (Pinus radiata) Hosts during Fusarium circinatum Challenge
Authors: Zamora-Ballesteros Cristina , Pinto Gloria , Amaral Joana , Valledor Luis , Alves Artur , Diez Julio J. , Martín-García Jorge
Published: May 2021

Fusarium circinatum causes one of the most important diseases of conifers worldwide, the pine pitch canker (PPC). However, no effective field intervention measures aiming to control or eradicate PPC are available. Due to the variation in host genetic resistance, the development of resistant varieties is postulated as a viable and promising strategy. By using an integrated approach, this study aimed to identify differences in the molecular responses and physiological traits of the highly susceptible Pinus radiata and the highly resistant Pinus pinea to F. circinatum at an early stage of infection. Dual RNA-Seq analysis also allowed to evaluate pathogen behavior when infecting each pine species. No significant changes in the physiological analysis were found upon pathogen infection, although transcriptional reprogramming was observed mainly in the resistant species. The transcriptome profiling of P. pinea revealed an early perception of the pathogen infection together with a strong and coordinated defense activation through the reinforcement and lignification of the cell wall, the antioxidant activity, the induction of PR genes, and the biosynthesis of defense hormones. On the contrary, P. radiata had a weaker response, possibly due to impaired perception of the fungal infection that led to a reduced downstream defense signaling. Fusarium circinatum showed a different transcriptomic profile depending on the pine species being infected. While in P. pinea, the pathogen focused on the degradation of plant cell walls, active uptake of the plant nutrients was showed in P. radiata. These findings present useful knowledge for the development of breeding programs to manage PPC.
Application of microRNA in Human Osteoporosis and Fragility Fracture: A Systemic Review of Literatures
Authors: Wu Yen-Zung , Huang Hsuan-Ti , Cheng Tsung-Lin , Lu Yen-Mou , Lin Sung-Yen , Ho Cheng-Jung , Lee Tien-Ching , Hsu Chia-Hao , Huang Peng-Ju , Huang Han Hsiang , Li Jhong-You , Su Yu-De , Chen Shih-Chieh , Kang Lin , Chen Chung-Hwan
Published: May 2021

MicroRNAs (miRNAs) could serve as ideal entry points to the deregulated pathways in osteoporosis due to their relatively simple upstream and downstream relationships with other molecules in the signaling cascades. Our study aimed to give a comprehensive review of the already identified miRNAs in osteoporosis from human blood samples and provide useful information for their clinical application. A systematic literature search for relevant studies was conducted in the Pubmed database from inception to December 2020. We set two essential inclusion criteria: human blood sampling and design of controlled studies. We sorted the results of analysis on human blood samples according to the study settings and compiled the most promising miRNAs with analyzed diagnostic values. Furthermore, in vitro and in vivo evidence for the mechanisms of the identified miRNAs was also illustrated. Based on both diagnostic value and evidence of mechanism from in vitro and in vivo experiments, miR-23b-3p, miR-140-3p, miR-300, miR-155-5p, miR-208a-3p, and miR-637 were preferred candidates in diagnostic panels and as therapeutic agents. Further studies are needed to build sound foundations for the clinical usage of miRNAs in osteoporosis.
Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs
Authors: Bogensperger Christina , Hofmann Julia , Messner Franka , Resch Thomas , Meszaros Andras , Cardini Benno , Weissenbacher Annemarie , Oberhuber Rupert , Troppmair Jakob , Öfner Dietmar , Schneeberger Stefan , Hautz Theresa
Published: May 2021

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.
Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides
Authors: Rebolledo Daniela L. , Acuña María José , Brandan Enrique
Published: May 2021

The Cellular Communication Network (CCN) family of matricellular proteins comprises six proteins that share conserved structural features and play numerous biological roles. These proteins can interact with several receptors or soluble proteins, regulating cell signaling pathways in various tissues under physiological and pathological conditions. In the skeletal muscle of mammals, most of the six CCN family members are expressed during embryonic development or in adulthood. Their roles during the adult stage are related to the regulation of muscle mass and regeneration, maintaining vascularization, and the modulation of skeletal muscle fibrosis. This work reviews the CCNs proteins’ role in skeletal muscle physiology and disease, focusing on skeletal muscle fibrosis and its regulation by Connective Tissue Growth factor (CCN2/CTGF). Furthermore, we review evidence on the modulation of fibrosis and CCN2/CTGF by the renin-angiotensin system and the kallikrein-kinin system of vasoactive peptides.
Molecular Structure of Cefuroxime Axetil Complexes with α-, β-, γ-, and 2-Hydroxypropyl-β-Cyclodextrins: Molecular Simulations and Raman Spectroscopic and Imaging Studies
Authors: Gieroba Barbara , Kalisz Grzegorz , Sroka-Bartnicka Anna , Płazińska Anita , Płaziński Wojciech , Starek Małgorzata , Dąbrowska Monika
Published: May 2021

The formation of cefuroxime axetil+cyclodextrin (CA+CD) complexes increases the aqueous solubility of CA, improves its physico-chemical properties, and facilitates a biomembrane-mediated drug delivery process. In CD-based tablet formulations, it is crucial to investigate the molecular details of complexes in final pharmaceutical preparation. In this study, Raman spectroscopy and mapping were applied for the detection and identification of chemical groups involved in α-, β-, γ-, and 2-hydroxypropyl-β-CD (2-HP- β-CD)+CA complexation process. The experimental studies have been complemented by molecular dynamics-based investigations, providing additional molecular details of CA+CD interactions. It has been demonstrated that CA forms the guest–host type inclusion complexes with all studied CDs; however, the nature of the interactions is slightly different. It seems that both α- and β-CD interact with furanyl and methoxy moieties of CA, γ-CD forms a more diverse pattern of interactions with CA, which are not observed in other CDs, whereas 2HP-β-CD binds CA with the contribution of hydrogen bonding. Apart from supporting this interpretation of the experimental data, molecular dynamics simulations allowed for ordering the CA+CD binding affinities. The obtained results proved that the molecular details of the host–guest complexation can be successfully predicted from the combination of Raman spectroscopy and molecular modeling.
Effect of Ecdysterone on the Hepatic Transcriptome and Lipid Metabolism in Lean and Obese Zucker Rats
Authors: Marschall Magdalena J. M. , Ringseis Robert , Gessner Denise K. , Grundmann Sarah M. , Most Erika , Wen Gaiping , Maheshwari Garima , Zorn Holger , Eder Klaus
Published: May 2021

Conflicting reports exist with regard to the effect of ecdysterone, the predominating representative of steroid hormones in insects and plants, on hepatic and plasma lipid concentrations in different rodent models of obesity, fatty liver, and diabetes, indicating that the effect is dependent on the rodent model used. Here, the hypothesis was tested for the first time that ecdysterone causes lipid-lowering effects in genetically obese Zucker rats. To test this hypothesis, two groups of male obese Zucker rats (n = 8) were fed a nutrient-adequate diet supplemented without or with 0.5 g ecdysterone per kg diet. To study further if ecdysterone is capable of alleviating the strong lipid-synthetic activity in the liver of obese Zucker rats, the study included also two groups of male lean Zucker rats (n = 8) which also received either the ecdysterone-supplemented or the non-supplemented diet. While hepatic and plasma concentrations of triglycerides and cholesterol were markedly higher in the obese compared to the lean rats (p < 0.05), hepatic and plasma triglyceride and cholesterol concentrations did not differ between rats of the same genotype fed the diets without or with ecdysterone. In conclusion, the present study clearly shows that ecdysterone supplementation does not exhibit lipid-lowering actions in the liver and plasma of lean and obese Zucker rats.
Microglia–Neuron Crosstalk in Obesity: Melodious Interaction or Kiss of Death?
Authors: Léon Stéphane , Nadjar Agnès , Quarta Carmelo
Published: May 2021

Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body’s metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia–neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders.
The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury
Authors: Munoz Kevin , Wasnik Samiksha , Abdipour Amir , Bi Hongzheng , Wilson Sean M. , Tang Xiaolei , Ghahramanpouri Mahdis , Baylink David J.
Published: May 2021

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1β, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.
BMAL1 Knockdown Leans Epithelial–Mesenchymal Balance toward Epithelial Properties and Decreases the Chemoresistance of Colon Carcinoma Cells
Authors: Zhang Yuan , Devocelle Aurore , Desterke Christophe , de Souza Lucas Eduardo Botelho , Hadadi Éva , Acloque Hervé , Foudi Adlen , Xiang Yao , Ballesta Annabelle , Chang Yunhua , Giron-Michel Julien
Published: May 2021

The circadian clock coordinates biological and physiological functions to day/night cycles. The perturbation of the circadian clock increases cancer risk and affects cancer progression. Here, we studied how BMAL1 knockdown (BMAL1-KD) by shRNA affects the epithelial–mesenchymal transition (EMT), a critical early event in the invasion and metastasis of colorectal carcinoma (CRC). In corresponding to a gene set enrichment analysis, which showed a significant enrichment of EMT and invasive signatures in BMAL1_high CRC patients as compared to BMAL1_low CRC patients, our results revealed that BMAL1 is implicated in keeping the epithelial–mesenchymal equilibrium of CRC cells and influences their capacity of adhesion, migration, invasion, and chemoresistance. Firstly, BMAL1-KD increased the expression of epithelial markers (E-cadherin, CK-20, and EpCAM) but decreased the expression of Twist and mesenchymal markers (N-cadherin and vimentin) in CRC cell lines. Finally, the molecular alterations after BMAL1-KD promoted mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (i.e., HCT116 and SW480) compared to the metastatic cell line SW620. As a consequence, migration/invasion and drug resistance capacities decreased in HCT116 and SW480 BMAL1-KD cells. Together, BMAL1-KD alerts the delicate equilibrium between epithelial and mesenchymal properties of CRC cell lines, which revealed the crucial role of BMAL1 in EMT-related CRC metastasis and chemoresistance.
Mast Cell Proteases Tryptase and Chymase Induce Migratory and Morphological Alterations in Bronchial Epithelial Cells
Authors: Berlin Frida , Mogren Sofia , Tutzauer Julia , Andersson Cecilia K.
Published: May 2021

Chronic respiratory diseases are often characterized by impaired epithelial function and remodeling. Mast cells (MCs) are known to home into the epithelium in respiratory diseases, but the MC-epithelial interactions remain less understood. Therefore, this study aimed to investigate the effect of MC proteases on bronchial epithelial morphology and function. Bronchial epithelial cells were stimulated with MC tryptase and/or chymase. Morphology and epithelial function were performed using cell tracking analysis and holographic live-cell imaging. Samples were also analyzed for motility-associated gene expression. Immunocytochemistry was performed to compare cytoskeletal arrangement. Stimulated cells showed strong alterations on gene, protein and functional levels in several parameters important for maintaining epithelial function. The most significant increases were found in cell motility, cellular speed and cell elongation compared to non-stimulated cells. Also, cell morphology was significantly altered in chymase treated compared to non-stimulated cells. In the current study, we show that MC proteases can induce cell migration and morphological and proliferative alterations in epithelial cells. Thus, our data imply that MC release of proteases may play a critical role in airway epithelial remodeling and disruption of epithelial function.
An Engineered Biliverdin-Compatible Cyanobacteriochrome Enables a Unique Ultrafast Reversible Photoswitching Pathway
Authors: Tachibana Sean R. , Tang Longteng , Zhu Liangdong , Takeda Yuka , Fushimi Keiji , Ueda Yoshibumi , Nakajima Takahiro , Kuwasaki Yuto , Sato Moritoshi , Narikawa Rei , Fang Chong
Published: May 2021

Cyanobacteriochromes (CBCRs) are promising optogenetic tools for their diverse absorption properties with a single compact cofactor-binding domain. We previously uncovered the ultrafast reversible photoswitching dynamics of a red/green photoreceptor AnPixJg2, which binds phycocyanobilin (PCB) that is unavailable in mammalian cells. Biliverdin (BV) is a mammalian cofactor with a similar structure to PCB but exhibits redder absorption. To improve the AnPixJg2 feasibility in mammalian applications, AnPixJg2_BV4 with only four mutations has been engineered to incorporate BV. Herein, we implemented femtosecond transient absorption (fs-TA) and ground state femtosecond stimulated Raman spectroscopy (GS-FSRS) to uncover transient electronic dynamics on molecular time scales and key structural motions responsible for the photoconversion of AnPixJg2_BV4 with PCB (Bpcb) and BV (Bbv) cofactors in comparison with the parent AnPixJg2 (Apcb). Bpcb adopts the same photoconversion scheme as Apcb, while BV4 mutations create a less bulky environment around the cofactor D ring that promotes a faster twist. The engineered Bbv employs a reversible clockwise/counterclockwise photoswitching that requires a two-step twist on ~5 and 35 picosecond (ps) time scales. The primary forward Pfr → Po transition displays equal amplitude weights between the two processes before reaching a conical intersection. In contrast, the primary reverse Po → Pfr transition shows a 2:1 weight ratio of the ~35 ps over 5 ps component, implying notable changes to the D-ring-twisting pathway. Moreover, we performed pre-resonance GS-FSRS and quantum calculations to identify the Bbv vibrational marker bands at ~659,797, and 1225 cm−1. These modes reveal a stronger H-bonding network around the BV cofactor A ring with BV4 mutations, corroborating the D-ring-dominant reversible photoswitching pathway in the excited state. Implementation of BV4 mutations in other PCB-binding GAF domains like AnPixJg4, AM1_1870g3, and NpF2164g5 could promote similar efficient reversible photoswitching for more directional bioimaging and optogenetic applications, and inspire other bioengineering advances.
Excessive Innate Immunity Steers Pathogenic Adaptive Immunity in the Development of Theiler’s Virus-Induced Demyelinating Disease
Authors: Kim Byung S.
Published: May 2021

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.
Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment
Authors: Capurro Valeria , Tomati Valeria , Sondo Elvira , Renda Mario , Borrelli Anna , Pastorino Cristina , Guidone Daniela , Venturini Arianna , Giraudo Alessandro , Mandrup Bertozzi Sine , Musante Ilaria , Bertozzi Fabio , Bandiera Tiziano , Zara Federico , Galietta Luis J. V. , Pedemonte Nicoletta
Published: May 2021

Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.
From Melanocytes to Melanoma Cells: Characterization of the Malignant Transformation by Four Distinctly Different Melanin Fluorescence Spectra (Review)
Authors: Leupold Dieter , Pfeifer Lutz , Hofmann Maja , Forschner Andrea , Wessler Gerd , Haenssle Holger
Published: May 2021

The melanin fluorescence emitted by pigment cells of the human skin has been a central research topic for decades, because melanin, on the one hand, protects against (solar) radiation in the near-UV range, whereas on the other hand, melanocytes are the starting point for the malignant transformation into melanoma. Until recently, however, melanin fluorescence was not accessible in the context of conventional spectroscopy, because it is ultraweak and is overshadowed by the more intense so-called autofluorescence of endogenous fluorophores. The advent of a new method of laser spectroscopy has made this melanin fluorescence measurable in vivo. A stepwise two-photon absorption with 800 nm photons is used, which more selectively excites melanin (dermatofluoroscopy). Our review summarizes the experimental results on melanin fluorescence of the four types of cutaneous pigment cells from healthy and malignant tissues. Outstanding is the finding that different types of melanocytes (i.e., melanocytes of common nevi, versus dysplastic nevi or versus melanoma cells) show characteristically different fluorescence spectra. The possibilities of using this melanin fluorescence for melanoma diagnosis are shown. Moreover, the uniform fluorescence spectra emitted by different melanoma subtypes are essential. Conclusions are drawn about the molecular processes in the melanosomes that determine fluorescence. Finally, experimental suggestions for further investigations are given.
Telocytes and Other Interstitial Cells: From Structure to Function
Authors: Crețoiu Sanda Maria
Published: May 2021

The Special Issue, “Telocytes and Other Interstitial Cells: From Structure to Function” of the International Journal of Molecular Sciences, is dedicated to recent progress in research on interstitial cells [...]