bluuebunny/crossref_metadata_2025 huggingface dataset:
A Randomized, Open-Label Study to Assess Efficacy of Weekly Assumption of Cholecalciferol versus Calcifediol in Older Patients with Hypovitaminosis D
Authors: Okoye Chukwuma , Calsolaro Valeria , Niccolai Filippo , Calabrese Alessia Maria , Franchi Riccardo , Rogani Sara , Coppini Giulia , Morelli Virginia , Caraccio Nadia , Monzani Fabio
Published: January 2022

The aim of this single-center, open-label, randomized controlled study was to evaluate which formulation of vitamin D—between cholecalciferol and calcifediol—is most effective in the treatment of hypovitaminosis D in older adults. Demographic characteristics, clinical history, and comprehensive geriatric assessment were recorded at admission. Eligible patients were randomly assigned an equivalent vitamin D supplement, either with cholecalciferol or calcifediol, from the time of hospital admission to three months after discharge. Among the 140 older patients included (mean age 83 ± 6.6 years, 57.8% females), 69 received cholecalciferol and 71 received calcifediol. The mean plasma values of 25-hydroxyvitamin D3 (25OH-vitamin D3) found at the time of enrollment were 16.8 ± 9.9 ng/mL in patients receiving cholecalciferol and 18.8 ± 13.3 ng/mL in those treated with calcifediol (p = 0.31). At the three month follow-up, the mean concentration of 25OH-vitamin D3 was significantly higher in patients treated with calcifediol than in those receiving cholecalciferol (30.7 ± 8.4 vs. 45.4 ± 9.8 ng/mL, respectively; p < 0.001). Supplementation with either cholecalciferol or calcifediol effectively results in reaching the optimal circulating values of 25OH-vitamin D3 in older patients suffering from hypovitaminosis D. However, supplementation with calcifediol led to average circulating values of 25OH-vitamin D3 that were significantly higher (over 50%) than those obtained with cholecalciferol.
Burden of Chronic Heart Failure in Romania
Authors: Lorenzovici László , Bârzan-Székely Andrea , Farkas-Ráduly Szabolcs , Pană Bogdan C. , Csanádi Marcell , Chiriac Nona Delia , Kaló Zoltán
Published: January 2022

Chronic heart failure (CHF) affects millions of people across the world, with increasing trends in prevalence, putting ever increasing pressure on the healthcare system. The aim of this study was to assess the financial burden of CHF hospital care on the public healthcare sector in Romania by estimating the number of inpatient episodes and the associated costs. Additionally, societal costs associated with missed work and premature death of CHF patients were also estimated. The national claims database was analyzed to estimate the number of CHF patients. Cost data was extracted from a pool of nine public hospitals in Romania. In 2019, 375,037 CHF patient episodes were identified on specific wards at the national level. The average cost calculated for the selected nine hospitals was EUR 996. The calculated weighted national average cost per patient episode was EUR 1002, resulting in a total cost of EUR 376 million at the national level. The cost of workdays missed summed up to EUR 122 million, while the annual costs associated with the premature death of CHF patients was EUR 230 million. In conclusion, the prevalence of CHF in Romania is high, accounting for a large proportion of hospitalizations, which translates into large costs for the national payer.
Prevalence of Frailty in the Middle East: Systematic Review and Meta-Analysis
Authors: Alqahtani Bader A. , Alshehri Mohammed M. , Elnaggar Ragab K. , Alsaad Saad M. , Alsayer Ahmed A. , Almadani Noura , Alhowimel Ahmed , Alqahtani Mohammed , Alenazi Aqeel M.
Published: January 2022

(1) We aimed to systematically search available data on the prevalence of frailty among community-dwelling elders in Middle Eastern countries. The results from available studies are cumulated to provide comprehensive evidence for the prevalence of frailty. (2) Methods: A meta-analysis was done. A literature search was carried out using PRISMA guidelines in PubMed, Web of Science, and SCOPUS websites for studies up to 2020. Inclusion criteria entailed all primary studies conducted in Middle Eastern countries on frailty in community-dwelling older adults aged 60 years and older. (3) Results: A total of 10 studies were selected for this study. Random-effects meta-analysis of nine studies indicated there was a pooled prevalence rate of 0.3924 with a standard error of 0.037. This pooled prevalence point estimate of 0.3924 was statistically significant (p < 0.001). The Egger’s regression test and the trim-fill method for detecting publication bias did not detect any evidence of publication bias in the sample of included studies. The Egger’s regression test was not statistically significant. The trim-fill method indicated zero studies were missing on either side; (4) Conclusions: The study’s findings indicate that the prevalence of frailty is higher in Middle Eastern nations. Despite indications that many of these nations’ populations are rapidly ageing, we presently lack information on the incidence of frailty in these populations; this information is essential to health, policymakers, and social care planning.
The Need for Health Education and Vaccination—Importance of Teacher Training and Family Involvement
Authors: García-Toledano Eduardo , López-Parra Emilio , Cebrián-Martínez Antonio , Palomares-Ruiz Ascensión
Published: January 2022

The health emergency due to COVID-19 has highlighted the importance of vaccination and its impact on social welfare. Inequalities have surfaced that affect the most vulnerable and those millions of children do not receive the necessary vaccines. Health education becomes a fundamental resource for citizens to access universal rights. One thousand people from 76 countries on five continents participated in this research in 2019–2020, from the health, education, and economic sectors. A descriptive cross-sectional study with a quantitative design was used. The instrument used was a correctly validated questionnaire: VACUNASEDUCA. The objectives were to reflect on the adequacy of teacher training and their awareness for the proper use of vaccines and to analyze the knowledge of parents about the consequences of vaccination. The results demonstrate the importance of teacher training and health education, with positive involvement of the family. The most favorable group is female, under 30 years, from the European continent, with a very high Human Development Index (HDI), and from the education sector. In conclusion, it is noted that, within the framework of the fourth industrial revolution, education must be configured with innovative approaches and tools, making it necessary to intervene in the context considering their cultural characteristics and promoting healthy lifestyle habits.
Awareness and Related Factors of Dyslipidemia in Menopausal Women in Korea
Authors: Jeong Jeonghee , Kim Mijin
Published: January 2022

This study aims to identify the awareness of dyslipidemia and the factors affecting it in menopausal women to prevent cardiovascular disease, a major cause of female mortality. This study used data from 2019, the first year of the eighth (2019–2021) Korea National Health and Nutrition Examination Survey conducted by the Korea Disease Control and Prevention Agency. A total of 975 women fulfilled the selection criteria. Dyslipidemia awareness and the related factors were analyzed with SPSS 26.0 complex sample software. Only 27.3% of menopausal women over age 40 with dyslipidemia were aware of the condition. Factors affecting their awareness level were age, subjective health awareness, body mass index, and underlying disease. The prevalence of dyslipidemia in menopausal women was high, but their awareness was significantly low. This finding confirms the need for measures to improve dyslipidemia awareness to prevent cardiovascular diseases in menopausal women.
Oral Hygiene Practice among Hospitalized Patients: An Assessment by Dental Hygiene Students
Authors: Lupi Saturnino Marco , Pascadopoli Maurizio , Maiorani Carolina , Preda Camilla , Trapani Benedetto , Chiesa Alessandro , Esposito Francesca , Scribante Andrea , Butera Andrea
Published: January 2022

Aim: An epidemiological study was carried out, in hospital wards, with the aim of assessing the oral health status of patients subjected to multiple medical treatments. Material and Methods: The study was conducted at Fondazione IRCCS Policlinico San Matteo (Pavia, Italy). A questionnaire was submitted to patients for the evaluation of oral hygiene devices used; then, a clinical examination was conducted to collect Decayed Missing Filled Teeth (DMFT) index, Plaque Index (PI), and Marginal Gingival Index (MGI) values. Results: Manual toothbrushes were used by a wide range of the sample study (65–100% among hospital wards), together with mouthwash (20–80%); interproximal aids were used by few patients (the lowest recorded value was 33.3%). Conclusion: dental hygienists could be integrated into hospital wards as oral hygiene procedure instructors, for the improvement of the oral health conditions of hospitalized patients.
Network Anonymity and Cyberbullying among Chinese Adolescents: A Moderated Mediation Model
Authors: Zhao Lingbo , Wu Yingru , Huang Xiayu , Zhang Lin
Published: January 2022

Cyberbullying is an important issue which prevails among children and adolescents. The present study aimed to investigate the association between network anonymity and cyberbullying behavior and examine the mediating role of network morality and the moderating role of self-control in the linkage of network anonymity and cyberbullying behavior. A total of 620 participants were recruited from three high schools in southeast China and were required to complete a questionnaire measuring network anonymity, cyberbullying behavior, network morality, and self-control. A moderated mediation model was conducted by using PROCESS Macro for SPSS 3.5. The results showed that network anonymity was negatively associated with cyberbullying behavior among Chinese adolescents. Network morality mediated the association and self-control moderated the indirect association between network anonymity and cyberbullying behavior via network morality. These findings indicate that improving the network morality and self-control of adolescents with the joint efforts of individuals, families, government, and society as a whole may be an effective intervention strategy for cyberbullying behavior under the framework of digital citizens.
Scientometric Analysis of Public Health Emergencies: 1994–2020
Authors: Liu Jing , Wang Yujie , Zhang Qian , Wei Jianxiang , Zhou Haihua
Published: January 2022

The purpose of this paper is to summarize the research hotspots and frontiers in the field of public health emergencies (PHE) between 1994–2020 through the scientometric analysis method. In total, 2247 literature works retrieved from the Web of Science core database were analyzed by CiteSpace software, and the results were displayed in knowledge mapping. The overall characteristics analysis showed that the number of publications and authors in the field of PHE kept an upward trend during the past decades, and the United States was in the leading position, followed by China and England. Switzerland has the highest central value and plays an important intermediary role in promoting the integration and exchange of international PHE research achievements. The keyword co-occurrence analysis indicated that COVID-19 was the most high-frequency keyword in this field, and there had been no new keywords for a long time until the outbreak of COVID-19 in 2019. The burst detection analysis showed that the top five burst keywords in terms of burst intensity were zika virus, Ebola, United States, emergency preparedness and microcephaly. The results indicated that the research theme of PHE is closely related to the major infectious diseases in a specific period. It will continue to develop with more attention paid to public health. The conclusions can provide help and reference for the PHE potential researchers.
Closing the Gap on COVID-19 Vaccinations in First Responders and Beyond: Increasing Trust
Authors: Gregory Megan E. , MacEwan Sarah R. , Gaughan Alice A. , Rush Laura J. , Powell Jonathan R. , Kurth Jordan D. , Kenah Eben , Panchal Ashish R. , Scheck McAlearney Ann
Published: January 2022

Although COVID-19 vaccines are widely available in the U.S. and much of the world, many have chosen to forgo this vaccination. Emergency medical services (EMS) professionals, despite their role on the frontlines and interactions with COVID-positive patients, are not immune to vaccine hesitancy. Via a survey conducted in April 2021, we investigated the extent to which first responders in the U.S. trusted various information sources to provide reliable information about COVID-19 vaccines. Those vaccinated generally trusted healthcare providers as a source of information, but unvaccinated first responders had fairly low trust in this information source—a group to which they, themselves, belong. Additionally, regardless of vaccination status, trust in all levels of government, employers, and their community as sources of information was low. Free-response explanations provided some context to these findings, such as preference for other COVID-19 management options, including drugs proven ineffective. A trusted source of COVID-19 vaccination information is not readily apparent. Individuals expressed a strong desire for the autonomy to make vaccination decisions for themselves, as opposed to mandates. Potential reasons for low trust, possible solutions to address them, generalizability to the broader public, and implications of low trust in official institutions are discussed.
Analysis of Movement Entropy during Community Dance Programs for People with Parkinson’s Disease and Older Adults: A Cohort Study
Authors: Gates Peter , Discenzo Fred M. , Kim Jin Hyun , Lemke Zachary , Meggitt Joan , Ridgel Angela L.
Published: January 2022

Dance therapy can improve motor skills, balance, posture, and gait in people diagnosed with Parkinson’s disease (PD) and healthy older adults (OA). It is not clear how specific movement patterns during dance promote these benefits. The purpose of this cohort study was to identify differences and complexity in dance movement patterns among different dance styles for PD and OA participants in community dance programs using approximate entropy (ApEn) analysis. The hypothesis was that PD participants will show greater ApEn during dance than OA participants and that the unique dance style of tango with more pronounced foot technique and sharp direction changes will show greater ApEn than smoother dance types such as foxtrot and waltz characterized by gradual changes in direction and gliding movement with rise and fall. Individuals participated in one-hour community dance classes. Movement data were captured using porTable 3D motion capture sensors attached to the arms, torso and legs. Classes were also video recorded to assist in analyzing the dance steps. Movement patterns were captured and ApEn was calculated to quantify the complexity of movements. Participants with PD had greater ApEn in right knee flexion during dance movements than left knee flexion (p = 0.02), greater ApEn of right than left hip flexion (p = 0.05), and greater left hip rotation than right (p = 0.03). There was no significant difference in ApEn of body movements (p > 0.4) or mean body movements (p > 0.3) at any body-segment in OA. ApEn analysis is valuable for quantifying the degree of control and predictability of dance movements and could be used as another tool to assess the movement control of dancers and aid in the development of dance therapies.
Perceived Discrimination at School and Developmental Outcomes among Bai Adolescents: The Mediating Roles of Self-Esteem and Ethnic Identity
Authors: Zhao Lifen , Ngai Steven Sek-yum
Published: January 2022

Although discrimination is widely acknowledged to impair developmental outcomes among ethnic minority adolescents, literature differentiating discrimination based on personal characteristics and group membership is lacking, especially in Chinese contexts, and the mechanisms of those relationships remain unclear. In response, the study presented here examined whether self-esteem mediates the relationship between perceived academic discrimination and developmental outcomes among such ethnic minority adolescents, and whether ethnic identity mediates the relationship between perceived ethnic discrimination and developmental outcomes. Multistage cluster random sampling performed in Dali and Kunming, China, yielded a sample of 813 Bai adolescents whose data was analysed in structural equation modelling. The results indicate that perceived academic discrimination had a direct negative effect on adolescents’ mental health, while perceived ethnic discrimination had direct negative effects on their behavioural adjustment and social competence. Perceived academic discrimination also indirectly affected adolescents’ behavioural adjustment, mental health, and social competence via self-esteem, whereas perceived ethnic discrimination indirectly affected their behavioural adjustment and social competence via ethnic identity. These findings deepen current understandings of how perceived discrimination, self-esteem, and ethnic identity affect the developmental outcomes of ethnic minority adolescents and provide practical recommendations for policymakers and social workers to promote those outcomes in China.
Impact of Exposome Factors on Epidermal Barrier Function in Patients with Obstructive Sleep Apnea Syndrome
Authors: Romera-Vilchez Maria , Montero-Vilchez Trinidad , Herrero-Fernandez Manuel , Rodriguez-Pozo Juan-Angel , Jimenez-Galvez Gonzalo , Morales-Garcia Concepcion , Buendia-Eisman Agustin , Arias-Santiago Salvador
Published: January 2022

Exposome factors, such as sleep deprivation and diet, could affect skin barrier function. The objectives of this study are to compare skin barrier function between patients with Obstructive Sleep Apnea Syndrome (OSAS) and healthy individuals, and to evaluate the effect of other exposome factors on skin. A cross-sectional study was conducted. Patients with OSAS and healthy volunteers matched by age and sex were included. OSAS severity was assessed by the Apnea-Hypopnea Index (AHI). Validated questionnaires were used to assess diet, anxiety, depression, and psychological stress. Skin barrier function parameters including temperature, erythema, melanin, pH, transepidermal water loss (TEWL), and stratum corneum hydration (SCH) were measured on the volar forearm. A total of 86 participants were included, 56 patients with OSAS and 30 healthy volunteers. TEWL was higher in OSAS patients than in healthy individuals (8.01 vs. 8.68 g·m−2·h−1). Regarding disease severity, severe patients had higher TEWL values (9.31 vs. 8.46 vs. 7.08 g·m−2·h−1) compared to moderate and mild patients. Patients with OSAS had significantly lower sleep quality (11.89 vs. 6.47 Pittsburgh Sleep Quality Index score; p < 0.001), poor adherence to the Mediterranean Diet (8.46 vs. 9.77; p = 0.005), and significantly higher anxiety and depression levels than healthy individuals. In conclusion, patients with OSAS may have skin barrier impairment, reflected in higher TEWL values. These patients also have higher levels of anxiety, depression, stress, and a lower adherence to a Mediterranean Diet, all exposome factors that might impact on skin barrier function.
The Role of Altered Mitochondrial Metabolism in Thyroid Cancer Development and Mitochondria-Targeted Thyroid Cancer Treatment
Authors: Dabravolski Siarhei A. , Nikiforov Nikita G. , Zhuravlev Alexander D. , Orekhov Nikolay A. , Mikhaleva Liudmila M. , Orekhov Alexander N.
Published: January 2022

Thyroid cancer (TC) is the most common type of endocrine malignancy. Tumour formation, progression, and metastasis greatly depend on the efficacy of mitochondria—primarily, the regulation of mitochondria-mediated apoptosis, Ca2+ homeostasis, dynamics, energy production, and associated reactive oxygen species generation. Recent studies have successfully confirmed the mitochondrial aetiology of thyroid carcinogenesis. In this review, we focus on the recent progress in understanding the molecular mechanisms of thyroid cancer relating to altered mitochondrial metabolism. We also discuss the repurposing of known drugs and the induction of mitochondria-mediated apoptosis as a new trend in the development of anti-TC therapy.
Aromatic Sulfonamides including a Sulfonic Acid Tail: New Membrane Impermeant Carbonic Anhydrase Inhibitors for Targeting Selectively the Cancer-Associated Isoforms
Authors: Giovannuzzi Simone , D’Ambrosio Mario , Luceri Cristina , Osman Sameh Mohamed , Pallecchi Marco , Bartolucci Gianluca , Nocentini Alessio , Supuran Claudiu T.
Published: January 2022

We report here a new drug design strategy for producing membrane-impermeant carbonic anhydrase (CA; EC 4.2.1.1) inhibitors selectively targeting the tumor-associated, membrane-bound human CAs IX and XII over off-target cytosolic isoforms. To date, this approach has only been pursued by including permanent positively charged pyridinium type or highly hydrophilic glycosidic moieties into the structure of aromatic sulfonamide CA inhibitors (CAIs). Aliphatic (propyl and butyl) sulfonic acid tails, deprotonated at physiological pH, were thus incorporated onto a benzenesulfonamide scaffold by a common 1,2,3-triazole linker and different types of spacers. Twenty such derivatives were synthesized and tested for their inhibition of target (hCAs IV, IX, and XII) and off-target CAs (hCAs I and II). Most sulfonate CAIs induced a potent inhibition of hCAs II, IX, and XII up to a low nanomolar KI range (0.9–459.4 nM) with a limited target/off-target CA selectivity of action. According to the drug design schedule, a subset of representative derivatives was assessed for their cell membrane permeability using Caco-2 cells and a developed FIA-MS/MS method. The complete membrane impermeability of the sulfonate tailed CAIs (≥98%) validated these negatively charged moieties as being suitable for achieving, in vivo, the selective targeting of the tumor-associated CAs over off-target ones.
Dysregulated Autophagy and Mitophagy in a Mouse Model of Duchenne Muscular Dystrophy Remain Unchanged Following Heme Oxygenase-1 Knockout
Authors: Mucha Olga , Kaziród Katarzyna , Podkalicka Paulina , Rusin Kinga , Dulak Józef , Łoboda Agnieszka
Published: January 2022

Dysregulation of autophagy may contribute to the progression of various muscle diseases, including Duchenne muscular dystrophy (DMD). Heme oxygenase-1 (HO-1, encoded by Hmox1), a heme-degrading enzyme, may alleviate symptoms of DMD, inter alia, through anti-inflammatory properties. In the present study, we determined the role of HO-1 in the regulation of autophagy and mitophagy in mdx animals, a commonly used mouse model of the disease. In the gastrocnemius of 6-week-old DMD mice, the mRNA level of mitophagy markers: Bnip3 and Pink1, as well as autophagy regulators, e.g., Becn1, Map1lc3b, Sqstm1, and Atg7, was decreased. In the dystrophic diaphragm, changes in the latter were less prominent. In older, 12-week-old dystrophic mice, diminished expressions of Pink1 and Sqstm1 with upregulation of Atg5, Atg7, and Lamp1 was depicted. Interestingly, we demonstrated higher protein levels of autophagy regulator, LC3, in dystrophic muscles. Although the lack of Hmox1 in mdx mice influenced blood cell count and the abundance of profibrotic proteins, no striking differences in mRNA and protein levels of autophagy and mitophagy markers were found. In conclusion, we demonstrated complex, tissue, and age-dependent dysregulation of mitophagic and autophagic markers in DMD mice, which are not affected by the additional lack of Hmox1.
Prospects and Applications of Natural Blood-Derived Products in Regenerative Medicine
Authors: Wessely-Szponder Joanna , Zdziennicka Joanna , Junkuszew Andrzej , Latalski Michał , Świeca Michał , Szponder Tomasz
Published: January 2022

Currently, there are a number of therapeutic schemes used for the treatment of various types of musculoskeletal disorders. However, despite the use of new treatment options, therapeutic failure remains common due to impaired and delayed healing, or implant rejection. Faced with this challenge, in recent years regenerative medicine started looking for alternative solutions that could additionally support tissue regeneration. This review aims to outline the functions and possible clinical applications of, and future hopes associated with, using autologous or heterologous products such as antimicrobial peptides (AMPs), microvesicles (MVs), and neutrophil degranulation products (DGP) obtained from circulating neutrophils. Moreover, different interactions between neutrophils and platelets are described. Certain products released from neutrophils are critical for interactions between different immune cells to ensure adequate tissue repair. By acting directly and indirectly on host cells, these neutrophil-derived products can modulate the body’s inflammatory responses in various ways. The development of new formulations based on these products and their clinically proven success would give hope for significant progress in regenerative therapy in human and veterinary medicine.
Cellular Interaction of Human Skin Cells towards Natural Bioink via 3D-Bioprinting Technologies for Chronic Wound: A Comprehensive Review
Authors: Masri Syafira , Zawani Mazlan , Zulkiflee Izzat , Salleh Atiqah , Fadilah Nur Izzah Md , Maarof Manira , Wen Adzim Poh Yuen , Duman Fatih , Tabata Yasuhiko , Aziz Izhar Abd , Bt Hj Idrus Ruszymah Bt Hj , Fauzi Mh Busra
Published: January 2022

Skin substitutes can provide a temporary or permanent treatment option for chronic wounds. The selection of skin substitutes depends on several factors, including the type of wound and its severity. Full-thickness skin grafts (SGs) require a well-vascularised bed and sometimes will lead to contraction and scarring formation. Besides, donor sites for full-thickness skin grafts are very limited if the wound area is big, and it has been proven to have the lowest survival rate compared to thick- and thin-split thickness. Tissue engineering technology has introduced new advanced strategies since the last decades to fabricate the composite scaffold via the 3D-bioprinting approach as a tissue replacement strategy. Considering the current global donor shortage for autologous split-thickness skin graft (ASSG), skin 3D-bioprinting has emerged as a potential alternative to replace the ASSG treatment. The three-dimensional (3D)-bioprinting technique yields scaffold fabrication with the combination of biomaterials and cells to form bioinks. Thus, the essential key factor for success in 3D-bioprinting is selecting and developing suitable bioinks to maintain the mechanisms of cellular activity. This crucial stage is vital to mimic the native extracellular matrix (ECM) for the sustainability of cell viability before tissue regeneration. This comprehensive review outlined the application of the 3D-bioprinting technique to develop skin tissue regeneration. The cell viability of human skin cells, dermal fibroblasts (DFs), and keratinocytes (KCs) during in vitro testing has been further discussed prior to in vivo application. It is essential to ensure the printed tissue/organ constantly allows cellular activities, including cell proliferation rate and migration capacity. Therefore, 3D-bioprinting plays a vital role in developing a complex skin tissue structure for tissue replacement approach in future precision medicine.
Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2
Authors: Barik Sailen
Published: January 2022

Virus infection of eukaryotes triggers cellular innate immune response, a major arm of which is the type I interferon (IFN) family of cytokines. Binding of IFN to cell surface receptors triggers a signaling cascade in which the signal transducer and activator of transcription 2 (STAT2) plays a key role, ultimately leading to an antiviral state of the cell. In retaliation, many viruses counteract the immune response, often by the destruction and/or inactivation of STAT2, promoted by specific viral proteins that do not possess protease activities of their own. This review offers a summary of viral mechanisms of STAT2 subversion with emphasis on degradation. Some viruses also destroy STAT1, another major member of the STAT family, but most viruses are selective in targeting either STAT2 or STAT1. Interestingly, degradation of STAT2 by a few viruses requires the presence of both STAT proteins. Available evidence suggests a mechanism in which multiple sites and domains of STAT2 are required for engagement and degradation by a multi-subunit degradative complex, comprising viral and cellular proteins, including the ubiquitin–proteasomal system. However, the exact molecular nature of this complex and the alternative degradation mechanisms remain largely unknown, as critically presented here with prospective directions of future study.
Radical Scavenging Activity and Pharmacokinetic Properties of Coumarin–Hydroxybenzohydrazide Hybrids
Authors: Antonijević Marko R. , Avdović Edina H. , Simijonović Dušica M. , Milanović Žiko B. , Amić Ana D. , Marković Zoran S.
Published: January 2022

Free radicals often interact with vital proteins, violating their structure and inhibiting their activity. In previous studies, synthesis, characterisation, and the antioxidative properties of the five different coumarin derivatives have been investigated. In the tests of potential toxicity, all compounds exhibited low toxicity with significant antioxidative potential at the same time. In this paper, the radical scavenging activity of the abovementioned coumarin derivatives towards ten different radical species was investigated. It was found that all investigated compounds show good radical scavenging ability, with results that are in correlation with the results published in the previous study. Three additional mechanisms of radical scavenging activity were investigated. It was found that all three mechanisms are thermodynamically plausible and in competition. Interestingly, it was found that products of the Double Hydrogen Atom Transfer (DHAT) mechanism, a biradical species in triplet spin state, are in some cases more stable than singlet spin state analogues. This unexpected trend can be explained by spin delocalisation over the hydrazide bridge and phenolic part of the molecule with a low probability of spin pairing. Besides radical-scavenging activity, the pharmacokinetic and drug-likeness of the coumarin hybrids were investigated. It was found that they exhibit good membrane and skin permeability and potential interactions with P-450 enzymes. Furthermore, it was found that investigated compounds satisfy all criteria of the drug-likeness tests, suggesting they possess a good preference for being used as potential drugs.
Role of Tyrosine Kinase Syk in Thrombus Stabilisation at High Shear
Authors: Perrella Gina , Montague Samantha J. , Brown Helena C. , Garcia Quintanilla Lourdes , Slater Alexandre , Stegner David , Thomas Mark , Heemskerk Johan W. M. , Watson Steve P.
Published: January 2022

Understanding the pathways involved in the formation and stability of the core and shell regions of a platelet-rich arterial thrombus may result in new ways to treat arterial thrombosis. The distinguishing feature between these two regions is the absence of fibrin in the shell which indicates that in vitro flow-based assays over thrombogenic surfaces, in the absence of coagulation, can be used to resemble this region. In this study, we have investigated the contribution of Syk tyrosine kinase in the stability of platelet aggregates (or thrombi) formed on collagen or atherosclerotic plaque homogenate at arterial shear (1000 s−1). We show that post-perfusion of the Syk inhibitor PRT-060318 over preformed thrombi on both surfaces enhances thrombus breakdown and platelet detachment. The resulting loss of thrombus stability led to a reduction in thrombus contractile score which could be detected as early as 3 min after perfusion of the Syk inhibitor. A similar loss of thrombus stability was observed with ticagrelor and indomethacin, inhibitors of platelet adenosine diphosphate (ADP) receptor and thromboxane A2 (TxA2), respectively, and in the presence of the Src inhibitor, dasatinib. In contrast, the Btk inhibitor, ibrutinib, causes only a minor decrease in thrombus contractile score. Weak thrombus breakdown is also seen with the blocking GPVI nanobody, Nb21, which indicates, at best, a minor contribution of collagen to the stability of the platelet aggregate. These results show that Syk regulates thrombus stability in the absence of fibrin in human platelets under flow and provide evidence that this involves pathways additional to activation of GPVI by collagen.
RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival
Authors: Taniue Kenzui , Tanu Tanzina , Shimoura Yuki , Mitsutomi Shuhei , Han Han , Kakisaka Rika , Ono Yusuke , Tamamura Nobue , Takahashi Kenji , Wada Youichiro , Mizukami Yusuke , Akimitsu Nobuyoshi
Published: January 2022

The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies’ datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.
Non-Alcoholic Steatohepatitis (NASH) and Organokines: What Is Now and What Will Be in the Future
Authors: Santos João Paulo Margiotti dos , Maio Mariana Canevari de , Lemes Monike Alves , Laurindo Lucas Fornari , Haber Jesselina Francisco dos Santos , Bechara Marcelo Dib , Prado Pedro Sidnei do , Rauen Eduardo Costa , Costa Fernando , Pereira Barbara Cristina de Abreu , Flato Uri Adrian Prync , Goulart Ricardo de Alvares , Chagas Eduardo Federighi Baisi , Barbalho Sandra Maria
Published: January 2022

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, and enlargement of the diameter of hepatocytes (ballooning hepatocytes), with or without fibrosis. It affects 20% of patients with non-alcoholic fatty liver disease (NAFLD). Due to liver dysfunction and the numerous metabolic changes that commonly accompany the condition (obesity, insulin resistance, type 2 diabetes, and metabolic syndrome), the secretion of organokines is modified, which may contribute to the pathogenesis or progression of the disease. In this sense, this study aimed to perform a review of the role of organokines in NASH. Thus, by combining descriptors such as NASH, organokines, oxidative stress, inflammation, insulin resistance, and dyslipidemia, a search was carried out in the EMBASE, MEDLINE-PubMed, and Cochrane databases of articles published in the last ten years. Insulin resistance, inflammation and mitochondrial dysfunction, fructose, and intestinal microbiota were factors identified as participating in the genesis and progression of NASH. Changes in the pattern of organokines secretion (adipokines, myokines, hepatokines, and osteokines) directly or indirectly contribute to aggravating the condition or compromise homeostasis. Thus, further studies involving skeletal muscle, adipose, bone, and liver tissue as endocrine organs are essential to better understand the modulation of organokines involved in the pathogenesis of NASH to advance in the treatment of this disease.
Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction
Authors: Bartolomé Alberto
Published: January 2022

Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.
Specific Mutations in Aph1 Cause γ-Secretase Activation
Authors: Watanabe Hikari , Yoshida Chika , Hidaka Masafumi , Ogawa Tomohisa , Tomita Taisuke , Futai Eugene
Published: January 2022

Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.
Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies
Authors: Chauvin Stéphanie , Cohen-Tannoudji Joëlle , Guigon Céline J.
Published: January 2022

Estradiol (E2) is a major hormone controlling women fertility, in particular folliculogenesis. This steroid, which is locally produced by granulosa cells (GC) within ovarian follicles, controls the development and selection of dominant preovulatory follicles. E2 effects rely on a complex set of nuclear and extra-nuclear signal transduction pathways principally triggered by its nuclear receptors, ERα and ERβ. These transcription factors are differentially expressed within follicles, with ERβ being the predominant ER in GC. Several ERβ splice isoforms have been identified and display specific structural features, which greatly complicates the nature of ERβ-mediated E2 signaling. This review aims at providing a concise overview of the main actions of E2 during follicular growth, maturation, and selection in human. It also describes the current understanding of the various roles of ERβ splice isoforms, especially their influence on cell fate. We finally discuss how E2 signaling deregulation could participate in two ovarian pathogeneses characterized by either a follicular arrest, as in polycystic ovary syndrome, or an excess of GC survival and proliferation, leading to granulosa cell tumors. This review emphasizes the need for further research to better understand the molecular basis of E2 signaling throughout folliculogenesis and to improve the efficiency of ovarian-related disease therapies.
A Novel Strategy for Creating an Antibacterial Surface Using a Highly Efficient Electrospray-Based Method for Silica Deposition
Authors: Levana Odelia , Hong Soonkook , Kim Se Hyun , Jeong Ji Hoon , Hur Sung Sik , Lee Jin Woo , Kwon Kye-Si , Hwang Yongsung
Published: January 2022

Adhesion of bacteria on biomedical implant surfaces is a prerequisite for biofilm formation, which may increase the chances of infection and chronic inflammation. In this study, we employed a novel electrospray-based technique to develop an antibacterial surface by efficiently depositing silica homogeneously onto polyethylene terephthalate (PET) film to achieve hydrophobic and anti-adhesive properties. We evaluated its potential application in inhibiting bacterial adhesion using both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) bacteria. These silica-deposited PET surfaces could provide hydrophobic surfaces with a water contact angle greater than 120° as well as increased surface roughness (root mean square roughness value of 82.50 ± 16.22 nm and average roughness value of 65.15 ± 15.26 nm) that could significantly reduce bacterial adhesion by approximately 66.30% and 64.09% for E. coli and S. aureus, respectively, compared with those on plain PET surfaces. Furthermore, we observed that silica-deposited PET surfaces showed no detrimental effects on cell viability in human dermal fibroblasts, as confirmed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and live/dead assays. Taken together, such approaches that are easy to synthesize, cost effective, and efficient, and could provide innovative strategies for preventing bacterial adhesion on biomedical implant surfaces in the clinical setting.
Healthy Subcutaneous and Omental Adipose Tissue Is Associated with High Expression of Extracellular Matrix Components
Authors: Soták Matúš , Rajan Meenu Rohini , Clark Madison , Biörserud Christina , Wallenius Ville , Hagberg Carolina E. , Börgeson Emma
Published: January 2022

Obesity is associated with extensive expansion and remodeling of the adipose tissue architecture, including its microenvironment and extracellular matrix (ECM). Although obesity has been reported to induce adipose tissue fibrosis, the composition of the ECM under healthy physiological conditions has remained underexplored and debated. Here, we used a combination of three established techniques (picrosirius red staining, a colorimetric hydroxyproline assay, and sensitive gene expression measurements) to evaluate the status of the ECM in metabolically healthy lean (MHL) and metabolically unhealthy obese (MUO) subjects. We investigated ECM deposition in the two major human adipose tissues, namely the omental and subcutaneous depots. Biopsies were obtained from the same anatomic region of respective individuals. We found robust ECM deposition in MHL subjects, which correlated with high expression of collagens and enzymes involved in ECM remodeling. In contrast, MUO individuals showed lower expression of ECM components but elevated levels of ECM cross-linking and adhesion proteins, e.g., lysyl oxidase and thrombospondin. Our data suggests that subcutaneous fat is more prone to express proteins involved in ECM remodeling than omental adipose tissues. We conclude that a more dynamic ability to deposit and remodel ECM may be a key signature of healthy adipose tissue, and that subcutaneous fat may adapt more readily to changing metabolic conditions than omental fat.
Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review
Authors: Harlacher Eva , Wollenhaupt Julia , Baaten Constance C. F. M. J. , Noels Heidi
Published: January 2022

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.