bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term High Flow Nasal Cannula Therapy in Primary and Secondary Bronchiectasis
Authors: Simioli Francesca , Fiorentino Giuseppe , Cauteruccio Rosa , Coppola Antonietta , Imitazione Pasquale , Marotta Antonella , Di Spirito Valentina , Annunziata Anna
Published: April 2023

Background: Bronchiectasis is the consequence of chronic bronchial inflammation, inappropriate mucus clearance, bacterial colonization, and recurrent or chronic infection. High flow therapy (HFT) is a type of non-invasive respiratory therapy, usually delivered through a nasal cannula interface (HFNC). It delivers heated and humidified air with a stable fraction of inspired oxygen and a wide range of possible flow rates. Aim of the study: Determine the effectiveness of HFNC as add-on therapy in adult primary and secondary bronchiectasis with frequent acute exacerbations (AEs) and/or hospitalizations. Methods: This is a single-center crossover study on long-term home therapy with HFNC in adult bronchiectasis. Pharmacological therapy included pulse therapy with mucolytics and bronchodilators. After one year, all patients were switched to additional HFNC. The temperature range was 31–37 °C. The flow range was 35–60 L/m. FiO2 was 0.21. Results: Seventy-eight patients completed the follow-up; 54% were females; the median age was 70 years (IQR 60–76). The etiology of bronchiectasis was mainly post-infective (51%), COPD related (26%), and congenital (11%). AEs at baseline were 2.81 (±2.15). A significant reduction in AEs was observed after 24 months with a mean of 0.45 (±0.66) (f-ratio value 79.703. p-value < 0.00001). No significant difference was observed after HFNC therapy on FEV1 (2.39 ± 0.87 vs. 2.55 ± 0.82; f-ratio 0.79. p-value 0.45) and FVC (2.73 ± 0.88 vs. 2.84 ± 0.90; f-ratio 0.411. p-value 0.66). A significant reduction in mMRC score was observed after HFNC therapy (2.40 ± 0.81 vs. 0.97 ± 0.97 at 2 months vs. 0.60 ± 0.78 at 24 months; f-ratio value 95.512. p-value < 0.00001). Conclusions: HFNC is a well-tolerated add-on therapy for adult bronchiectasis. Dyspnea improved after 2 months and further after 2 years. The exacerbation rate decreased during the 2 years follow-up. No significant difference was observed in lung function.
Establishing Reference Data for Fitness Assessment of Law Enforcement Officers Using a Qualitative Systematic Review
Authors: Massuça Luís Miguel , Santos Vanessa , Monteiro Luís
Published: April 2023

Physical fitness tests are a standard means of evaluating the competence of police officers. This qualitative review aims (i) to document, compare, and examine the reference values available in the current literature regarding fitness tests for Law Enforcement Officers (LEOs), and (ii) to define reference values for the most used fitness tests to assess and predict police officer performance. A total of 1879 records were collected for review from two major literature databases, PubMed and ScienceDirect. After applying our exclusion criteria, a total of 19 studies were considered. All studies demonstrated acceptable methodological quality in fitness assessment, and the most used components were muscle strength, muscular endurance, muscle power, aerobic and anaerobic capacity, flexibility, and agility. This review provides (i) a methodological definition for the physical fitness assessment that helps select the most used fitness tests, (ii) a standardised methodology for establishing reference data for fitness tests appropriate for LEOs; and (iii) aggregate reference values for selected fitness tests. This may improve selection and retention procedures, considering that this group performs its duties in an environment and under conditions that differ from those of other occupational groups. Complementarily, this qualitative review also provides a foundation for developing effective interventions to improve each aspect of fitness testing for police officers.
Awareness of Food Allergies and Allergens on the Menus of Restaurants and Cafes among Saudi Female University Students
Authors: Aljameel Ghzail M. , AlSedairy Sahar Abdulaziz , Binobead Manal Abdulaziz , Alhussain Maha H. , Bin Obaid Manar Abdulaziz , Al-Harbi Laila Naif , Alshammari Ghedeir M. , Arzoo Shaista
Published: April 2023

Exposure to allergens could be life-threatening for people with food allergies. Restaurants and cafes are challenging environments for accommodating food allergies. This study aimed to measure King Saud University female students’ awareness about food allergens on restaurants’ and cafes’ menus. This cross-sectional study was conducted on 379 students aged 18 years and above. A paper-based questionnaire was used, which comprised 16 questions related to the definition of food allergies, food allergens, and food allergy symptoms; the definition and prevention of cross-contact of food allergies; emergency treatment procedures for food allergies; strategies for the prevention of food allergy reactions; customer expectations towards restaurants; and preventive measures taken for food allergies. The results indicate that the overall average score of food allergen awareness was 10.90, which falls in the higher range. Furthermore, female students in the age groups of 23 to 27 years and 33 to 37 years had higher levels of awareness than female students in the age group of 18 to 22 years. The results also showed that the level of awareness among science college and health college students was statistically significantly higher (p < 0.05) than that among humanities college students. Post-graduate students also showed a higher level of awareness of food allergens than bachelor’s students. These findings also indicate that listing all allergens in the restaurants and cafes’ menus statistically significantly (p < 0.05) increased the level of awareness of female students about food allergens on restaurants’ and cafes’ menus, compared to restaurants and cafes that do not list all allergens on their menus. In general, female students at King Saud University showed a high level of awareness about food allergies on restaurants’ and cafes’ menus. The study recommends assessing the impact of awareness of female students with and without food allergies on their practices and behaviors.
The Association of Eating Behaviour with Physical Activity and Screen Time among Adolescents in the Klang Valley, Malaysia: A Cross-Sectional Study
Authors: Saat N. Z. M. , Hanawi Siti Aishah , Chew Nurul Hasanah Hasmuni , Ahmad Mahadir , Farah Nor M. F. , Kadar Masne , Yahya Hanis Mastura , Warif Nor Malia Abd , Daud Muhammad Khairuddin Md
Published: April 2023

Over the last few decades, the time adolescents spend using electronic devices has increased significantly. The aim of this study was to evaluate the impact of screen time and physical activity on eating behaviour in adolescents. This study used the Physical Activity Questionnaire for Adolescents (PAQ-A) Malay version and the Dutch Eating Behaviour Questionnaire (DEBQ) Malay version methods with secondary students around the Klang Valley. The sampling technique used was purposive sampling. With parents’ consent, an online survey was conducted among adolescent school children aged between 13 and 17 years during the COVID-19 pandemic in the Klang Valley, Malaysia. There were 372 respondents participating in this study. The results showed that 99.4% of them had more than 4 h screen time a day, and that 38.5% have more than three devices at home. Moreover, there was a significant mean difference in screen time for console games without a handheld device between male and female adolescents (p < 0.05). There was also a significant mean difference in the emotional, restricted and external eating behaviour scores between male and female adolescents (p < 0.001). There was a significant relationship between physical activity and the time duration spent on a television, telephone and laptop during weekends (p < 0.05). There was a significant relationship between eating behaviour and time spent watching television and using laptops during weekends (p < 0.05). Based on the moderation model, gender as a moderator variable indicated that there was a significant relationship between screen time and interaction screen time and gender with emotional eating (p < 0.001). Female adolescents had a stronger relationship between screen time and emotional eating compared to male adolescents (p < 0.05). Meanwhile, for physical activity level as a moderator variable, the results showed that there was a significant interaction between screen time and physical activity for emotional eating behaviour (p < 0.05). In conclusion, this study indicates that screen time was higher among female adolescents and significantly related to emotional eating behaviour. Therefore, the educational sector should emphasise the motivation of adolescents to engage in physical activity, reduce their screen time and eat healthy foods such as fruits and vegetables.
Comparison of Frailty Criteria, Cognitive Function, Depressive and Insomnia Symptoms in Men with Localized and Advanced Prostate Cancer under Androgen Deprivation Therapy
Authors: Mafla-España Mayra Alejandra , Torregrosa María Dolores , Beamud-Cortés Manel , Bermell-Marco Lorena , Rubio-Briones José , Cauli Omar
Published: April 2023

Background: Prostate cancer (PCa) is considered one of the most important medical problems in the male population, with a very high incidence after the age of 65. Frailty represents one of the most critical issues facing healthcare due to its inherent relationship with poor healthcare outcomes. The physical phenotype of frailty syndrome based on Fried criteria has been associated with poor outcomes, morbidity, and premature mortality. To date, there are few studies that have analyzed frailty syndrome in patients with localized and advanced (mPCa) disease under androgen-deprivation therapy. Objective: Our goal was to assess whether there are differences in frailty criteria between mPCa and localized PCa. We also evaluated the role of other geriatric variables such as depressive and insomnia symptoms, which are frequently reported in cancer patients. Methods: In this cross-sectional study, frailty syndrome was evaluated in both groups, as well as its possible relationship with cognitive functions, depressive and insomnia symptoms, and other clinical variables related to PCa and its treatment. Frailty was defined on Fried’s criteria: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed; prefrailty was defined as having one or two of those criteria and frailty as having three or more, depressive symptoms were defined by the Yesavage scale, cognitive functions with the Mini-Mental examination test, and insomnia symptoms by the Athens scale and self-reported health status. Results: The prevalence of prefrailty/frailty was slightly higher in mPCa compared to localized PCa (81.5% versus 72.3%, respectively), however by analyzing each of the frailty criteria, two of them were significantly reduced in mPCa compared to localized PCa patients, e.g., gait speed (p = 0.001) and muscle strength (p = 0.04). The reduced gait speed and muscle strength in mPCa were not due to the increased age in mPCa group, or to an increase in comorbidities or shorter time under androgen-deprivation therapy. The symptoms of insomnia were significantly higher in mPCa patients compared to those with localized PCa (p < 0.05) whereas cognitive functions or depressive symptoms were not significantly different between the two groups. Conclusion: Patients with mPCa under androgen-deprivation therapy display higher alterations in gait speed and muscular strength and insomnia symptoms, thus interventions should be aimed to reduce these alterations in order to limit adverse outcomes related to them and to improve quality of life in these patients.
Lessons Learned from the COVID-19 Outbreak as Experienced by ICU Nurses: Manifest Qualitative Content Analysis
Authors: Alharthi Hind , Youssef Hanan A. M. , Al Thobaity Abdulellah , Yassen Ruba W. , Felemban Ebaa M. , Almalki Mohammed , Al-Moteri Modi
Published: April 2023

From the moment the World Health Organization (WHO) declared the coronavirus (COVID-19) a global pandemic, intensive care unit (ICU) nurses struggled to care for the COVID-19 patients. As the pandemic became increasingly critical, the task of daily care for critically ill patients fell upon the shoulders of ICU nurses. Understanding the lived experience of ICU nurses, as well as their perception of the experience, is important to identify key lessons to further improve ICU nurses’ psychological well-being and resilience. This study explored the lived experiences of ICU nurses who cared for COVID-19 patients using exploratory manifest qualitative content analysis. The findings of this study revealed that these ICU nurses offer important information concerning the crucial role of nurses’ family support and religious–spiritual practices in helping them to maintain well-being and cope with the intense situations caused by the pandemic. The lessons emerging from the study findings show that family support and religious–spiritual practices are resources for coping and resilience in times of future pandemics. This implies that ICU nurses who provide care during stressful emergency surges require relief by nurses working in other areas to provide them the opportunity to rest, reconnect with family and become emotionally re-energized.
Historical Textile Dye Analysis Using DESI-MS
Authors: Sandström Edith , Vettorazzo Chiara , Mackay C. Logan , Troalen Lore G. , Hulme Alison N.
Published: April 2023

Desorption electrospray ionization mass spectrometry (DESI-MS) is an ambient mass spectrometry technique that shows great potential for the analysis of fragile heritage objects in situ. This article focuses on the application of a recently built DESI source to characterize natural dyestuffs in historical textiles and a presentation of initial imaging experiments. Optimization of the instrumental settings, geometrical parameters, and solvent system on the DESI-MS analysis was conducted on rhodamine B samples. Some variables, including an increased flow rate, a narrower range of optimized geometrical variables and a solvent system without additives, were applicable to both early synthetic and natural dyes. Direct dye turmeric (Curcuma longa L.) could be reliably analyzed on both silk and wool, as could anthraquinone standards without mordanting. These preliminary results suggest that the dye application process (direct, mordant, vat) has a large impact on the ionization efficiency of DESI-MS. Imaging trials highlighted the suitability of DESI-MS for the analysis of patterned textiles that are difficult to sample, such as calico fabrics, or other currently inaccessible objects.
A Distance Measurement Approach for Large Fruit Picking with Single Camera
Authors: Liu Jie , Zhou Dianzhuo , Wang Yifan , Li Yan , Li Weiqi
Published: April 2023

Target ranging is the premise for manipulators to complete agronomic operations such as picking and field management; however, complex environmental backgrounds and changing crop shapes increase the difficulty of obtaining target distance information based on binocular vision or depth cameras. In this work, a method for ranging large-sized fruit based on monocular vision was proposed to provide a low-cost and low-computation alternative solution for the fruit thinning or picking robot. The regression relationships between the changes in the number of pixels occupied by the target area and the changes in the imaging distance were calculated based on the images of square-shaped checkerboards and circular-shaped checkerboards with 100 cm2, 121 cm2, 144 cm2, 169 cm2, 196 cm2, 225 cm2, 256 cm2, 289 cm2, and 324 cm2 as the area, respectively. The 918 checkerboard images were collected by the camera within the range from 0.25 m to 1.5 m, with 0.025 m as the length of each moving step, and analyzed in MATLAB to establish the ranging models. A total of 2448 images of four oval watermelons, four pyriform pomelos, and four oblate pomelos, as the representatives of large fruit with different shapes, were used to evaluate and optimize the performance of the models. The images of the front were the input, while the imaging distances were the output. The results showed that the absolute error would be less than 0.06 m for both models and would linearly increase with a decrease in the distance. The relative error could be controlled at 5%. The results proved the proposed monocular method could be a solution for the ranging of large fruit targets.
Uncovering the Expansin Gene Family in Pomegranate (Punica granatum L.): Genomic Identification and Expression Analysis
Authors: Xu Xintong , Wang Yuying , Zhao Xueqing , Yuan Zhaohe
Published: April 2023

Expansins, which are important components of plant cell walls, act as loosening factors to directly induce turgor-driven cell wall expansion, regulate the growth and development of roots, leaves, fruits, and other plant organs, and function essentially under environmental stresses. In multiple species, many expansin genes (EXPs) have been cloned and functionally validated but little is known in pomegranate. In this study, a total of 33 PgEXPs were screened from the whole genome data of ‘Taishanhong’ pomegranate, belonging to the EXPA(25), EXPB(5), EXLA(1), and EXLB(2) subfamilies. Subsequently, the composition and characteristics were analyzed. Members of the same branch shared similar motif compositions and gene structures, implying they had similar biological functions. According to cis-acting element analysis, PgEXPs contained many light and hormone response elements in promoter regions. Analysis of RNA-seq data and protein interaction network indicated that PgEXP26 had relatively higher transcription levels in all pomegranate tissues and might be involved in pectin lyase protein synthesis, whilst PgEXP5 and PgEXP31 might be involved in the production of enzymes associated with cell wall formation. Quantitative real-time PCR (qRT-PCR) results revealed that PgEXP expression levels in fruit peels varied considerably across fruit developmental phases. PgEXP23 was expressed highly in the later stages of fruit development, suggesting that PgEXP23 was essential in fruit ripening. On the other hand, the PgEXP28 expression level was minimal or non-detected. Our work laid a foundation for further investigation into pomegranate expansin gene functions.
Interaction Effects of Cultivars and Nutrition on Quality and Yield of Tomato
Authors: Rusu Oana-Raluca , Mangalagiu Ionel , Amăriucăi-Mantu Dorina , Teliban Gabriel-Ciprian , Cojocaru Alexandru , Burducea Marian , Mihalache Gabriela , Roșca Mihaela , Caruso Gianluca , Sekara Agnieszka , Stoleru Vasile
Published: April 2023

Tomato is considered the most important vegetable crop worldwide. Improving the nutritional value of fruits must be based on sustainable production in terms of varieties and fertilization management. This study aimed to improve the nutritional value (total soluble solids, acidity, lycopene, β-carotene, polyphenols, macro and microelements) of two tomato varieties (‘Cristal’ and ‘Siriana’) under three fertilization types (NPK chemical fertilizer, chicken manure and biological fertilizer with microorganisms) for the greenhouse. Primary metabolism compounds do not vary significantly according to the type of fertilizer used. The results for the antioxidant compounds showed a better effect of biological fertilization compared to chemical fertilizer and control unfertilized. Thus, the antioxidant activity was improved by 28% compared to chemical fertilization, the lycopene content by 36% and β-carotene by 96%, respectively. The tomato fruits from the local cultivar (‘Siriana’) are richer in nutritional compounds such as rutin, regardless of the type of fertilization, which denotes a good ability to adapt to crop conditions. Tomato cultivars reacted positively to microbiological fertilization compared to chemical, thus producing nutritious fruits under sustainable management. Tomato fruits were richer in the quality of microelement contents.
Assessing SDI Implementation Scenarios to Facilitate Emergency Mapping Operations in the Dominican Republic
Authors: Rosario Michel Gregorio , Gonzalez-Campos María Ester , Manzano Aybar Fernando , Crompvoets Joep
Published: April 2023

The Dominican Republic (DR) is a small island developing state (SIDS) highly exposed to disaster-risk phenomena, such as earthquakes, hurricanes, etc. The Spatial Data Infrastructure (SDI) enables coordination and sharing of spatial information and services from multiple sources, while emergency mapping operations (EMO) help decision-makers build a common operational picture (COP) of impacted communities. Assessment of future scenarios for SDI implementation to meet emergency mapping goals requires the consideration of a wide range of stakeholders with different objectives. We make use of multi-actor multi-criteria analysis (MAMCA) in the case study of DR to evaluate government, private sector, emergency mapping team (EMT), and academia perspectives of three governance scenarios (Going-Concern, Increasing-Hierarchy, and Increasing-Network) for SDI implementation. Our findings suggest that the ‘Increasing Network’ scenario is the most suitable for SDI implementation. A well-coordinated inter-organizational network through a SDI should empower more stakeholders to participate in EMO. This work highlighted the increase of public-private partnerships as a key criterion to share costs and efforts to effectively support emergency mapping tasks. Findings reported herein could assist decision-makers in designing roadmaps to enhance SDI implementation in the DR. This knowledge will also support future studies/practices in other SIDS, which share similar natural hazards and development issues.
Multiplexing Biosensor for the Detection of Extracellular Vesicles as Biomarkers of Tissue Damage and Recovery after Ischemic Stroke
Authors: Picciolini Silvia , Mangolini Valentina , Rodà Francesca , Montesano Angelo , Arnaboldi Francesca , Liuzzi Piergiuseppe , Mannini Andrea , Bedoni Marzia , Gualerzi Alice
Published: April 2023

The inflammatory, reparative and regenerative mechanisms activated in ischemic stroke patients immediately after the event cooperate in the response to injury, in the restoration of functions and in brain remodeling even weeks after the event and can be sustained by the rehabilitation treatment. Nonetheless, patients’ response to treatments is difficult to predict because of the lack of specific measurable markers of recovery, which could be complementary to clinical scales in the evaluation of patients. Considering that Extracellular Vesicles (EVs) are carriers of multiple molecules involved in the response to stroke injury, in the present study, we have identified a panel of EV-associated molecules that (i) confirm the crucial involvement of EVs in the processes that follow ischemic stroke, (ii) could possibly profile ischemic stroke patients at the beginning of the rehabilitation program, (iii) could be used in predicting patients’ response to treatment. By means of a multiplexing Surface Plasmon Resonance imaging biosensor, subacute ischemic stroke patients were proven to have increased expression of vascular endothelial growth factor receptor 2 (VEGFR2) and translocator protein (TSPO) on the surface of small EVs in blood. Besides, microglia EVs and endothelial EVs were shown to be significantly involved in the intercellular communications that occur more than 10 days after ischemic stroke, thus being potential tools for the profiling of patients in the subacute phase after ischemic stroke and in the prediction of their recovery.
Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors
Authors: Ji Cheng
Published: April 2023

Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.
The CFTR Gene Germline Heterozygous Pathogenic Variants in Russian Patients with Malignant Neoplasms and Healthy Carriers: 11,800 WGS Results
Authors: Makarova Maria , Nemtsova Marina , Danishevich Anastasiia , Chernevskiy Denis , Belenikin Maxim , Krinitsina Anastasiia , Baranova Elena , Sagaydak Olesya , Vorontsova Maria , Khatkov Igor , Zhukova Lyudmila , Bodunova Natalia , Nikolaev Sergey , Byakhova Mariya , Semenova Anna , Galkin Vsevolod , Gadzhieva Saida
Published: April 2023

More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer.
The State of Research and Weight of Evidence on the Epigenetic Effects of Bisphenol A
Authors: Besaratinia Ahmad
Published: April 2023

Bisphenol A (BPA) is a high-production-volume chemical with numerous industrial and consumer applications. BPA is extensively used in the manufacture of polycarbonate plastics and epoxy resins. The widespread utilities of BPA include its use as internal coating for food and beverage cans, bottles, and food-packaging materials, and as a building block for countless goods of common use. BPA can be released into the environment and enter the human body at any stage during its production, or in the process of manufacture, use, or disposal of materials made from this chemical. While the general population is predominantly exposed to BPA through contaminated food and drinking water, non-dietary exposures through the respiratory system, integumentary system, and vertical transmission, as well as other routes of exposure, also exist. BPA is often classified as an endocrine-disrupting chemical as it can act as a xenoestrogen. Exposure to BPA has been associated with developmental, reproductive, cardiovascular, neurological, metabolic, or immune effects, as well as oncogenic effects. BPA can disrupt the synthesis or clearance of hormones by binding and interfering with biological receptors. BPA can also interact with key transcription factors to modulate regulation of gene expression. Over the past 17 years, an epigenetic mechanism of action for BPA has emerged. This article summarizes the current state of research on the epigenetic effects of BPA by analyzing the findings from various studies in model systems and human populations. It evaluates the weight of evidence on the ability of BPA to alter the epigenome, while also discussing the direction of future research.
Exploring the Genetic Predisposition to Epigenetic Changes in Alzheimer’s Disease
Authors: Bryzgalov Leonid O. , Korbolina Elena E. , Merkulova Tatiana I.
Published: April 2023

Alzheimer’s disease (AD) is a prevalent type of dementia in elderly populations with a significant genetic component. The accumulating evidence suggests that AD involves a reconfiguration of the epigenetic landscape, including DNA methylation, post-translational modification of histone proteins, and chromatin remodeling. Along with environmental factors, individual specific genetic features play a considerable role in the formation of epigenetic architecture. In this study, we attempt to identify the non-coding regulatory SNPs (rSNPs) able to affect the epigenetic mechanisms in AD. To this end, the multi-omics approach is used. The GEO (Gene Expression Omnibus) available data (GSE153875) for AD patients and controls are integrated to reveal the rSNPs that display allele-specific features in both ChIP-seq profiles of four histone modifications and RNA-seq. Furthermore, we analyze the presence of rSNPs in the promoters of genes reported to be differentially expressed between AD and the normal brain (AD-related genes) and involved in epigenetic regulation according to the EpiFactors database. We also searched for the rSNPs in the promoters of the genes coding for transcription regulators of the identified AD-related genes. These regulators were selected based on the corresponding ChIP-seq peaks (ENCODE) in the promoter regions of these genes. Finally, we formed a panel of rSNPs localized to the promoters of genes that contribute to the epigenetic landscape in AD and, thus, to the genetic predisposition for this disease.
Immunosenescence and Skin: A State of Art of Its Etiopathogenetic Role and Crucial Watershed for Systemic Implications
Authors: Papa Vincenzo , Li Pomi Federica , Borgia Francesco , Vaccaro Mario , Pioggia Giovanni , Gangemi Sebastiano
Published: April 2023

Immunosenescence is a complex multifactorial phenomenon consisting of wide-ranging remodeling of the immune system during the life span, resulting in an age-related qualitative–quantitative decline of immune cells and cytokines. A growing body of evidence in the international literature is highlighting the etiopathogenetic role of skin immunosenescence in the onset of various dermatologic conditions. Skin immunosenescence also serves as an interesting watershed for the onset of system-wide conditions in the context of allergic inflammation. Moreover, in recent years, an increasingly emerging and fascinating etiopathogenetic parallelism has been observed between some mechanisms of immunosenescence, both at cutaneous and systemic sites. This would help to explain the occurrence of apparently unconnected comorbidities. Throughout our review, we aim to shed light on emerging immunosenescent mechanisms shared between dermatologic disorders and other organ-specific diseases in the context of a more extensive discussion on the etiopathogenetic role of skin immunosenescence. A promising future perspective would be to focus on better understanding the mutual influence between skin and host immunity, as well as the influence of high inter-individual variability on immunosenescence/inflammaging. This can lead to a more comprehensive “immunobiographic” definition of each individual.
NanoLuc Luciferase as a Fluorogen-Activating Protein for GFP Chromophore Based Fluorogens
Authors: Bogdanova Yulia A. , Zaitseva Elvira R. , Smirnov Alexander Yu. , Baleeva Nadezhda S. , Gavrikov Alexey S. , Myasnyanko Ivan N. , Goncharuk Sergey A. , Kot Erik F. , Mineev Konstantin S. , Mishin Alexander S. , Baranov Mikhail S.
Published: April 2023

In this work, we showed that the well-known NanoLuc luciferase can act as a fluorogen activating protein for various arylidene-imidazolones structurally similar to the Kaede protein chromophore. We showed that such compounds can be used as fluorescent sensors for this protein and can also be used in pairs with it in fluorescent microscopy as a genetically encoded tag.
Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration
Authors: Vogiatzi Angeliki , Keklikoglou Kleoniki , Makris Konstantinos , Argyrou Dionysia Stamatia , Zacharopoulos Athanasios , Sotiropoulou Varvara , Parthenios Nikolaos , Gkikas Angelos , Kokkori Maria , Richardson Melodie S. W. , Fenwick Aimée L. , Archontidi Sofia , Arvanitidis Christos , Robertson Jeremy , Parthenios John , Zacharakis Giannis , Twigg Stephen R. F. , Wilkie Andrew O. M. , Mavrothalassitis George
Published: April 2023

ETS2 repressor factor (ERF) insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease. Erf insufficiency appears to cause an initially compromised frontal bone formation and subsequent multisuture synostosis, reflecting distinct roles of Erf on the cells that give rise to skull and facial bones. We treated animals with Mek1/2 and nuclear export inhibitors, U0126 and KPT-330, respectively, to increase Erf activity by two independent pathways. We implemented both a low dosage locally over the calvaria and a systemic drug administration scheme to evaluate the possible indirect effects from other systems and minimize toxicity. The treatment of mice with either the inhibitors or the administration scheme alleviated the synostosis phenotype with minimal adverse effects. Our data suggest that the ERF level is an important regulator of cranial bone development and that pharmacological modulation of its activity may represent a valid intervention approach both in CRS4 and in other syndromic forms of craniosynostosis mediated by the FGFR-RAS-ERK-ERF pathway.
Molecular Mechanisms Underlying the Progression of Aortic Valve Stenosis: Bioinformatic Analysis of Signal Pathways and Hub Genes
Authors: Tojo Taiki , Yamaoka-Tojo Minako
Published: April 2023

The calcification of the aortic valve causes increased leaflet stiffness and leads to the development and progression of stenotic aortic valve disease. However, the molecular and cellular mechanisms underlying stenotic calcification remain poorly understood. Herein, we examined the gene expression associated with valve calcification and the progression of calcific aortic valve stenosis. We downloaded two publicly available gene expression profiles (GSE83453 and GSE51472) from NCBI-Gene Expression Omnibus database for the combined analysis of samples from human aortic stenosis and normal aortic valve tissue. After identifying the differentially expressed genes (DEGs) using the GEO2R online tool, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We also analyzed the protein–protein interactions (PPIs) of the DEGs using the NetworkAnalyst online tool. We identified 4603 upregulated and 6272 downregulated DEGs, which were enriched in the positive regulation of cell adhesion, leukocyte-mediated immunity, response to hormones, cytokine signaling in the immune system, lymphocyte activation, and growth hormone receptor signaling. PPI network analysis identified 10 hub genes: VCAM1, FHL2, RUNX1, TNFSF10, PLAU, SPOCK1, CD74, SIPA1L2, TRIB1, and CXCL12. Through bioinformatic analysis, we identified potential biomarkers and therapeutic targets for aortic stenosis, providing a theoretical basis for future studies.
Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents
Authors: Bertašiūtė Monika , Kavaliauskas Povilas , Vaickelionienė Rita , Grybaitė Birutė , Petraitis Vidmantas , Petraitienė Rūta , Naing Ethan , Garcia Andrew , Šiugždaitė Jūratė , Lelešius Raimundas , Mickevičius Vytautas
Published: April 2023

Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathogens. In this study, we explored 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid and its 3,5-dichloro-2-hydroxyphenyl analogue for their in vitro antimicrobial activity against multidrug-resistant pathogens. The compounds showed structure-dependent antimicrobial activity against Gram-positive pathogens (S. aureus, E. faecalis, C. difficile). Compounds 14 and 24b showed promising activity against vancomycin-intermediate S. aureus strains, and favorable cytotoxic profiles in HSAEC-1 cells, making them attractive scaffolds for further development. 5-Fluorobenzimidazole, having a 3,5-dichloro-2-hydroxyphenyl substituent, was found to be four-fold, and hydrazone, with a thien-2-yl fragment, was two-fold stronger than clindamycin against methicillin resistant S. aureus TCH 1516. Moreover, hydrazone, bearing a 5-nitrothien-2-yl moiety, showed promising activity against three tested multidrug-resistant C. auris isolates representing major genetic lineages (MIC 16 µg/mL) and azole-resistant A. fumigatus strains harboring TR34/L98H mutations in the CYP51A gene. The anticancer activity characterization demonstrated that the 5-fluorobenzimidazole derivative with a 3,5-dichloro-2-hydroxyphenyl substituent showed the highest anticancer activity in an A549 human pulmonary cancer cell culture model. Collectively these results demonstrate that 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives could be further explored for the development of novel candidates targeting Gram-positive pathogens and drug-resistant fungi.
Combined Metabolome and Transcriptome Analysis Highlights the Host’s Influence on Cistanche deserticola Metabolite Accumulation
Authors: Feng Ru , Wei Hongshuang , Xu Rong , Liu Sai , Wei Jianhe , Guo Kun , Qiao Haili , Xu Changqing
Published: April 2023

The medicinal plant Cistanche deserticola Ma (Orobanchaceae) is a holoparasitic angiosperm that takes life-essential materials from Haloxylon ammodendron (C. A. Mey.) Bunge (Amaranthaceae) roots. Although many experiments have been conducted to improve the quality of C. deserticola, little attention has been paid to the host’s influence on metabolite accumulation. In this study, transcriptomic and metabolomic analyses were performed to unveil the host’s role in C. deserticola’s metabolite accumulation, especially of phenylethanoid glycosides (PhGs). The results indicate that parasitism by C. deserticola causes significant changes in H. ammodendron roots in relation to metabolites and genes linked to phenylalanine metabolism, tryptophan metabolism and phenylpropanoid biosynthesis pathways, which provide precursors for PhGs. Correlation analysis of genes and metabolites further confirms that C. deserticola’s parasitism affects PhG biosynthesis in H. ammodendron roots. Then we found specific upregulation of glycosyltransferases in haustoria which connect the parasites and hosts. It was shown that C. deserticola absorbs PhG precursors from the host and that glycosylation takes place in the haustorium. We mainly discuss how the host resists C. deserticola parasitism and how this medicinal parasite exploits its unfavorable position and takes advantage of host-derived metabolites. Our study highlights that the status of the host plant affects not only the production but also the quality of Cistanches Herba, which provides a practical direction for medicinal plant cultivation.
Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats
Authors: Karádi David Á. , Galambos Anna Rita , Lakatos Péter P. , Apenberg Joost , Abbood Sarah K. , Balogh Mihály , Király Kornél , Riba Pál , Essmat Nariman , Szűcs Edina , Benyhe Sándor , Varga Zoltán V. , Szökő Éva , Tábi Tamás , Al-Khrasani Mahmoud
Published: April 2023

Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [35S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose–response curve of morphine in the [35S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component.
Extracellular Vesicles Isolation from Large Volume Samples Using a Polydimethylsiloxane-Free Microfluidic Device
Authors: Bajo-Santos Cristina , Priedols Miks , Kaukis Pauls , Paidere Gunita , Gerulis-Bergmanis Romualds , Mozolevskis Gatis , Abols Arturs , Rimsa Roberts
Published: April 2023

Extracellular vesicles (EV) have many attributes important for biomedicine; however, current EV isolation methods require long multi-step protocols that generally involve bulky equipment that cannot be easily translated to clinics. Our aim was to design a new cyclic olefin copolymer–off-stoichiometry thiol-ene (COC–OSTE) asymmetric flow field fractionation microfluidic device that could isolate EV from high-volume samples in a simple and efficient manner. We tested the device with large volumes of urine and conditioned cell media samples, and compared it with the two most commonly used EV isolation methods. Our device was able to separate particles by size and buoyancy, and the attained size distribution was significantly smaller than other methods. This would allow for targeting EV size fractions of interest in the future. However, the results were sample dependent, with some samples showing significant improvement over the current EV separation methods. We present a novel design for a COC–OSTE microfluidic device, based on bifurcating asymmetric flow field-flow fractionation (A4F) technology, which is able to isolate EV from large volume samples in a simple, continuous-flow manner. Its potential to be mass-manufactured increases the chances of implementing EV isolation in a clinical or industry-friendly setting, which requires high repeatability and throughput.
Autophagy in Cancer Progression and Therapeutics
Authors: Kantserova Kamilla , Ulasov Ilya
Published: April 2023

Autophagy is a catabolic process that is necessary for cellular homeostasis maintenance [...]
Single-Cell RNA Sequencing Reveals Atlas of Yak Testis Cells
Authors: Wang Xingdong , Pei Jie , Xiong Lin , Guo Shaoke , Cao Mengli , Kang Yandong , Ding Ziqiang , La Yongfu , Liang Chunnian , Yan Ping , Guo Xian
Published: April 2023

Spermatogenesis is a complex process that involves proliferation and differentiation of diploid male germ cells into haploid flagellated sperm and requires intricate interactions between testicular somatic cells and germ cells. The cellular heterogeneity of this process presents a challenge in analyzing the different cell types at various developmental stages. Single-cell RNA sequencing (scRNA-seq) provides a useful tool for exploring cellular heterogeneity. In this study, we performed a comprehensive and unbiased single-cell transcriptomic study of spermatogenesis in sexually mature 4-year-old yak using 10× Genomics scRNA-seq. Our scRNA-seq analysis identified six somatic cell types and various germ cells, including spermatogonial stem cells, spermatogonia, early-spermatocytes, late-spermatocytes, and spermatids in yak testis. Pseudo-timing analysis showed that Leydig and myoid cells originated from common progenitor cells in yaks. Moreover, functional enrichment analysis demonstrated that the top expressed genes in yak testicular somatic cells were significantly enriched in the cAMP signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and ECM receptor interactions. Throughout the spermatogenesis process, genes related to spermatogenesis, cell differentiation, DNA binding, and ATP binding were expressed. Using immunohistochemical techniques, we identified candidate marker genes for spermatogonial stem cells and Sertoli cells. Our research provides new insights into yak spermatogenesis and the development of various types of cells in the testis, and presents more reliable marker proteins for in vitro culture and identification of yak spermatogonial stem cells in the later stage.
The Role of the Estrogen-Related Receptor Alpha (ERRa) in Hypoxia and Its Implications for Cancer Metabolism
Authors: Chaltel-Lima Leslie , Domínguez Fabiola , Domínguez-Ramírez Lenin , Cortes-Hernandez Paulina
Published: April 2023

Under low oxygen conditions (hypoxia), cells activate survival mechanisms including metabolic changes and angiogenesis, which are regulated by HIF-1. The estrogen-related receptor alpha (ERRα) is a transcription factor with important roles in the regulation of cellular metabolism that is overexpressed in hypoxia, suggesting that it plays a role in cell survival in this condition. This review enumerates and analyses the recent evidence that points to the role of ERRα as a regulator of hypoxic genes, both in cooperation with HIF-1 and through HIF-1- independent mechanisms, in invertebrate and vertebrate models and in physiological and pathological scenarios. ERRα’s functions during hypoxia include two mechanisms: (1) direct ERRα/HIF-1 interaction, which enhances HIF-1′s transcriptional activity; and (2) transcriptional activation by ERRα of genes that are classical HIF-1 targets, such as VEGF or glycolytic enzymes. ERRα is thus gaining recognition for its prominent role in the hypoxia response, both in the presence and absence of HIF-1. In some models, ERRα prepares cells for hypoxia, with important clinical/therapeutic implications.