bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine Learning Algorithms for Lithofacies Classification of the Gulong Shale from the Songliao Basin, China
Authors: Hou Mingqiu , Xiao Yuxiang , Lei Zhengdong , Yang Zhi , Lou Yihuai , Liu Yuming
Published: March 2023

Lithofacies identification and classification are critical for characterizing the hydrocarbon potential of unconventional resources. Although extensive applications of machine learning models in predicting lithofacies have been applied to conventional reservoir systems, the effectiveness of machine learning models in predicting clay-rich, lacustrine shale lithofacies has yet to be tackled. Here, we apply machine learning models to conventional well log data to automatically identify the shale lithofacies of Gulong Shale in the Songliao Basin. The shale lithofacies were classified into six types based on total organic carbon and mineral composition data from core analysis and geochemical logs. We compared the accuracy of Multilayer Perceptron (MLP), Support Vector Machine (SVM), Extreme Gradient Boosting (XGBoost), and Random Forest models. We mitigated the bias of imbalanced data by applying oversampling algorithms. Our results show that ensemble methods (XGBoost and Random Forest) have a better performance in shale lithofacies identification than the other models do, with accuracies of 0.868 and 0.884, respectively. The organic siliceous shale proposed to have the best hydrocarbon potential in Gulong Shale can be identified with F1 scores of 0.853 by XGBoost and 0.877 by Random Forest. Our study suggests that ensemble machine learning models can effectively identify the lithofacies of clay-rich shale from conventional well logs, providing insight into the sweet spot prediction of unconventional reservoirs. Further improvements in model performances can be achieved by adding domain knowledge and employing advanced well log data.
Vine Foliar Treatments at Veraison and Post-Veraison with Methyl Jasmonate Enhanced Aromatic, Phenolic and Nitrogen Composition of Tempranillo Blanco Grapes
Authors: Sáenz de Urturi Itziar , Ribeiro-Gomes Freud M. , Marín-San Román Sandra , Murillo-Peña Rebeca , Torres-Díaz Lesly , González-Lázaro Miriam , Pérez-Álvarez Eva P. , Garde-Cerdán Teresa
Published: March 2023

Methyl jasmonate (MeJ) is an elicitor that, when applied in the vineyard, can improve grape quality. There are several studies about the MeJ influence on red grape varieties; however, to our knowledge, there is little information about white grape varieties, specifically Tempranillo Blanco. Therefore, the aim of this work is to evaluate the effect of MeJ foliar treatments, carried out at veraison and post-veraison, on the aromatic, phenolic and nitrogen composition of Tempranillo Blanco grapes. The results showed that grape volatile compounds content increased after MeJ application, especially terpenoids, C13 norisoprenoids, benzenoids and alcohols, and, in general, mainly at post-veraison. Regarding phenolic and nitrogen compounds, their concentrations were enhanced after MeJ treatments, regardless of application time. Consequently, MeJ treatment improved grape volatile, phenolic and nitrogen composition, particularly when this elicitor was applied post-veraison. Therefore, this is a good and easy tool to modulate white grape quality.
Effect of Physicochemical Characteristics and Storage Atmosphere on Microbiological Stability and Shelf-Life of Minimally Processed European Sea Bass (Dicentrarchus labrax) Fillets
Authors: Anagnostopoulos Dimitrios , Parlapani Foteini , Tsara Evangelia , Eirinaki Maria , Kokioumi Despoina , Ampatzidou Evdoxia , Boziaris Ioannis
Published: March 2023

The aim of the present work was to evaluate the effect of various hurdles such as aw and pH as well as the storage atmosphere on the microbiological and sensory changes of minimally processed (lightly brined or marinated with acetic or citric acid) European sea bass (Dicentrarchus labrax) fillets. The results indicated that the shelf-life of brined fillets stored aerobically was 6 d while that of vacuum and MAP-stored was 12 d, since a reduced growth rate of spoilage bacteria was recorded. The physicochemical characteristics such as aw and water phase salt (WPS) were not considerably changed, while the oxygen levels into the packages ensure the microbiological safety of the product. The fillets marinated with acetic acid exhibited a longer shelf-life at 30 and 40 d under aerobic and reduced oxygen conditions, respectively, while the products marinated with citric acid were at 25 and 35 d respectively. A low pH resulted in reduced or even limited microbial levels, especially for the fillets marinated with acetic acid; something that ensures microbiological safety as well. The low or limited microbial levels in conjugation with the sensory attributes indicated that spoilage may be due to other mechanisms such as autolysis rather than microbial activity. Overall, the present work highlights the potential for further research and development of minimally processed, microbiologically safe and stable with extended shelf-life value added seafood to satisfy the corresponding consumer demands.
A Reinforcement Learning Framework to Discover Natural Flavor Molecules
Authors: Queiroz Luana P. , Rebello Carine M. , Costa Erbet A. , Santana Vinícius V. , Rodrigues Bruno C. L. , Rodrigues Alírio E. , Ribeiro Ana M. , Nogueira Idelfonso B. R.
Published: March 2023

Flavor is the focal point in the flavor industry, which follows social tendencies and behaviors. The research and development of new flavoring agents and molecules are essential in this field. However, the development of natural flavors plays a critical role in modern society. Considering this, the present work proposes a novel framework based on scientific machine learning to undertake an emerging problem in flavor engineering and industry. It proposes a combining system composed of generative and reinforcement learning models. Therefore, this work brings an innovative methodology to design new flavor molecules. The molecules were evaluated regarding synthetic accessibility, the number of atoms, and the likeness to a natural or pseudo-natural product. This work brings as contributions the implementation of a web scraper code to sample a flavors database and the integration of two scientific machine learning techniques in a complex system as a framework. The implementation of the complex system instead of the generative model by itself obtained 10% more molecules within the optimal results. The designed molecules obtained as an output of the reinforcement learning model’s generation were assessed regarding their existence or not in the market and whether they are already used in the flavor industry or not. Thus, we corroborated the potentiality of the framework presented for the search of molecules to be used in the development of flavor-based products.
Comparative Metabolomic Analysis of the Nutritional Aspects from Ten Cultivars of the Strawberry Fruit
Authors: Wang Xinlu , Wu Linxia , Qiu Jing , Qian Yongzhong , Wang Meng
Published: March 2023

Strawberry (Fragaria × ananassa) is among the most widely cultivated fruits with good taste and rich nutrients. Many strawberry species, including white strawberries, are planted all over the world. The metabolic profiles of strawberry and distinctions among different cultivars are not fully understood. In this study, non-targeted metabolomics based on UHPLC-Q-Exactive Orbitrap MS was used to analysis the metabolites in 10 strawberry species. A total of 142 compounds were identified and were divided into six categories. Tochiotome may differ most from the white strawberry (Baiyu) by screening 72 differential metabolites. Histidine, apigenin, cyanidin 3-glucoside and peonidin 3-glucoside had potential as biomarkers for distinguishing Baiyu and another 11 strawberry groups. Amino acid metabolisms, anthocyanin biosynthesis and flavonoid biosynthesis pathways were mainly involved in the determination of the nutrition distinctions. This research contributes to the determination of the nutrition and health benefits of different strawberry species.
Technological Characterization of Lactic Acid Bacteria Strains for Potential Use in Cheese Manufacture
Authors: Nicosia Fabrizio Domenico , Pino Alessandra , Maciel Guilherme Lembi Ramalho , Sanfilippo Rosamaria Roberta , Caggia Cinzia , de Carvalho Antonio Fernandes , Randazzo Cinzia Lucia
Published: March 2023

A total of 26 lactic acid bacteria isolates from both Italian and Brazilian cheeses were tested for their use in cheesemaking. Isolates were screened for salt tolerance, exopolysaccharide and diacetyl production, lipolytic, acidifying, and proteolytic activities. In addition, the aminopeptidase (Pep N and Pep X) activities, were evaluated. Most of the strains demonstrated salt tolerance to 6% of NaCl, while only two L. delbruekii (P14, P38), one L. rhamnosus (P50) and one L. plantarum (Q3C4) were able to grow in the presence of 10% (w/v) of NaCl. Except for 2 L. plantarum (Q1C6 and Q3C4), all strains showed low or medium acidifying activity and good proteolytic features. Furthermore, lipolytic activity was revealed in none of the strains, while the production of EPS and diacetyl was widespread and variable among the tested strains. Finally, regarding aminopeptidase activities, 1 L. delbrueckii (P10), 1 L. rhamnosus (P50), and 1 L. lactis (Q5C6) were considered as the better performing, showing high values of both Pep N and Pep X. Based on data presented here, the aforementioned strains could be suggested as promising adjunct cultures in cheesemaking.
Glyphosate and Glufosinate Residues in Honey and Other Hive Products
Authors: Rampazzo Giulia , Gazzotti Teresa , Zironi Elisa , Pagliuca Giampiero
Published: March 2023

Hive products have numerous beneficial properties; however, the hive’s health is affected by the surrounding environment. The widespread use of herbicides in agriculture, such as glyphosate and glufosinate, has raised alarm among consumers, beekeepers, and environmentalists due to their potential to harm bees and humans through the consumption of bee products. This review aims to provide a comprehensive overview of the presence of glyphosate, glufosinate, and their metabolites in hive products, collecting and comparing available data from peer-reviewed research and surveys conducted across several countries. Moreover, it analyzes and discusses the potential impacts of these substances on human and bee health, analytical aspects, and recent regulatory developments. The data has revealed that these substances can be present in the different matrices tested, but the concentrations found are usually lower than the maximum residue limits set. However, the use of different methodologies with non-uniform analytical performances, together with an incomplete search for regulated analytes, leads to heterogeneity and makes comparisons challenging. In addition to the completion of studies on the toxicology of herbicide active ingredients, further monitoring actions are necessary, harmonizing analytical methodologies and data management procedures.
Evaluating the Effect of Overburden Depth, Mining Height, and Support Density on Coal Rib Damage Using DEM Modeling
Authors: Sunkpal Maurice , Sherizadeh Taghi , Guner Dogukan
Published: March 2023

There has been a global effort in the past decade, especially in major coal-producing countries, toward understanding the mechanics involved in the stability of coal mine ribs. Buckling and spalling of mine ribs are known to have an impact on their stability and degradation. The generation, propagation, and coalescence of cracks in mine pillar ribs are significantly affected by the overburden depths. In addition, the in situ stress magnitudes tend to affect the rib damage process. High horizontal stresses and increased depths can lead to unfavorable stress conditions, inducing coal mass damage and strength loss. Understanding the dynamics involved in rib behavior will inform better rib control practices. This study intended to assess the effect of mining depth, mining height, and supports on coal mine rib stability. In this research, the response of the coal mass was studied using distinct element modeling to better understand the failure process of coal mine ribs. The study confirmed mining depth as a significant factor controlling the rib loading and failure mechanism. In addition, increased mining heights increased the rib deformation and failure process. The evaluated support effect revealed that at shallower depths, shorter bolt lengths are sufficient to control rib stability. Increasing the bolt length for depths greater than 250 m is in order, but higher depths do not correlate with longer supports. The approach used in this study demonstrated its capacity to be used in designing rib support requirements and understanding coal mass and support mechanisms.
Identification and Illustration of Means to a Critical Assessment of Music and Health Research Literature
Authors: Shriraam Jahnusha , Comeau Gilles , Swirp Mikael
Published: March 2023

In 2019, the WHO released a scoping review investigating art therapies in evidence-based healthcare practices to identify and understand the gaps in the literature. However, the studies curated were not evaluated for their quality. To address this limitation, several assessment tools to critically appraise music-based research studies that investigate therapies pertaining to preventative healthcare were investigated. Two critical appraisal tools were selected for their robustness and appropriateness for the studies in question: the Joanna Briggs Institute checklists and the Music-Based Intervention Guidelines. These tools were tested by two assessors on a total of 23 music studies from the Preventative and Prevention Health section of the WHO report. Based on the requirements for each critical appraisal tool, seven studies received a full assessment utilizing both checklists. Of these seven, two studies scored on the higher index, indicating that the studies followed a detailed methodology to provide concrete and accurate results. The findings of the study highlighted the limitations of study designs and music-based interventions. With this information, beneficial recommendations for future research in this domain are provided to improve the quality of research, ensuring its place in evidence-based healthcare practices.
Predictors of Discontinued E-Cigarette Use at One-Year Follow-Up in a Sample of Young Adults
Authors: Pokhrel Pallav , Kawamoto Crissy T. , Mettias Hannah , Elwir Taha , Herzog Thaddeus
Published: March 2023

Background: Currently, the research on factors associated with young adults’ discontinuation of e-cigarette use behavior is limited. This study tested the predictors of self-reported e-cigarette abstinence at one-year follow-up among young adult baseline current e-cigarette users. The following variables were tested as predictors: demographics, cigarette smoking, e-cigarette use dependence, e-cigarette use duration, harm perceptions, and preferred aspects of e-cigarette use, including sensations, flavor, and device characteristics. Methods: Data were provided at two time-points one year apart by 435 ethnically diverse young adults (M age = 22.3, SD = 3.1; 63% women) who reported current e-cigarette use at baseline. Results: Approximately 42% of those who reported current e-cigarette use at baseline (i.e., 184 out of 435 participants) reported discontinuation of e-cigarette use at one-year follow-up. Results indicated that higher e-cigarette dependence, longer history of e-cigarette use, lower e-cigarette harm perceptions, greater preference for both menthol and sweet flavors, for open-pod-based devices, and for e-cigarette use sensations such as buzz, taste and smell of flavors, and throat hit at baseline were associated with lower likelihood of e-cigarette use discontinuation at one-year follow-up. Conclusions: Characteristics associated with nicotine (e.g., dependence) and flavors (e.g., taste and smell) appear to drive the continuation/discontinuation of e-cigarette use among young adults. Thus, cessation strategies may need to be developed with a focus on dependence and harm perceptions related to nicotine and flavors. Furthermore, better regulating open-pod-based devices and sweet–menthol flavors may help e-cigarette use prevention.
Automation, Climate Change, and the Future of Farm Work: Cross-Disciplinary Lessons for Studying Dynamic Changes in Agricultural Health and Safety
Authors: Comi Matt , Becot Florence , Bendixsen Casper
Published: March 2023

In this review, we first assess the state of agricultural health and safety research as it pertains to the dynamic challenges facing automating agriculture on a warming planet. Then, we turn to social science fields such as rural sociology, science and technology studies, and environmental studies to leverage relevant insights on the introduction of new technologies, environmental risks, and associated workplace hazards. Increased rates of automation in agriculture alongside new risks associated with climate change create the need for anticipatory governance and adaptive research to study novel mechanisms of worker health and safety. The use of the PRISMA framework led to the 137 articles for our review. We identify three themes in the literature on agricultural health and safety: (1) adoption outcomes, (2) discrete cases of health risks, and (3) an emphasis on care and wellbeing in literature on dairy automation Our review led to the identification of research gaps, noting that current research (a) tends to examine these forces separately, instead of together, (b) has not made robust examination of these forces as socially embedded, and (c) has hesitated to examine the broad, transferable themes for how these forces work across industries. In response to these gaps, we suggest that attention to outside disciplines may provide agricultural health and safety research with a toolset to examine needed inquiry into the multiplicity of experiences of rural stakeholders, the industry specific problems arising from automation and climate change, and the socially embedded aspects of agricultural work in the future.
Condom-Related Stigma Scale among Men Who Have Sex with Men in China: Development and Psychometric Tests
Authors: Shen Yan , Zhang Ci , Goldsamt Lloyd A. , Peng Wenwen , Wang Run , Li Xianhong
Published: March 2023

Condom-related stigma is a frequently mentioned barrier to consistent condom use among men who have sex with men (MSM). Based on the concept and operational definition of condom-related stigma recently defined by our team, we developed the 20-item condom-related stigma scale (CRSS) and examined its psychometric properties among 433 MSM in China, following DeVellis’s scale development guidelines. The content validity, convergent validity, empirical validity, factorial validity, scale score reliability, split-half reliability, and test–retest reliability for the CRSS were all assessed. The scale consists of four domains: perceived distrust, perceived potential HIV/STI risk, perceived embarrassment, and perceived violation of the traditional understanding of sexual intercourse. The CRSS has good validity (the scale-level content validity index was 0.99; the empirical validity was greater than 0.70) and high reliability (the Cronbach’s alpha coefficient overall was 0.926; the split-half reliability overall was 0.795; the test–retest reliability overall was 0.950). This scale is recommended for assessing the level of condom-related stigma among Chinese MSM, which can serve as an evaluating indicator for safer-sex interventions to prevent HIV infection among the MSM population in a Chinese cultural context.
Handheld Raman Spectroscopy in the First UK Home Office Licensed Pharmacist-Led Community Drug Checking Service
Authors: Mullin Anthony , Scott Mark , Vaccaro Giorgia , Gittins Rosalind , Ferla Salvatore , Schifano Fabrizio , Guirguis Amira
Published: March 2023

Across the world, the interest in point-of-care drug checking as a harm-reduction intervention is growing. This is an attempt to improve intelligence about current drug trends and reduce drug-related morbidity and mortality. In the UK, drug-related harm is increasing exponentially year after year. As such, specialist community treatment services are exploring new methods to improve engagement with people who use drugs (PWUD), who may require support for their problematic drug use. This need has driven the requirement to pilot an on-site, time-responsive, readily available drug-checking service at point-of-support centres. In this study, we piloted the UK’s first Home Office-licensed drug-checking service that was embedded into a community substance-misuse service and had all on-site analysis and harm-reduction interventions led and delivered by pharmacists. We report on the laboratory findings from the associated confirmatory analysis (UHPLC-MS, GC-MS, and 1H NMR) to assess the performance of the on-site hand-held Raman spectrometer and outline the challenges of providing real-time analysis of psychoactive substances in a clinical setting. Whilst acknowledging the limitation of the small sample size (n = 13), we demonstrate the potential suitability of using this technology for the purposes of screening substances in community-treatment services. Portability of equipment and timeliness of results are important and only very small samples may be provided by people who use the service. The challenges of accurately identifying substances from complex mixtures were equally found with both point-of-care Raman spectroscopy and laboratory confirmatory-analysis techniques. Further studies are required to confirm these findings.
Reply to Yigit, S.; Akinci, B. Comment on “Vázquez-Gandullo et al. Inspiratory Muscle Training in Patients with Chronic Obstructive Pulmonary Disease (COPD) as Part of a Respiratory Rehabilitation Program Implementation of Mechanical Devices: A Systematic Review. Int. J. Environ. Res. Public Health 2022, 19, 5564”
Authors: Vázquez-Gandullo Eva , Hidalgo-Molina Antonio , Montoro-Ballesteros Francisca , Morales-González María , Muñoz-Ramírez Isabel , Arnedillo-Muñoz Aurelio
Published: March 2023

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Construction and Simulation of High-Quality Development of China’s Resource-Based Cities Driven by Innovation Based on System Dynamics
Authors: Liu Shuai , Jiang Guoxin , Chang Le , Huang Chao
Published: March 2023

Innovation is the primary driving force for development; the high-quality development of resource-based cities is ultimately driven by innovation. We constructed an innovation-driven high-quality development system for resource-based cities, including resource, economic, social, and environmental subsystems; according to the interaction between the internal elements of each subsystem, a dynamic model of the innovation-driven high-quality development system of resource-based cities was established, and we selected policy adjustment variables to simulate six policy scenarios. Thus, we simulated high-quality development trends from 2008 to 2035. The results indicate that the policy scenario of increasing innovation investment can promote high-quality development; the policy of increasing innovation investment has a significant effect on economic growth, while it damages the urban ecological environment, and the ideal policy scenario is the environmental priority mode, which appropriately increases innovation investment and reasonably allocates it within the system.
How Can Sport-Based Interventions Improve Health among Women and Girls? A Scoping Review
Authors: Pedersen Maja , King Abby C.
Published: March 2023

Sport has been identified by the World Health Organization as an underutilized yet important contributor to global physical activity, by UNESCO as a fundamental right, and by the United Nations as a promising driver for gender equity through improved long-term health of women and girls. Although sport-based interventions have been popularized to advance educational, social, and political development globally, little attention has been given to its impacts on health outcomes among women and girls. We undertook a scoping review of research on sport-based interventions for health among women and girls to summarize current research approaches and findings. PRISMA scoping review guidelines were observed. Online databases (PubMed, PsycINFO, Web of Science) were used to identify peer-reviewed records published through August 2022. The interventions identified (n = 4) targeted health outcomes such as gender-based violence, HIV prevention, reproductive health, and child marriage. Based on our review, we recommend four key opportunities to advance the field of sport-based interventions in addressing health equity among women and girls. In addition, we highlight promising future research directions to broaden sport engagement of women and girls, improve long-term health, and build capacity toward health equity.
Academic Burnout of Polish Students: A Latent Profile Analysis
Authors: Chirkowska-Smolak Teresa , Piorunek Magdalena , Górecki Tomasz , Garbacik Żaneta , Drabik-Podgórna Violetta , Kławsiuć-Zduńczyk Anna
Published: March 2023

According to Maslach and Leiter, burnout syndrome consists of three elements: exhaustion, cynicism, and a sense of ineffectiveness experienced by individuals in the work environment. However, burnout does not only apply to professional activity but can also be experienced by students pursuing higher education. This is important because the consequences of student burnout can be related to students’ mental and physical health. Until recently, the dominant diagnostic trend in the studies of burnout syndrome was based on a variable-focused approach. This approach focuses primarily on identifying subgroups in the population and presents different configurations of the various dimensions of burnout. However, there is emerging research using a person-centered approach and including the analysis of latent profiles to study professional and student burnout. This approach allows us to isolate subgroups of individuals in the study sample who have a similar burnout pattern. It focuses on the differences between individuals, which helps us to look at the phenomenon of professional burnout from a different perspective and shows the individuality of its experience. Our research aimed at identifying latent profiles, was conducted on a sample of 1519 Polish students, and partly confirms reports from other countries. We identified four profiles: low burnout, moderate below-average burnout, moderate above-average burnout, and very high burnout groups.
Beneficial Effect of Cuban Policosanol on Blood Pressure and Serum Lipoproteins Accompanied with Lowered Glycated Hemoglobin and Enhanced High-Density Lipoprotein Functionalities in a Randomized, Placebo-Controlled, and Double-Blinded Trial with Healthy Japanese
Authors: Cho Kyung-Hyun , Nam Hyo-Seon , Baek Seung-Hee , Kang Dae-Jin , Na Hyejee , Komatsu Tomohiro , Uehara Yoshinari
Published: March 2023

This study evaluated the efficacy and safety of 20 mg of Cuban policosanol in blood pressure (BP) and lipid/lipoprotein parameters of healthy Japanese subjects via a placebo-controlled, randomized, and double-blinded human trial. After 12 weeks of consumption, the policosanol group showed significantly lower BP, glycated hemoglobin (HbA1c), and blood urea nitrogen (BUN) levels. The policosanol group also showed lower aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GTP) levels at week 12 than those at week 0: A decrease of up to 9% (p < 0.05), 17% (p < 0.05), and 15% (p < 0.05) was observed, respectively. The policosanol group showed significantly higher HDL-C level and HDL-C/TC (%), approximately 9.5% (p < 0.001) and 7.2% (p = 0.003), respectively, than the placebo group and a difference in the point of time and group interaction (p < 0.001). In lipoprotein analysis, the policosanol group showed a decrease in oxidation and glycation extent in VLDL and LDL with an improvement of particle shape and morphology after 12 weeks. HDL from the policosanol group showed in vitro stronger antioxidant and in vivo anti-inflammatory abilities. In conclusion, 12 weeks of Cuban policosanolconsumption in Japanese subjects showed significant improvement in blood pressure, lipid profiles, hepatic functions, and HbA1c with enhancement of HDL functionalities.
Emerging Strategies in Proteolysis-Targeting Chimeras (PROTACs): Highlights from 2022
Authors: Tamatam Rekha , Shin Dongyun
Published: March 2023

Targeted protein degradation (TPD) is a promising therapeutic modality that has garnered attention in academic, industrial, and pharmaceutical research for treating diseases such as cancer, neurodegenerative disorders, inflammation, and viral infections. In this context, proteolysis-targeting chimeras (PROTACs) present a reliable technology for degrading disease-causing proteins. PROTACs complement small-molecule inhibitors, which primarily rely on direct protein regulation. From concept-to-clinic, PROTACs have evolved from cell impermeable peptide molecules to orally bioavailable drugs. Despite their potential in medicinal chemistry, certain aspects regarding PROTACs remain unclear. The clinical significance of PROTACs is primarily limited owing to their lack of selectivity and drug-like properties. This review focused on recently reported PROTAC strategies, particularly in 2022. It aimed to address and overcome the challenges posed by classical PROTACs by correlating them with emerging approaches with improved selectivity and controllability, cell permeability, linker flexibility, druggability, and PROTAC-based approaches, developed in 2022. Furthermore, recently reported PROTAC-based approaches are discussed, highlighting each of their advantages and limitations. We predict that several improved PROTAC molecules will be accessible for treating patients exhibiting various conditions, including cancer, neurodegenerative disorders, inflammation, and viral infections.
Serum Levels of Lipoprotein Lipase Are Increased in Patients with Inflammatory Bowel Disease
Authors: Rodríguez-Hernández Orvelindo , Carrillo-Palau Marta , Hernández-Camba Alejandro , Alonso-Abreu Inmaculada , Ramos Laura , de Armas-Rillo Laura , Martín-González Candelaria , López-Mejías Raquel , González-Gay Miguel Á. , Ferraz-Amaro Iván
Published: March 2023

Disruption of the lipid profile is commonly found in patients with inflammatory bowel disease (IBD). Lipoprotein lipase (LPL) is a key molecule involved in triglyceride metabolism that plays a significant role in the progression of atherosclerosis. In this study, our aim was to study whether serum LPL levels are different in IBD patients and controls and whether IBD features are related to LPL. This was a cross-sectional study that encompassed 405 individuals; 197 IBD patients with a median disease duration of 12 years and 208 age- and sex-matched controls. LPL levels and a complete lipid profile were assessed in all individuals. A multivariable analysis was performed to determine whether LPL serum levels were altered in IBD and to study their relationship with IBD characteristics. After the fully multivariable analysis, including cardiovascular risk factors and the changes in lipid profile that the disease causes itself, patients with IBD showed significantly higher levels of circulating LPL (beta coefficient 196 (95% confidence interval from 113 to 259) ng/mL, p < 0.001). LPL serum levels did not differ between Crohn’s disease and ulcerative colitis. However, serum C-reactive protein levels, disease duration, and the presence of an ileocolonic Crohn’s disease phenotype were found to be significantly and independently positively related to LPL. In contrast, LPL was not associated with subclinical carotid atherosclerosis. In conclusion, serum LPL levels were independently upregulated in patients with IBD. Inflammatory markers, disease duration and disease phenotype were responsible for this upregulation.
A Novel Fluorescence-Based Screen of Gene Editing Molecules for Junctional Epidermolysis Bullosa
Authors: Zwicklhuber Janine , Kocher Thomas , Liemberger Bernadette , Hainzl Stefan , Bischof Johannes , Strunk Dirk , Raninger Anna , Gratz Iris , Wally Verena , Guttmann-Gruber Christina , Hofbauer Josefina , Bauer Johann , Koller Ulrich
Published: March 2023

Junctional epidermolysis bullosa (JEB) is a severe blistering skin disease caused by mutations in genes encoding structural proteins essential for skin integrity. In this study, we developed a cell line suitable for gene expression studies of the JEB-associated COL17A1 encoding type XVII collagen (C17), a transmembrane protein involved in connecting basal keratinocytes to the underlying dermis of the skin. Using the CRISPR/Cas9 system of Streptococcus pyogenes we fused the coding sequence of GFP to COL17A1 leading to the constitutive expression of GFP-C17 fusion proteins under the control of the endogenous promoter in human wild-type and JEB keratinocytes. We confirmed the accurate full-length expression and localization of GFP-C17 to the plasma membrane via fluorescence microscopy and Western blot analysis. As expected, the expression of GFP-C17mut fusion proteins in JEB keratinocytes generated no specific GFP signal. However, the CRISPR/Cas9-mediated repair of a JEB-associated frameshift mutation in GFP-COL17A1mut-expressing JEB cells led to the restoration of GFP-C17, apparent in the full-length expression of the fusion protein, its accurate localization within the plasma membrane of keratinocyte monolayers as well as within the basement membrane zone of 3D-skin equivalents. Thus, this fluorescence-based JEB cell line provides the potential to serve as a platform to screen for personalized gene editing molecules and applications in vitro and in appropriate animal models in vivo.
Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells
Authors: Yeom Mina , Hong Jin-Kyung , Shin Joo-Ho , Lee Yunjong , Guengerich Frederick Peter , Choi Jeong-Yun
Published: March 2023

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced cis-syn cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and cisplatin sensitivity, but the functional impacts of its germline variants remain unclear. We evaluated the functional properties of eight human POLH germline in silico-predicted deleterious missense variants, using biochemical and cell-based assays. In enzymatic assays, utilizing recombinant pol η (residues 1—432) proteins, the C34W, I147N, and R167Q variants showed 4- to 14-fold and 3- to 5-fold decreases in specificity constants (kcat/Km) for dATP insertion opposite the 3’-T and 5′-T of a CTD, respectively, compared to the wild-type, while the other variants displayed 2- to 4-fold increases. A CRISPR/Cas9-mediated POLH knockout increased the sensitivity of human embryonic kidney 293 cells to UV and cisplatin, which was fully reversed by ectopic expression of wild-type pol η, but not by that of an inactive (D115A/E116A) or either of two XPV-pathogenic (R93P and G263V) mutants. Ectopic expression of the C34W, I147N, and R167Q variants, unlike the other variants, did not rescue the UV- and cisplatin-sensitivity in POLH-knockout cells. Our results indicate that the C34W, I147N, and R167Q variants—substantially reduced in TLS activity—failed to rescue the UV- and cisplatin-sensitive phenotype of POLH-deficient cells, which also raises the possibility that such hypoactive germline POLH variants may increase the individual susceptibility to UV irradiation and cisplatin chemotherapy.
The Antimicrobial Peptide AMP-IBP5 Suppresses Dermatitis-like Lesions in a Mouse Model of Atopic Dermatitis through the Low-Density Lipoprotein Receptor-Related Protein-1 Receptor
Authors: Nguyen Hai Le Thanh , Peng Ge , Trujillo-Paez Juan Valentin , Yue Hainan , Ikutama Risa , Takahashi Miho , Umehara Yoshie , Okumura Ko , Ogawa Hideoki , Ikeda Shigaku , Niyonsaba François
Published: March 2023

The antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) exhibits antimicrobial activities and immunomodulatory functions in keratinocytes and fibroblasts. However, its role in regulating skin barrier function remains unclear. Here, we investigated the effects of AMP-IBP5 on the skin barrier and its role in the pathogenesis of atopic dermatitis (AD). 2,4-Dinitrochlorobenzene was used to induce AD-like skin inflammation. Transepithelial electrical resistance and permeability assays were used to investigate tight junction (TJ) barrier function in normal human epidermal keratinocytes and mice. AMP-IBP5 increased the expression of TJ-related proteins and their distribution along the intercellular borders. AMP-IBP5 also improved TJ barrier function through activation of the atypical protein kinase C and Rac1 pathways. In AD mice, AMP-IBP5 ameliorated dermatitis-like symptoms restored the expression of TJ-related proteins, suppressed the expression of inflammatory and pruritic cytokines, and improved skin barrier function. Interestingly, the ability of AMP-IBP5 to alleviate inflammation and improve skin barrier function in AD mice was abolished in mice treated with an antagonist of the low-density lipoprotein receptor-related protein-1 (LRP1) receptor. Collectively, these findings indicate that AMP-IBP5 may ameliorate AD-like inflammation and enhance skin barrier function through LRP1, suggesting a possible role for AMP-IBP5 in the treatment of AD.
Nanoparticles in the New Era of Cardiovascular Therapeutics: Challenges and Opportunities
Authors: Yang Pingping , Ren Jun , Yang Lifang
Published: March 2023

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Although a cadre of therapeutic strategies have been made available for CVDs in the clinical setting, predominantly through medication and surgery, these do not fully address the clinical needs of patients with CVD. As a new technique for CVD treatment, nanocarriers are employed to modify and package medications to ease the targeting of tissues, cells and molecules within the cardiovascular system. Nanocarriers are made of biomaterials, metals, or a combination of these materials, with sizes similar to bioactive molecules such as proteins and DNA. Cardiovascular nanomedicine (CVN) has only surfaced in recent years and is still in its infancy. Ample studies have displayed promise for the clinical utility of nanomedicine techniques, courtesy of continued perfection in nanocarrier design to optimize drug delivery and treatment outcomes. Here in this review, we will summarize the research advances in the literature on nanoparticles in the management of CVDs, including ischemic and coronary heart disease (e.g., atherosclerosis, angina pectoris and myocardial infarction), myocardial ischemia-reperfusion injury, aortic aneurysm, myocarditis, hypertension, and pulmonary artery hypertension and thrombosis.
The Role of Olfactomedin 2 in the Adipose Tissue–Liver Axis and Its Implication in Obesity-Associated Nonalcoholic Fatty Liver Disease
Authors: Barrientos-Riosalido Andrea , Bertran Laia , Vilaró-Blay Mercè , Aguilar Carmen , Martínez Salomé , Paris Marta , Sabench Fàtima , Riesco David , Binetti Jessica , Castillo Daniel Del , Richart Cristóbal , Auguet Teresa
Published: March 2023

This study’s objective was to assess the involvement of olfactomedin 2 (OLFM2), a secreted glycoprotein related to lipid metabolism regulation, in nonalcoholic fatty liver disease (NAFLD) mediated by the adipose-tissue–liver axis. OLFM2 mRNA expression was analyzed in subcutaneous (SAT) and visceral (VAT) adipose tissue by RT–qPCR. The cohort included women with normal weight (n = 16) or morbid obesity (MO, n = 60) who were subclassified into normal liver (n = 20), simple steatosis (n = 21), and nonalcoholic steatohepatitis (NASH, n = 19) groups. The results showed that OLFM2 expression in SAT was enhanced in MO individuals and in the presence of NAFLD. Specifically, OLFM2 expression in SAT was increased in mild and moderate degrees of steatosis in comparison to the absence of it. Moreover, OLFM2 expression in SAT was negatively correlated with interleukin-6 levels. On the other hand, OLFM2 expression in VAT decreased in the presence of NASH and exhibited a positive correlation with adiponectin levels. In conclusion, OLFM2 in SAT seems to be implicated in hepatic lipid accumulation. Additionally, since we previously suggested the possible implication of hepatic OLFM2 in NAFLD progression, now we propose a possible interaction between the liver and SAT, reinforcing the potential implication of this tissue in NAFLD development.
Special Issue on “Pleiotropic Benefits of Melatonin: From Basic Mechanisms to Disease”
Authors: Potes Yaiza , Caballero Beatriz
Published: March 2023

Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional hormone that is naturally produced from tryptophan and released rhythmically throughout the night by the pineal gland to regulate sleep–wake cycles [...]
BrCWM Mutation Disrupted Leaf Flattening in Chinese Cabbage (Brassica rapa L. ssp. pekinensis)
Authors: Wu Yanji , Xin Yue , Zou Jiaqi , Huang Shengnan , Wang Che , Feng Hui
Published: March 2023

Leaf flattening plays a vital role in the establishment of plant architecture, which is closely related to plant photosynthesis and, thus, influences the product yield and quality of Chinese cabbage. In this study, we used the doubled haploid line ‘FT’ of Chinese cabbage as the wild type for ethyl methanesulfonate (EMS) mutagenesis and obtained a mutant cwm with stably inherited compact and wrinkled leaves. Genetic analysis revealed that the mutated trait was controlled by a single recessive nuclear gene, Brcwm. Brcwm was preliminarily mapped to chromosome A07 based on bulked segregant RNA sequencing (BSR-seq) and fine-mapped to a 205.66 kb region containing 39 genes between Indel12 and Indel21 using SSR and Indel analysis. According to the whole-genome re-sequencing results, we found that there was only one nonsynonymous single nucleotide polymorphism (SNP) (C to T) within the target interval on exon 4 of BraA07g021970.3C, which resulted in a proline to serine amino acid substitution. The mutated trait co-segregated with the SNP. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) revealed that BraA07g021970.3C expression was dramatically higher in ‘FT’ leaves than that in cwm leaves. BraA07g021970.3C is homologous to AT3G55000 encoding a protein related to cortical microtubule organization. A similar phenotype of dwarfism and wrinkled leaves was observed in the recessive homozygous mutant cwm-f1 of AT3G55000, and its T3 transgenic lines were restored to the Arabidopsis wild-type phenotype through ectopic overexpression of BraA07g021970.3C. These results verified that BraA07g021970.3C was the target gene essential for leaf flattening in Chinese cabbage.
Gut Microbes Meet Machine Learning: The Next Step towards Advancing Our Understanding of the Gut Microbiome in Health and Disease
Authors: Giuffrè Mauro , Moretti Rita , Tiribelli Claudio
Published: March 2023

The human gut microbiome plays a crucial role in human health and has been a focus of increasing research in recent years. Omics-based methods, such as metagenomics, metatranscriptomics, and metabolomics, are commonly used to study the gut microbiome because they provide high-throughput and high-resolution data. The vast amount of data generated by these methods has led to the development of computational methods for data processing and analysis, with machine learning becoming a powerful and widely used tool in this field. Despite the promising results of machine learning-based approaches for analyzing the association between microbiota and disease, there are several unmet challenges. Small sample sizes, disproportionate label distribution, inconsistent experimental protocols, or a lack of access to relevant metadata can all contribute to a lack of reproducibility and translational application into everyday clinical practice. These pitfalls can lead to false models, resulting in misinterpretation biases for microbe–disease correlations. Recent efforts to address these challenges include the construction of human gut microbiota data repositories, improved data transparency guidelines, and more accessible machine learning frameworks; implementation of these efforts has facilitated a shift in the field from observational association studies to experimental causal inference and clinical intervention.
Saliva and Saliva Extracellular Vesicles for Biomarker Candidate Identification—Assay Development and Pilot Study in Amyotrophic Lateral Sclerosis
Authors: Sjoqvist Sebastian , Otake Kentaro
Published: March 2023

Saliva is gaining increasing attention as a source of biomarkers due to non-invasive and undemanding collection access. Extracellular vesicles (EVs) are nano-sized, cell-released particles that contain molecular information about their parent cells. In this study, we developed methods for saliva biomarker candidate identification using EV-isolation and proteomic evaluation. We used pooled saliva samples for assay development. EVs were isolated using membrane affinity-based methods followed by their characterization using nanoparticle tracking analysis and transmission electron microscopy. Subsequently, both saliva and saliva-EVs were successfully analyzed using proximity extension assay and label-free quantitative proteomics. Saliva-EVs had a higher purity than plasma-EVs, based on the expression of EV-proteins and albumin. The developed methods could be used for the analysis of individual saliva samples from amyotrophic lateral sclerosis (ALS) patients and controls (n = 10 each). The starting volume ranged from 2.1 to 4.9 mL and the amount of total isolated EV-proteins ranged from 5.1 to 42.6 µg. Although no proteins were significantly differentially expressed between the two groups, there was a trend for a downregulation of ZNF428 in ALS-saliva-EVs and an upregulation of IGLL1 in ALS saliva. In conclusion, we have developed a robust workflow for saliva and saliva-EV analysis and demonstrated its technical feasibility for biomarker discovery.
Feasibility of Seated Stepping and Handshaking as a Cardiopulmonary Exercise Testing: A Pilot Study
Authors: Imashiro Kyosuke , Nishioka Yasuko , Teramura Kenzo , Hashimoto Hiromi , Kimura Hiroki , Tanabe Naoya , Taniguchi Yasuhiro , Nakai Koya , Umemoto Yasunori , Ito Tomoyuki , Tajima Fumihiro , Mikami Yasuo
Published: March 2023

Cardiopulmonary function is usually assessed by cardiopulmonary exercise testing (CPX) using a cycle ergometer (CE-CPX) or a treadmill, which is difficult in patients with lower extremity motor dysfunction. A stepping and handshaking (SHS) exercise has been developed that can be performed safely and easily while sitting on a chair. This study compared peak oxygen uptake (peak V.O2) between CE-CPX and SHS-CPX in healthy adults and investigated the safety and validity of SHS-CPX. Twenty young adults (mean age 27.8 ± 4.4 years) were randomly assigned to perform CE-CPX or SHS-CPX, with the other test to follow 1–2 weeks later. The peak V.O2, respiratory exchange ratio (RER), peak heart rate, blood pressure, and test completion time were compared between CE-CPX and SHS-CPX. All subjects completed the examination and met the criteria for peak V.O2. SHS-CPX and CE-CPX showed a strong correlation with peak V.O2 (r = 0.85, p < 0.0001). The peak V.O2 (40.4 ± 11.3 mL/min/kg vs. 28.9 ± 8.0 mL/min/kg), peak heart rate (190.6 ± 8.9 bpm vs. 172.1 ± 12.6 bpm), and test completion time (1052.8 ± 143.7 s vs. 609.1 ± 96.2 s) were significantly lower in the SHS-CPX (p < 0.0001). There were no adverse events. The peak V.O2 with SHS-CPX was equivalent to about 70% of that with CE-CPX despite the exercise being performed in a sitting position, suggesting its suitability as a submaximal exercise test.