bluuebunny/crossref_metadata_2025 huggingface dataset:
Socialization, Relaxation, and Leisure across the Day by Social Determinants of Health: Results from the American Time Use Survey, 2014–2016
Authors: Davis James , Taira Deborah A. , Lim Eunjung , Chen John
Published: May 2023

This study used the American Time Use Survey (ATUS) to examine socialization, relaxation, and leisure activities throughout the day as related to social determinants of health (SDOH). The study population was adults aged 25 years and older who participated in the ATUS in 2014–2016, the most recent years for collecting SDOH. Descriptive analyses provide characteristics of the study population. Graphical analyses display socialization by SDOH across the hours of the day based on adjusted regression models. Quasi-binomial models analyzed the association between the numbers of minutes of various activities and SDOH. Associations between SDOH and sleeplessness (yes or no) were explored using logistic regression. For much of the day, being female, having less education, living in poverty, and having food insecurity were associated with more time socializing and relaxing. The major activities under socializing and relaxation are watching television and movies. Having a college degree was strongly associated with increased minutes of sports activity, whereas living in poverty and food insecurity were associated with fewer minutes. Less education, living in poverty, and having food insecurity were associated with sleeplessness. A possible mechanism of the effects of SODH on health is by its altering of the patterns of daily life.
Regular Dental Check-Ups Are Associated with Choosing Uninsured Dental Restoration/Prosthesis Treatment in Japan
Authors: Oshima Katsuo
Published: May 2023

Since Japan has implemented Universal Health Coverage (UHC), most dental treatments are covered by public health insurance. Therefore, when receiving fixed dental restoration/prosthesis (FDRP) treatment, such as inlays, crowns, and bridges, the patient can choose whether or not it is covered by insurance. This study aimed to evaluate whether those who receive dental check-ups regularly chose uninsured FDRP treatment. Data were collected from 2088 participants, who had undergone FDRP treatment, via a web-based survey and analyzed. Among them, 1233 (59.1%) had received regular dental check-ups (RDC group) and 855 (40.9%) had not (non-RDC group). The multivariate logistic regression model showed that compared to the non-RDC group, those in the RDC group were statistically significantly associated with higher rates of good oral health behaviors (brushing teeth ≥ 3 times daily, odds ratios (OR):1.46; practiced interdental cleaning habitually, OR: 2.22) and received uninsured FDRP treatment more often (OR: 1.59), adjusted for socioeconomic factors. These results suggest that health policy interventions to promote access to RDC among individuals may improve the oral health of people and reduce the financial burden on the public health insurance system.
Development of a Nurse Turnover Prediction Model in Korea Using Machine Learning
Authors: Kim Seong-Kwang , Kim Eun-Joo , Kim Hye-Kyeong , Song Sung-Sook , Park Bit-Na , Jo Kyoung-Won
Published: May 2023

Nurse turnover is a critical issue in Korea, as it affects the quality of patient care and increases the financial burden on healthcare systems. To address this problem, this study aimed to develop and evaluate a machine learning-based prediction model for nurse turnover in Korea and analyze factors influencing nurse turnover. The study was conducted in two phases: building the prediction model and evaluating its performance. Three models, namely, decision tree, logistic regression, and random forest were evaluated and compared to build the nurse turnover prediction model. The importance of turnover decision factors was also analyzed. The random forest model showed the highest accuracy of 0.97. The accuracy of turnover prediction within one year was improved to 98.9% with the optimized random forest. Salary was the most important decision factor for nurse turnover. The nurse turnover prediction model developed in this study can efficiently predict nurse turnover in Korea with minimal personnel and cost through machine learning. The model can effectively manage nurse turnover in a cost-effective manner if utilized in hospitals or nursing units.
Role of Natural Products in the Management of COVID-19: A Saudi Arabian Perspective
Authors: Almuqbil Mansour , Alshaikh Sarah , Alrumayh Nura , Alnahdi Fay , Fallatah Eiman , Almutairi Shahad , Imran Mohd , Kamal Mehnaz , Almehmadi Mazen , Alsaiari Ahad Amer , Alqarni Wafa Ali Abdulrhman , Alasmari Ali Mohammed , Alwarthan Sara , Rabaan Ali A. , Almadani Moneer E. , Asdaq Syed Mohammed Basheeruddin
Published: May 2023

The coronavirus disease of 2019 (COVID-19) pandemic has resulted in an unprecedented circumstance that has never previously occurred. This has caused the Saudi Arabian people to recognize the necessity of preventive measures and explore alternative systems, such as using natural products (NPs), for treating their infection. Therefore, the specific objectives of this study were to explore the factors that influence the selection of NPs for COVID-19 management and to know the outcome of using NPs in COVID-19 infection management. This observational cross-sectional study was conducted in Saudi Arabia between February and April 2022. The validated pretested questionnaire was distributed among different regions of the country via a purposive snowball sampling procedure. Both descriptive statistics and stepwise regression analyses were carried out to evaluate the parameters related to the use of medicinal plants for the prevention of COVID-19 and the treatment of respiratory symptoms during the pandemic. The data obtained were statistically analyzed using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA). Of the 677 participants, 65% reported using NPs for themselves or family members during COVID-19. Utilizing NPs is always given priority by a significant (p < 0.001) percentage of survey respondents. Further, a highly significant (p < 0.001) percentage of participants felt that using NPs reduced their COVID-19 symptoms without having any remarkable (p < 0.001) adverse effects. Family and friends (59%) were the most frequent sources of information about utilizing NPs, followed by personal experience (41%). Honey (62.7%) and ginger (53.8%) were the most utilized NP among participants. Moreover, black seeds, garlic and turmeric were used by 40.5%, 37.7% and 26.3% of the surveyors, respectively. Those who used NPs before COVID-19 were 72.9% more likely to use them during COVID-19. NPs are more likely to be used by 75% of people who live in the central part of the country and whose families prefer it. This is true even if other factors are considered, such as the practice of using NPs along with traditional therapies and the fact that some participants’ families prefer it. Our findings show that NPs were commonly used to treat COVID-19 infection among Saudi Arabian residents. Close friends and family members mainly encouraged the use of NPs. Overall, the use of NPs was high among those who participated in our study; such practices are strongly impacted by society. It is essential to promote extensive studies to improve the recognition and accessibility of these products. Authorities should also educate the people about the benefits and risks of using commonly used NPs, especially those reported in this study.
The Value of Natural Stones to Gain in the Cultural and Geological Diversity of Our Global Heritage
Authors: Pereira Dolores
Published: May 2023

The use of stone to build shelters was an important step in terms of ensuring buildings’ durability and security in pre-historic times. It was also an acknowledgment of power and grandeur when societies demonstrated their respect for their leaders and gods by building stone monuments. For this reason, cathedrals, churches, and other magnificent religious monuments were built around the globe; however, the importance of the stone used in their construction itself is not sufficiently appreciated as the key factor ensuring the endurance of these historic buildings. While Western countries have long used iconic buildings to promote their heritage and advance in other socio-economic aspects, including tourism, other regions are yet to take full advantage of this outlook, even though their monumental structures may be equally impressive. Those important monuments are built of stone, which were referred to as Heritage Stones by some research groups, and their recognition would showcase the cultural and geological diversity of the world. However, there are many stones of heritage importance from geographic areas that are under-represented in the scientific literature and the work of research groups. This paper presents a review of the degree of geographical diversity in the recognition of stones and their heritage value.
Expression Analysis of Trihelix Transcription Factor Family in Strawberries and Functional Characterization of FvTrihelix6
Authors: Fan Jianshuai , Jiang Fan , Sun Hongyuan , He Tiannan , Liu Yuhan , Jiao Gaozhen , Ahmad Bilal , Bokhari Syeda Anum Masood , Chen Qingxi , Wen Zhifeng
Published: May 2023

The Trihelix is a plant-specific transcription factor family and has critical roles in plant growth and development and stress resistance. There is less information about Trihelix transcription factor genes and their potential functions in strawberries (Fragaria vesca). In the present study, we performed a detailed bioinformatics analysis of the Trihelix family in strawberries including physicochemical properties, chromosomal location, exon–intron distribution, domain arrangement, and subcellular localization. Thirty Trihelix family members were identified and divided into five subfamilies. The expression of FvTrihelix genes in different tissues/organs, i.e., root, stolon, leaf, flower, and fruit, was measured in strawberries after infection with Colletotrichum. gloeosporioides and foliar applications of salicylic acid (SA) and jasmonic acid (JA). Most of the genes showed differential expression responses following C. gloeosporioides infection and hormone treatments (SA and JA), suggesting critical roles in disease resistance and hormonal signaling pathways. As anticipated, the ectopic expression of FvTrihelix6 in Arabidopsis thaliana increased resistance against Colletotrichum. higginsianum infection. FvTrihelix6 protein was localized in the nucleus. We surmise that FvTrihelix6 enhances resistance against pathogens through the SA and JA signaling pathways. This study provides novel insights into the strawberry Trihelix transcription factor genes and new candidates for disease-resistance breeding of strawberries.
Impacts of Max-Stable Process Areal Exceedance Calculations to Study Area Sampling Density, Surface Network Precipitation Gage Extent and Density, and Model Fitting Method
Authors: Skahill Brian , Smith Cole Haden , Russell Brook T. , England John F.
Published: May 2023

Max-stable process (MSP) models can be fit to data collected over a spatial domain to estimate areal-based exceedances while accounting for spatial dependence in extremes. They have theoretical grounding within the framework of extreme value theory (EVT). In this work, we fit MSP models to three-day duration cool season precipitation maxima in the Willamette River Basin (WRB) of Oregon and to 48 h mid-latitude cyclone precipitation annual maxima in the Upper Trinity River Basin (TRB) of Texas. In total, 14 MSP models were fit (seven based on the WRB data and seven based on the TRB data). These MSP model fits were developed and applied to explore how user choices of study area sampling density, gage extent, and model fitting method impact areal precipitation-frequency calculations. The impacts of gage density were also evaluated. The development of each MSP involved the application of a recently introduced trend surface modeling methodology. Significant reductions in computing times were achieved, with little loss in accuracy, applying random sample subsets rather than the entire grid when calculating areal exceedances for the Cougar dam study area in the WRB. Explorations of gage extent revealed poor consistency among the TRB MSPs with modeling the generalized extreme value (GEV) marginal distribution scale parameter. The gauge density study revealed the robustness of the trend surface modeling methodology. Regardless of the fitting method, the final GEV shape parameter estimates for all fourteen MSPs were greater than their prescribed initial values which were obtained from spatial GEV fits that assumed independence among the extremes. When two MSP models only differed by their selected fitting method, notable differences were observed with their dependence and trend surface parameter estimates and resulting areal exceedances calculations.
The Boron Budget in Waters of the Mono Basin, California
Authors: Han Mengqu , Rasbury E. Troy , Hemming N. Gary , Hemming Sidney R. , Tomascak Paul B.
Published: May 2023

Mono Lake in eastern California has the highest natural boron concentrations measured in a natural water body. Inputs to Mono Lake are from creeks that drain from the Sierra Nevada, accounting for over 80% of the total water input, and springs account for most of the rest of the water budget. We measured boron concentrations and isotope compositions of water sources in the lake and lake water collected over several seasons. The δ11B offset of at least +2.5‰ between Mono Lake water compared to its inputs suggests that, like seawater, the boron isotopic composition of the lake is influenced by the removal of light boron by coprecipitation and/or sorption of borate. Given the alkalinity of the lake, boron fractionation likely occurs before or as the water sources enter the lake. The famous tufa towers around the lake are a physical representation of a ‘chemical delta’ that alters the boron isotopic composition of the source fluids as they enter the lake. Based on different combinations of the measured end members, the residence time of boron in Mono Lake is estimated to be within the range of 5~80 ka.
The Impact of Age and Body Composition on Bone Density among Office Worker Women in Hungary
Authors: Vári Beáta , Győri Ferenc , Katona Zoltán , Berki Tamás
Published: May 2023

The study’s aim was to investigate bone condition and see its associations with body composition and age among office worker women in Hungary. In total, 316 individuals participated in this study from Csongrad-Csanad county in 2019. Participants’ ages ranged from 18 to 62, with a mean of 41 years. A questionnaire was used to gather sociodemographic information, whereas body composition was measured using the Inbody 230, and bone density and bone quality were measured with the SONOST 3000 ultrasound device. Results were analyzed using descriptive statistics, ANOVA with Tukey’s post hoc test, correlation analysis, and an independent sample t-test. The results show that Body Fat Mass, Body Mass Index, Obesity Degree, and Percent Body Fat increase significantly as age increases, and Bone Quality Index and t-score decrease substantially. Furthermore, Bone Density and Bone Quality Index were positively influenced by most components of body composition. The differences between normal and osteopenia bone quality showed that Basal Metabolic Rate, Bone Mineral Content, Fat-Free Mass, Mineral Mass, Skeletal Lean Mass, and Skeletal Muscle Mass were lower in participants with osteopenia. Our results provide more evidence of the effects of body composition and age on bone density and quality. It was the first study in Hungary investigating this phenomenon, which could be useful for professionals and researchers who intend to understand the associations of bone density.
Particle Exposure Hazards of Visiting Outdoor Smoking Areas for Patients with Asthma or COPD Even in EU Countries with Comprehensive Smokefree Laws
Authors: Keogan Sheila , Alonso Tamara , Sunday Salome , Hanafin Joan , Tigova Olena , Fernandez Esteve , Lopez Maria Jose , Gallus Silvano , Semple Sean , Tzortzi Anna , Boffi Roberto , Gorini Giuseppe , Lopez-Nicolas Angel , Arvind D. K. , Radu-Loghin Cornel , Soriano Joan B. , Clancy Luke
Published: May 2023

Smokefree laws are intended to protect against second-hand smoke (SHS) in outdoor areas. We examined if exposure to PM2.5 particles in outdoor smoking areas changed breathing rates in 60 patients with asthma (n = 30) or with COPD (n = 30), in an open, non-randomised, interventional study model in Czechia, Ireland and Spain. The patients wore a PM2.5 particle monitor (AirSpeck) and a breath monitor (RESpeck) for 24 h to determine changes in breathing rates (Br) at rest and during a visit to an outside smoking area. Spirometry and breath CO were measured before and the day after visiting an outdoor smoking area. The PM2.5 levels at the 60 venues were highly variable, ranging from ≥2000 µg/m3 (in 4 premises) to ≤10 µg/m3 (in 3 premises, which had only a single wall in the structure). At 39 venues, the mean PM 2.5 levels were ≥25 µg/m3. The breathing rate changed significantly in 57 of the 60 patients, resulting in an increase in some patients and a decrease in others. Comprehensive smokefree laws were ineffective in protecting asthma and COPD patients from exposure to high levels of SHS in outside areas of pubs and terraces, which should be avoided by these patients. These findings also support the extension of smokefree laws to outside areas.
Pandemic upon Pandemic: Middle-Aged and Older Men Who Have Sex with Men Living with HIV Coping and Thriving during the Peak of COVID-19
Authors: Bell Sherry , Ranuschio Brandon , Waldron John M. , Barnes Lianne , Sheik-Yosef Nadia , Villalobos Esmeralda , Wackens Janelle , Liboro Renato M.
Published: May 2023

When the COVID-19 pandemic emerged in early 2020, not only did it abruptly impede the progress that was being made toward achieving global targets to end the HIV pandemic, but it also created significant impacts on the physical and mental health of middle-aged and older men who have sex with men living with HIV. Utilizing a qualitative, community-based participatory research approach, we conducted semi-structured, one-on-one interviews with 16 ethnoracially diverse, middle-aged and older men who have sex with men living with HIV residing in Southern Nevada, to examine the different ways the COVID-19 pandemic directly impacted their physical and mental health, and explore how they eventually coped and thrived during the peak of the crisis. Using thematic analysis to analyze our interview data, we identified three prominent themes: (1) challenges to obtaining credible health information, (2) the physical and mental health impacts of the COVID-19-pandemic-imposed social isolation, and (3) digital technologies and online connections for medical and social purposes. In this article, we extensively discuss these themes, the current discourse on these themes in academic literature, and how the perspectives, input, and lived experiences of our participants during the peak of the COVID-19 pandemic could be critical to addressing issues they had already been experiencing prior to the emergence of the pandemic in 2020, and just as importantly, helping us best prepare in stark anticipation of the next potentially devastating pandemic.
Effect of Cognitive Behavioral Intervention Combined with the Resilience Model to Decrease Depression and Anxiety Symptoms and Increase the Quality of Life in ESRD Patients Treated with Hemodialysis
Authors: González-Flores Cristina J. , Garcia-Garcia Guillermo , Lerma Claudia , Guzmán-Saldaña Rebeca María Elena , Lerma Abel
Published: May 2023

The aim of this study was to compare the effect of cognitive behavioral intervention (CBI) combined with the resilience model (CBI + R) vs CBI alone on depression symptoms, anxiety symptoms, and quality of life of end-stage renal disease (ESRD) patients undergoing hemodialysis replacement therapy. Method: Fifty-three subjects were randomly assigned to one of two treatment groups. The control group (n = 25) was provided with treatment strategies based on a cognitive behavioral approach, while the experimental group (n = 28) were given the same techniques plus resilience model strategies. Five psychological instruments were applied: Beck Depression Inventory, Beck Anxiety Inventory, Mexican Resilience Scale, cognitive distortions scale, and the Kidney Disease related Quality of Life questionnaire. Participants were assessed at baseline (before treatment), eight weeks later (end of treatment), and four weeks after the end of treatment (follow up). The results were analyzed by ANOVA for repeated measures with a Bonferroni-adjusted test method, with p < 0.05 considered significant. Results: The experimental group had significant differences in total and somatic depression as well as differences in the dimensions of cognitive distortions and a significant increase in the dimensions of resilience. The control group had significant differences in all variables but showed lower scores in the evaluated times. Conclusions: The resilience model strengthens and enhances the effectiveness of the cognitive behavioral approach to reduce symptoms of depression and anxiety in patients with ESRD.
Possible Projection of the First Military Survey of the Habsburg Empire in Lower Austria and Hungary (Late 18th Century)—An Improvement in Fitting Historical Topographic Maps to Modern Cartographic Systems
Authors: Timár Gábor
Published: May 2023

Map mosaics of the First Military Survey showing Lower Austria and Hungary (two separate zones and coordinate systems of 1:28,800 survey sections) were georeferenced. Compared to the previous fitting carried out in the framework of the publicly available MAPIRE project, an attempt was made here to determine the true native projections, despite the assumption, according to the literature, that these map works have no real geodetic basis and no real cartographic projection. In the case of Lower Austria, the native coordinate system of the Brno–Wien–Varaždin degree measurement of Father Joseph Liesganig, the Cassini projection centred on Stephansdom in Vienna, proved to be the survey’s own projection. In Hungary, in addition to the centre of a similar degree measurement, a fundamental point of the also documented Budapest-surrounding network of Colonel Neu proved to be a possible starting point of the Cassini projection used. Thus, with these centres, the Cassini projection is a good mathematical model for the native coordinate system of the surveys in these provinces. This achievement opens the possibility of better georeferencing of old maps of the survey, providing a database of land use and environmental change analyses and a step forward in understanding the survey technology of the 18th century.
Reverse-Polarization High-Performance Layer Electrochromatography—A New Approach to Anion Separation
Authors: Gwarda Radosław Łukasz , Dzido Tadeusz Henryk
Published: May 2023

High-performance layer electrochromatography (HPLEC) combines the advantages of overpressured-layer chromatography (OPLC) and pressurized planar electrochromatography (PPEC) while overcoming some of their limitations. HPLEC equipment can work in various HPLEC, OPLC, and PPEC modes. The equipment enables HPLEC analysis also with an electroosmotic effect directed against the hydrodynamic flow of the mobile phase. The change in the electric field direction in the separation system does not result in a change in either the direction of the mobile phase flow or the direction of solute migration. The hydrodynamic flow generated by the pump dominates the electroosmotic effect and enables separation against the direction of the latter. Reversed-polarization HPLEC may be advantageous for the analysis of anionic compounds, as it facilitates faster and more selective separation than OPLC performed in similar conditions. This separation mode provides a new possibility to develop and optimize separation methods by performing separation against the electroosmotic effect and without need of any modification of the adsorbent surface. A drawback of this separation mode is the increase in the backpressure at the mobile phase inlet and the limitation of the mobile phase flow rate. Currently, contrary to the single-channel mode, multi-channel reverse-polarity HPLEC still requires some technical and methodological improvements.
Defects in Mitochondrial Functions Affect the Survival of Yeast Cells Treated with Non-Thermal Plasma
Authors: Strížová Anna , Šmátralová Paulína , Chovančíková Petra , Machala Zdenko , Polčic Peter
Published: May 2023

Exposure of living cells to non-thermal plasma produced in various electrical discharges affects cell physiology and often results in cell death. Even though plasma-based techniques have started finding practical applications in biotechnology and medicine, the molecular mechanisms of interaction of cells with plasma remain poorly understood. In this study, the involvement of selected cellular components or pathways in plasma-induced cell killing was studied employing yeast deletion mutants. The changes in yeast sensitivity to plasma-activated water were observed in mutants with the defect in mitochondrial functions, including transport across the outer mitochondrial membrane (∆por1), cardiolipin biosynthesis (∆crd1, ∆pgs1), respiration (ρ0) and assumed signaling to the nucleus (∆mdl1, ∆yme1). Together these results indicate that mitochondria play an important role in plasma-activated water cell killing, both as the target of the damage and the participant in the damage signaling, which may lead to the induction of cell protection. On the other hand, our results show that neither mitochondria-ER contact sites, UPR, autophagy, nor proteasome play a major role in the protection of yeast cells from plasma-induced damage.
A Novel Defined PANoptosis-Related miRNA Signature for Predicting the Prognosis and Immune Characteristics in Clear Cell Renal Cell Carcinoma: A miRNA Signature for the Prognosis of ccRCC
Authors: Wang Yanmei , Zhou Jia , Zhang Nan , Zhu Yiran , Zhong Yiming , Wang Zhuo , Jin Hongchuan , Wang Xian
Published: May 2023

Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent cancers, and PANoptosis is a distinct, inflammatory-programmed cell death regulated by the PANoptosome. The essential regulators of cancer occurrence and progression are microRNAs (miRNAs). However, the potential function of PANoptosis-related microRNAs (PRMs) in ccRCC remains obscure. This study retrieved ccRCC samples from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets. PRMs were recognized based on previous reports in the scientific literature. Regression analyses were used to identify the prognosis PRMs and construct a PANoptosis-related miRNA prognostic signature based on the risk score. We discovered that high-risk patients had poorer survival prognoses and were significantly linked to high-grade and advanced-stage tumors, using a variety of R software packages and web analysis tools. Furthermore, we demonstrated that the low-risk group had significant changes in their metabolic pathways. In contrast, the high-risk group was characterized by high immune cell infiltration, immune checkpoint expression, and low half-maximum inhibition concentration (IC50) values of chemotherapeutic agents. This suggests that high-risk patients may benefit more from immunotherapy and chemotherapy. In conclusion, we constructed a PANoptosis-related microRNA signature and revealed its potential significance in clinicopathological features and tumor immunity, thereby providing new precise treatment strategies.
Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review
Authors: Anagnostakis Filippos , Kokkorakis Michail , Markouli Mariam , Piperi Christina
Published: May 2023

Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.
Haemophilia and Fragility Fractures: From Pathogenesis to Multidisciplinary Approach
Authors: Alito Angelo , Bellone Federica , Portaro Simona , Leonardi Giulia , Cannavò Vittorio , Coppini Francesca , Leonetti Danilo , Catalano Antonino , Squadrito Giovanni , Fenga Domenico
Published: May 2023

Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.
An In Vivo Whole-Transcriptomic Approach to Assess Developmental and Reproductive Impairments Caused by Flumequine in Daphnia magna
Authors: Pietropoli Edoardo , Pauletto Marianna , Tolosi Roberta , Iori Silvia , Lopparelli Rosa Maria , Montanucci Ludovica , Giantin Mery , Dacasto Mauro , De Liguoro Marco
Published: May 2023

Among veterinary antibiotics, flumequine (FLU) is still widely used in aquaculture due to its efficacy and cost-effectiveness. Although it was synthesized more than 50 years ago, a complete toxicological framework of possible side effects on non-target species is still far from being achieved. The aim of this research was to investigate the FLU molecular mechanisms in Daphnia magna, a planktonic crustacean recognized as a model species for ecotoxicological studies. Two different FLU concentrations (2.0 mg L−1 and 0.2 mg L−1) were assayed in general accordance with OECD Guideline 211, with some proper adaptations. Exposure to FLU (2.0 mg L−1) caused alteration of phenotypic traits, with a significant reduction in survival rate, body growth, and reproduction. The lower concentration (0.2 mg L−1) did not affect phenotypic traits but modulated gene expression, an effect which was even more evident under the higher exposure level. Indeed, in daphnids exposed to 2.0 mg L−1 FLU, several genes related with growth, development, structural components, and antioxidant response were significantly modulated. To the best of our knowledge, this is the first work showing the impact of FLU on the transcriptome of D. magna.
A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice
Authors: Lee Avelina , Lebedyeva Iryna , Zhi Wenbo , Senthil Vani , Cheema Herjot , Brands Michael W. , Bush Weston , Lambert Nevin A. , Snipes Madeline , Browning Darren D.
Published: May 2023

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug–drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.
TRAX-CHEMxt: Towards the Homogeneous Chemical Stage of Radiation Damage
Authors: Camazzola Gianmarco , Boscolo Daria , Scifoni Emanuele , Dorn Alexander , Durante Marco , Krämer Michael , Abram Valentino , Fuss Martina C.
Published: May 2023

The indirect effect of radiation plays an important role in radio-induced biological damages. Monte Carlo codes have been widely used in recent years to study the chemical evolution of particle tracks. However, due to the large computational efforts required, their applicability is typically limited to simulations in pure water targets and to temporal scales up to the µs. In this work, a new extension of TRAX-CHEM is presented, namely TRAX-CHEMxt, able to predict the chemical yields at longer times, with the capability of exploring the homogeneous biochemical stage. Based on the species coordinates produced around one track, the set of reaction–diffusion equations is solved numerically with a computationally light approach based on concentration distributions. In the overlapping time scale (500 ns–1 µs), a very good agreement to standard TRAX-CHEM is found, with deviations below 6% for different beam qualities and oxygenations. Moreover, an improvement in the computational speed by more than three orders of magnitude is achieved. The results of this work are also compared with those from another Monte Carlo-based algorithm and a fully homogeneous code (Kinetiscope). TRAX-CHEMxt will allow for studying the variation in chemical endpoints at longer timescales with the introduction, as the next step, of biomolecules, for more realistic assessments of biological response under different radiation and environmental conditions.
Exploring the Impact of Cyanidin-3-Glucoside on Inflammatory Bowel Diseases: Investigating New Mechanisms for Emerging Interventions
Authors: Frountzas Maximos , Karanikki Eva , Toutouza Orsalia , Sotirakis Demosthenis , Schizas Dimitrios , Theofilis Panagiotis , Tousoulis Dimitris , Toutouzas Konstantinos G.
Published: May 2023

Cyanidin-3-O-glucoside (C3G), the most widely distributed anthocyanin (ACN) in edible fruits, has been proposed for several bioactivities, including anti-inflammatory, neuro-protective, antimicrobial, anti-viral, anti-thrombotic and epigenetic actions. However, habitual intake of ACNs and C3G may vary widely among populations, regions, and seasons, among individuals with different education and financial status. The main point of C3G absorption occurs in the small and large bowel. Therefore, it has been supposed that the treating properties of C3G might affect inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). IBDs develop through complex inflammatory pathways and sometimes may be resistant to conventional treatment strategies. C3G presents antioxidative, anti-inflammatory, cytoprotective, and antimicrobial effects useful for IBD management. In particular, different studies have demonstrated that C3G inhibits NF-κB pathway activation. In addition, C3G activates the Nrf2 pathway. On the other hand, it modulates the expression of antioxidant enzymes and cytoprotective proteins, such as NAD(P)H, superoxide dismutase, heme-oxygenase (HO-1), thioredoxin, quinone reductase-oxide 1 (NQO1), catalase, glutathione S-transferase and glutathione peroxidase. Interferon I and II pathways are downregulated by C3G inhibiting interferon-mediating inflammatory cascades. Moreover, C3G reduces reactive species and pro-inflammatory cytokines, such as C reactive protein, interferon-γ, tumor necrosis factor-α, interleukin (IL)-5, IL-9, IL-10, IL-12p70, and IL-17A in UC and CD patients. Finally, C3G modulates gut microbiota by inducing an increase in beneficial gut bacteria and increasing microbial abundances, thus mitigating dysbiosis. Thus, C3G presents activities that may have potential therapeutic and protective actions against IBD. Still, in the future, clinical trials should be designed to investigate the bioavailability of C3G in IBD patients and the proper therapeutic doses through different sources, aiming to the standardization of the exact clinical outcome and efficacy of C3G.
Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors
Authors: Martínez-Montiel Mónica , Romero-Hernández Laura L. , Giovannuzzi Simone , Begines Paloma , Puerta Adrián , Ahuja-Casarín Ana I. , Fernandes Miguel X. , Merino-Montiel Penélope , Montiel-Smith Sara , Nocentini Alessio , Padrón José M. , Supuran Claudiu T. , Fernández-Bolaños José G. , López Óscar
Published: May 2023

The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1–4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor–enzyme interactions.
Lysine Deprivation Suppresses Adipogenesis in 3T3-L1 Cells: A Transcriptome Analysis
Authors: Lee Leo Man-Yuen , Lin Zhi-Qiang , Zheng Lu-Xi , Tu Yi-Fan , So Yik-Hing , Zheng Xiu-Hua , Feng Tie-Jun , Wang Xi-Yue , Wong Wai-Ting , Leung Yun-Chung
Published: May 2023

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes’ response to amino acid level changes is crucial. It has been reported that a low concentration of lysine suppresses lipid accumulation and transcription of several adipogenic genes in 3T3-L1 preadipocytes. However, the detailed lysine-deprivation-induced cellular transcriptomic changes and the altered pathways have yet to be fully studied. Here, using 3T3-L1 cells, we performed RNA sequencing on undifferentiated and differentiated cells, and differentiated cells under a lysine-free environment, and the data were subjected to KEGG enrichment. We found that the differentiation process of 3T3-L1 cells to adipocytes required the large-scale upregulation of metabolic pathways, mainly on the mitochondrial TCA cycle, oxidative phosphorylation, and downregulation of the lysosomal pathway. Single amino acid lysine depletion suppressed differentiation dose dependently. It disrupted the metabolism of cellular amino acids, which could be partially reflected in the changes in amino acid levels in the culture medium. It inhibited the mitochondria respiratory chain and upregulated the lysosomal pathway, which are essential for adipocyte differentiation. We also noticed that cellular interleukin 6 (IL6) expression and medium IL6 level were dramatically increased, which was one of the targets for suppressing adipogenesis induced by lysine depletion. Moreover, we showed that the depletion of some essential amino acids such as methionine and cystine could induce similar phenomena. This suggests that individual amino acid deprivation may share some common pathways. This descriptive study dissects the pathways for adipogenesis and how the cellular transcriptome was altered under lysine depletion.
The Verticillium dahliae Small Cysteine-Rich Protein VdSCP23 Manipulates Host Immunity
Authors: Wang Jie , Wang Dan , Ji Xiaobin , Wang Jun , Klosterman Steven J. , Dai Xiaofeng , Chen Jieyin , Subbarao Krishna V. , Hao Xiaojuan , Zhang Dandan
Published: May 2023

Verticillium wilt caused by Verticillium dahliae is a notorious soil-borne fungal disease and seriously threatens the yield of economic crops worldwide. During host infection, V. dahliae secretes many effectors that manipulate host immunity, among which small cysteine-rich proteins (SCPs) play an important role. However, the exact roles of many SCPs from V. dahliae are unknown and varied. In this study, we show that the small cysteine-rich protein VdSCP23 inhibits cell necrosis in Nicotiana benthamiana leaves, as well as the reactive oxygen species (ROS) burst, electrolyte leakage and the expression of defense-related genes. VdSCP23 is mainly localized in the plant cell plasma membrane and nucleus, but its inhibition of immune responses was independent of its nuclear localization. Site-directed mutagenesis and peptide truncation showed that the inhibition function of VdSCP23 was independent of cysteine residues but was dependent on the N-glycosylation sites and the integrity of VdSCP23 protein structure. Deletion of VdSCP23 did not affect the growth and development of mycelia or conidial production in V. dahliae. Unexpectedly, VdSCP23 deletion strains still maintained their virulence for N. benthamiana, Gossypium hirsutum and Arabidopsis thaliana seedlings. This study demonstrates an important role for VdSCP23 in the inhibition of plant immune responses; however, it is not required for normal growth or virulence in V. dahliae.
A Novel Photopharmacological Tool: Dual-Step Luminescence for Biological Tissue Penetration of Light and the Selective Activation of Photodrugs
Authors: Menéndez-Velázquez Amador , García-Delgado Ana Belén
Published: May 2023

Conventional pharmacology lacks spatial and temporal selectivity in terms of drug action. This leads to unwanted side effects, such as damage to healthy cells, as well as other less obvious effects, such as environmental toxicity and the acquisition of resistance to drugs, especially antibiotics, by pathogenic microorganisms. Photopharmacology, based on the selective activation of drugs by light, can contribute to alleviating this serious problem. However, many of these photodrugs are activated by light in the UV–visible spectral range, which does not propagate through biological tissues. In this article, to overcome this problem, we propose a dual-spectral conversion technique, which simultaneously makes use of up-conversion (using rare earth elements) and down-shifting (using organic materials) techniques in order to modify the spectrum of light. Near-infrared light (980 nm), which penetrates tissue fairly well, can provide a “remote control” for drug activation. Once near-IR light is inside the body, it is up-converted to the UV–visible spectral range. Subsequently, this radiation is down-shifted in order to accurately adjust to the excitation wavelengths of light which can selectively activate hypothetical and specific photodrugs. In summary, this article presents, for the first time, a “dual tunable light source” which can penetrate into the human body and deliver light of specific wavelengths; thus, it can overcome one of the main limitations of photopharmacology. It opens up promising possibilities for the moving of photodrugs from the laboratory to the clinic.
Calpain-3 Is Not a Sodium Dependent Protease and Simply Requires Calcium for Activation
Authors: Wette Stefan G. , Lamb Graham D. , Murphy Robyn M.
Published: May 2023

Calpain-3 (CAPN3) is a muscle-specific member of the calpain family of Ca2+-dependent proteases. It has been reported that CAPN3 can also be autolytically activated by Na+ ions in the absence of Ca2+, although this was only shown under non-physiological ionic conditions. Here we confirm that CAPN3 does undergo autolysis in the presence of high [Na+], but this only occurred if all K+ normally present in a muscle cell was absent, and it did not occur even in 36 mM Na+, higher than what would ever be reached in exercising muscle if normal [K+] was present. CAPN3 in human muscle homogenates was autolytically activated by Ca2+, with ~50% CAPN3 autolysing in 60 min in the presence of 2 µM Ca2+. In comparison, autolytic activation of CAPN1 required about 5-fold higher [Ca2+] in the same conditions and tissue. After it was autolysed, CAPN3 unbound from its tight binding on titin and became diffusible, but only if the autolysis led to complete removal of the IS1 inhibitory peptide within CAPN3, reducing the C-terminal fragment to 55 kDa. Contrary to a previous report, activation of CAPN3, either by raised [Ca2+] or Na+ treatment, did not cause proteolysis of the skeletal muscle Ca2+ release channel-ryanodine receptor, RyR1, in physiological ionic conditions. Treatment of human muscle homogenates with high [Ca2+] caused autolytic activation of CAPN1, accompanied by proteolysis of some titin and complete proteolysis of junctophilin (JP1, full length ~95 kDa), generating an equimolar amount of a diffusible ~75 kDa N-terminal JP1 fragment, but without any proteolysis of RyR1.