bluuebunny/crossref_metadata_2025 huggingface dataset:
Classical and Alternative Pathways of the Renin–Angiotensin–Aldosterone System in Regulating Blood Pressure in Hypertension and Obese Adolescents
Authors: Martyniak Adrian , Drożdż Dorota , Tomasik Przemysław J.
Published: March 2024

Primary hypertension (PH) is the leading form of arterial hypertension (AH) in adolescents. Hypertension is most common in obese patients, where 20 to 40% of the population has elevated blood pressure. One of the most effective mechanisms for regulating blood pressure is the renin–angiotensin–aldosterone system (RAAS). The new approach to the RAAS talks about two opposing pathways between which a state of equilibrium develops. One of them is a classical pathway, which is responsible for increasing blood pressure and is represented mainly by the angiotensin II (Ang II) peptide and, to a lesser extent, by angiotensin IV (Ang IV). The alternative pathway is responsible for the decrease in blood pressure and is mainly represented by angiotensin 1–7 (Ang 1–7) and angiotensin 1–9 (Ang 1–9). Our research study aimed to assess changes in angiotensin II, angiotensin IV, angiotensin 1–7, and angiotensin 1–9 concentrations in the plasma of adolescents with hypertension, with hypertension and obesity, and obesity patients. The Ang IV concentration was lower in hypertension + obesity versus control and obesity versus control, respectively p = 0.01 and p = 0.028. The Ang 1–9 concentration was lower in the obesity group compared to the control group (p = 0.036). There were no differences in Ang II and Ang 1–7 peptide concentrations in the hypertension, hypertension and obesity, obesity, and control groups. However, differences were observed in the secondary peptides, Ang IV and Ang 1–9. In both cases, the differences were related to obesity.
Low-Volume Metastases in Cervical Cancer: Does Size Matter?
Authors: Bianchi Tommaso , Grassi Tommaso , Di Martino Giampaolo , Negri Serena , Trezzi Gaetano , Fruscio Robert , Landoni Fabio
Published: March 2024

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer, and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. Part of the undisputed value of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make reaching any conclusions on this topic hard. Current guidelines suggest considering micrometastases (MIC) as a node-positive disease, while considering isolated tumor cells (ITC) as a node-negative disease with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, and prognostic and therapeutic roles of LVM and to underline the present and future challenges we are facing. We hope that this review will guide further research, giving robust evidence on LVM and their impacts on clinical practice.
A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation
Authors: Guo Wancheng , Strouse Christopher , Mery David , Siegel Eric R. , Munshi Manit N. , Ashby Timothy Cody , Cheng Yan , Sun Fumou , Wanchai Visanu , Zhang Zijun , Bailey Clyde , Alapat Daisy V. , Peng Hongling , Al Hadidi Samer , Thanendrarajan Sharmilan , Schinke Carolina , Zangari Maurizio , van Rhee Frits , Tricot Guido , Shaughnessy John D. , Zhan Fenghuang
Published: March 2024

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.
An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer
Authors: Duan Ningjun , Hua Yijia , Yan Xueqi , He Yaozhou , Zeng Tianyu , Gong Jue , Fu Ziyi , Li Wei , Yin Yongmei
Published: March 2024

tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments.
Genome-Wide Analysis of VILLIN Gene Family Associated with Stress Responses in Cotton (Gossypium spp.)
Authors: Deep Akash , Pandey Dhananjay K.
Published: March 2024

The VILLIN (VLN) protein plays a crucial role in regulating the actin cytoskeleton, which is involved in numerous developmental processes, and is crucial for plant responses to both biotic and abiotic factors. Although various plants have been studied to understand the VLN gene family and its potential functions, there has been limited exploration of VLN genes in Gossypium and fiber crops. In the present study, we characterized 94 VLNs from Gossypium species and 101 VLNs from related higher plants such as Oryza sativa and Zea mays and some fungal, algal, and animal species. By combining these VLN sequences with other Gossypium spp., we classified the VLN gene family into three distinct groups, based on their phylogenetic relationships. A more in-depth examination of Gossypium hirsutum VLNs revealed that 14 GhVLNs were distributed across 12 of the 26 chromosomes. These genes exhibit specific structures and protein motifs corresponding to their respective groups. GhVLN promoters are enriched with cis-elements related to abiotic stress responses, hormonal signals, and developmental processes. Notably, a significant number of cis-elements were associated with the light responses. Additionally, our analysis of gene-expression patterns indicated that most GhVLNs were expressed in various tissues, with certain members exhibiting particularly high expression levels in sepals, stems, and tori, as well as in stress responses. The present study potentially provides fundamental insights into the VLN gene family and could serve as a valuable reference for further elucidating the diverse functions of VLN genes in cotton.
Pro-Vaccination Flu and COVID-19 Messages: Evidence of Congenial Targeted and Spillover Effects
Authors: Dillard James , Shen Lijiang
Published: March 2024

Given the plentitude of messages in the public arena that promote vaccination against different diseases or raise the possibility of vaccine mandates, we asked whether message effects in one disease domain might spill over into other domains. Our experiment exposed individuals (N = 1755) recruited from an opt-in online panel (Qualtrics) on influenza or COVID-19 pro-vaccination messages then measured intentions to vaccinate for each disease and intentions to support a vaccine mandate for each disease. Messages that targeted flu (vs. COVID-19) exhibited stronger effects on intentions to vaccinate for corresponding (vs. noncorresponding) disease. We observed positive spillover from intention to vaccinate against one disease to intention to vaccinate against the other disease, as well as from vaccination intention type to support for corresponding and noncorresponding vaccine mandates. Although pro-vaccination flu and COVID-19 messages have multiple effects, those effects are congenial. The results adjudicate differences in spillover theory and suggest synergistic effects between pro-vaccination campaigns.
Temporal Properties of Self-Prioritization
Authors: Lu Zhuoen , He Xun , Yi Dewei , Sui Jie
Published: March 2024

Using electroencephalogram (EEG), we tested the hypothesis that the association of a neutral stimulus with the self would elicit ultra-fast neural responses from early top-down feedback modulation to late feedforward periods for cognitive processing, resulting in self-prioritization in information processing. In two experiments, participants first learned three associations between personal labels (self, friend, stranger) and geometric shapes (Experiment 1) and three colors (Experiment 2), and then they judged whether the shape/color–label pairings matched. Stimuli in Experiment 2 were shown in a social communicative setting with two avatars facing each other, one aligned with the participant’s view (first-person perspective) and the other with a third-person perspective. The color was present on the t-shirt of one avatar. This setup allowed for an examination of how social contexts (i.e., perspective taking) affect neural connectivity mediating self-related processing. Functional connectivity analyses in the alpha band (8–12 Hz) revealed that self–other discrimination was mediated by two distinct phases of neural couplings between frontal and occipital regions, involving an early phase of top-down feedback modulation from frontal to occipital areas followed by a later phase of feedforward signaling from occipital to frontal regions. Moreover, while social communicative settings influenced the later feedforward connectivity phase, they did not alter the early feedback coupling. The results indicate that regardless of stimulus type and social context, the early phase of neural connectivity represents an enhanced state of awareness towards self-related stimuli, whereas the later phase of neural connectivity may be associated with cognitive processing of socially meaningful stimuli.
Study on the Performance and Emissions of Triple Blends of Diesel/Waste Plastic Oil/Vegetable Oil in a Diesel Engine: Advancing Eco-Friendly Solutions
Authors: Estevez Rafael , Aguado-Deblas Laura , López-Tenllado Francisco J. , Bautista Felipa M. , Romero Antonio A. , Luna Diego
Published: March 2024

To provide technical and economical solutions regarding management of plastic waste, which is constantly increasing worldwide, this study addresses the possibility of using plastic oils (PO) obtained from these plastic wastes as biofuels. To this end, the replacement of the fossil diesel employed in internal combustion diesel engines with triple diesel/PO/vegetable oil mixtures has been investigated. Sunflower (SO) and castor oil (CO) mixed with PO in the most appropriate proportion are evaluated as pure vegetable oils (SVO). Thus, diesel/PO/SVO triple blends were prepared, characterized, and then tested on a diesel engine operating as electricity generator, evaluating power output, consumption, and exhaust emissions. The obtained results show that, with the incorporation of relatively small quantities of pure, non-edible vegetable oils, in double mixtures of PO/SO and PO/CO, an effective alternative fuel for transport is obtained, that allows for 100% of fossil diesel to be replaced. In fact, with these double PO/SVO biofuel mixtures, higher engine power values and lower consumption levels are obtained than those achieved with fossil diesel. Regarding exhaust emissions, these are produced with a slightly greater opacity than with fossil diesel, but there are lower values of carbon gases as a whole (CO + CO2) and in NOx gases.
An Experimental Study on the Performance and Emissions of an 8% Water-in-Diesel Emulsion Stabilized by a Hydrophilic Surfactant Blend
Authors: Oliveira Pedro , Brójo Francisco
Published: March 2024

Diesel engines are known for their excellent efficiency and are therefore used in a variety of applications. However, they are also one of the main sources of hazardous emissions such as nitrogen oxides (NOx) and smoke. Water-in-Diesel Emulsion (WiDE) is an alternative fuel that can possibly reduce some of the pollutant emissions without compromising engine performance. The surfactant formulation for WiDE usually follows the one used in water-in-oil (w/o) emulsions, where low hydrophilic–lipophilic balance (HLB) emulsifiers are preferred for better solubility in the diesel phase and stabilization at storage temperatures. However, by using a hydrophilic blend with a non-ionic surfactant, it is possible to develop an optimized formulation at higher fuel temperatures, which occur during an engine’s operating condition, achieving possibly higher benefits. Across the different speeds, the results for the emulsion show 7.57% mean improvement in specific fuel consumption (SFC), 19.14% mean improvement in thermal efficiency (TE), 5.54% mean reduction in carbon dioxide (CO2), 20.50% mean reduction in nitric oxide (NO) and 75.19% mean reduction in smoke levels. However, carbon monoxide (CO) and hydrocarbons (HC) emissions were higher, with a mean increase of 81.09% and 93.83%, respectively.
Equilibrium between Environmental and Economic Objectives: An Activity-Based Costing Approach Application for Carbon Emissions Management in the Aluminum Alloy Wheel Industry
Authors: Tsai Wen-Hsien , Chang Shuo-Chieh , Teng Yuchun
Published: March 2024

In the face of the increasingly dire threat of global climate change, reducing carbon emissions has become an urgent priority for governments and corporations worldwide. The aluminum alloy wheel manufacturing industry bears an even heavier burden for emission mitigation due to its high production volume, complex processes, and proportionally higher carbon footprint. With impending carbon taxes and trading policies looming, the industry urgently needs to strike a balance between maximizing profits and minimizing carbon emissions. Leveraging real-world industry data, this research develops four green Activity-Based Costing (ABC) models and utilizes optimization software to compare the following scenarios: non-continuous carbon tax, carbon tax with trading, tiered tax with exemptions, and exemptions combined with trading. Results demonstrate that integrating carbon trading and targeted tax reductions can improve corporate financial positions without severely compromising environmental goals. Although identifying optimal balance points remains a highly complex process, this study equips enterprises and policymakers with quantitative tools to navigate fluctuating carbon regulatory environments. As national policies progress, more multifaceted dynamic carbon tax models will likely provide more profound insights for sustainable development.
Theoretical Framework and Research Proposal for Energy Utilization, Conservation, Production, and Intelligent Systems in Tropical Island Zero-Carbon Building
Authors: Wang Qiankun , Zhu Ke , Guo Peiwen
Published: March 2024

This study aims to theoretically explore the technological systems of tropical island zero-carbon building (TIZCB) to scientifically understand the characteristics of these buildings in terms of energy utilization, energy conservation, energy production, and intelligent system mechanisms. The purpose is to address the inefficiencies and resource wastage caused by the traditional segmented approach to building energy consumption management. Thus, it seeks to achieve a comprehensive understanding and application of the zero-carbon building (ZCB) technology system. This article focuses on the demands for energy-efficient comfort and innovative industrialization in construction. Through an analysis of the characteristics of TIZCB and an explanation of their concepts, it establishes a theoretical framework for examining the system mechanisms of these buildings. Additionally, it delves into the energy utilization, energy conservation, energy production, and intelligent system from macro, meso, and micro perspectives. This approach results in the development of an implementation strategy for studying the mechanisms of energy usage, conservation, and intelligent production systems in TIZCB. The results show that: (1) this study delves into the theoretical underpinnings of TIZCB, emphasizing their evolution from a foundation of low-carbon and near-zero energy consumption. The primary goal is to achieve zero carbon emissions during building operation, with reliance on renewable energy sources. Design considerations prioritize adaptation to high-temperature and high-humidity conditions, integrating regional culture along with the utilization of new materials and technologies. (2) A comprehensive technical framework for TIZCB is proposed, encompassing energy utilization, conservation, production capacity, and intelligent systems. Drawing from systems theory, control theory, and synergy theory, the research employs a macro–meso–micro analytical framework, offering extensive theoretical support for the practical aspects of design and optimization. (3) The research implementation plan establishes parameterized models, unveiling the intricate relationships with building performance. It provides optimized intelligent system design parameters for economically viable zero-carbon operations. This study contributes theoretical and practical support for the sustainable development of TIZCB and aligns with the dual carbon strategy in China and the clean energy free trade zone construction in Hainan.
Transition to the Fluid Dynamic Limit: Mathematical Models and Simulation Results
Authors: Babovsky Hans
Published: March 2024

Numerical simulations of standard situations in the transition region from gas kinetics to fluid dynamics at small Mach numbers indicate a clear dependence of the simulation results on the underlying kinetic model (here: nonlinear and linearized Boltzmann collision operator vs. BGK relaxation model). We develop an improved mathematical framework (trace theory) to explain these differences. In particular we reveal certain deficiencies for the classical BKG system as well as for the standard Navier Stokes approach.
Metataxonomic Identification of Microorganisms during the Coffee Fermentation Process in Colombian Farms (Cesar Department)
Authors: Góngora Carmenza E. , Holguín-Sterling Laura , Pedraza-Claros Bertilda , Pérez-Salinas Rosangela , Ortiz Aristofeles , Navarro-Escalante Lucio
Published: March 2024

The metataxonomic diversity and microbial composition of microorganisms during the coffee fermentation process as well as their relationship with coffee quality were determined across 20 farms in the department of Cesar, Colombia, by sampling coffee fruits from Coffea arabica; Var. Castillo General®, Var. Colombia, and Var. Cenicafé 1. In each farm, the fruits were processed and the fermentation process took place between 10 and 42 h following this. Three samples of mucilage and washed coffee seeds were collected per farm during the fermentation process. The microorganisms present in the mucilage were identified using metataxonomic methods by amplifying the 16S rRNA gene for bacteria and ITS for fungi. The microorganisms’ morphotypes were isolated and identified. The analysis of bacteria allowed for the identification of the following genera: Gluconobacter, Leuconostoc, Acetobacter, Frateuria, Pantoea, Pseudomonas, Tatumella, and Weisella, as well as unclassified enterobacteria; the Lactobacillacea and Secundilactobacillus families were only identified in the Var. Cenicafé 1. For fungi, the top 11 genera and families found included Hanseniaspora, Candida, Meyerozyma, Wickerhamomyces, Pichia, f-Saccharomycodaceae, f-Nectriciae, unclassified fungi, and Saccharomycetaceae, which were only found in Cenicafé 1. A total of 92% of the coffee samples obtained scored between 80.1 and 84.9, indicating “Very Good” coffee (Specialty Coffee Association (SCA) scale). Farms with the longest fermentation times showed better coffee attributes related to acidity, fragrance, and aroma. During coffee fermentation, there is a central microbiome. The differences between the microorganisms’ genera could be influenced by the coffee variety, while the specific conditions of each farm (i.e., altitude and temperature) and its fermentation processes could determine the proportions of and interactions between the microbial groups that favor the sensory characteristics responsible for coffee cup quality.
Ethanol Extracts from Torreya grandis Seed Have Potential to Reduce Hyperuricemia in Mouse Models by Influencing Purine Metabolism
Authors: Yao Jianghui , Bai Enhe , Duan Yanwen , Huang Yong
Published: March 2024

The purpose of this study was to evaluate the efficacy of ethanol extracts from Torreya grandis seed (EST) as a functional food in hyperuricemia mice. We investigated EST by analyzing its chemical composition. Using a mouse model of hyperuricemia induced by potassium oxonate (PO), we evaluated the effects of EST on uric acid (UA) production, inflammation-related cytokines, and gut microbiota diversity. The primary constituents of EST consist of various flavonoids and phenolic compounds known for their antioxidant and anti-inflammatory properties in vitro. Notably, our findings demonstrate that EST significantly reduced UA levels in hyperuricemia mice by 71.9%, which is comparable to the effects observed with xanthine treatment. Moreover, EST exhibited an inhibitory effect on xanthine oxidase activity in mouse liver, with an IC50 value of 20.90 μg/mL (36%). EST also provided protective effects to the mouse kidneys by modulating oxidative stress and inflammation in damaged tissues, while also enhancing UA excretion. Finally, EST influenced the composition of the intestinal microbiota, increasing the relative abundance of beneficial bacteria such as Akkermansia muciniphila, Corynebacterium parvum, Enterorhabdus, Muribaculaceae, Marvinbryantia, and Blautia. In summary, our research unveils additional functions of Torreya grandis and offers new insights into the future of managing hyperuricemia.
Effective Natural Language Processing Algorithms for Early Alerts of Gout Flares from Chief Complaints
Authors: Oliveira Lucas Lopes , Jiang Xiaorui , Babu Aryalakshmi Nellippillipathil , Karajagi Poonam , Daneshkhah Alireza
Published: March 2024

Early identification of acute gout is crucial, enabling healthcare professionals to implement targeted interventions for rapid pain relief and preventing disease progression, ensuring improved long-term joint function. In this study, we comprehensively explored the potential early detection of gout flares (GFs) based on nurses’ chief complaint notes in the Emergency Department (ED). Addressing the challenge of identifying GFs prospectively during an ED visit, where documentation is typically minimal, our research focused on employing alternative Natural Language Processing (NLP) techniques to enhance detection accuracy. We investigated GF detection algorithms using both sparse representations by traditional NLP methods and dense encodings by medical domain-specific Large Language Models (LLMs), distinguishing between generative and discriminative models. Three methods were used to alleviate the issue of severe data imbalances, including oversampling, class weights, and focal loss. Extensive empirical studies were performed on the Gout Emergency Department Chief Complaint Corpora. Sparse text representations like tf-idf proved to produce strong performances, achieving F1 scores higher than 0.75. The best deep learning models were RoBERTa-large-PM-M3-Voc and BioGPT, which had the best F1 scores for each dataset, with a 0.8 on the 2019 dataset and a 0.85 F1 score on the 2020 dataset, respectively. We concluded that although discriminative LLMs performed better for this classification task when compared to generative LLMs, a combination of using generative models as feature extractors and employing a support vector machine for classification yielded promising results comparable to those obtained with discriminative models.
Study on Carbonation of Porcine Blood Hydrogel in the Composite Mortar of Ancient Chinese Architectural Painting
Authors: Cheng Cong , Ma Wenhua , Chen Rui , Zhu Yeting , Zheng Lizhen , Li Wei , Hu Daodao
Published: March 2024

In the ancient Chinese recipe for composite mortar used in the construction of ground layers for architectural painting, the mixture of porcine blood and lime water is one of the constituent materials. Herein, according to the traditional recipe, the interaction between porcine blood and lime water was systematically and deeply investigated. The experimental investigation demonstrated that porcine blood mixed with lime water at the ratio found in the recipe can form a hydrogel with a hydrophobic surface. During air-drying, the lime water in porcine blood hydrogel can react with CO2 to form calcium carbonate. The crystal morphology of the formed calcium carbonate depends on the surrounding micro-environment of calcium ions in the porcine blood hydrogel. The formed morphology of calcium carbonate includes small calcite crystallites, small graininess calcite crystals with round features, calcite aggregates with layered ladder-like structures, and amorphous calcium carbonate (ACC). Interestingly, the calcium carbonate formed in the inner part of the porcine blood hydrogel exhibits lamellar distribution due to a Liesegang pattern formation. Based on the findings that the porcine blood hydrogel has surface hydrophobicity and brittleness, it can be predicted that in the preparation process of composite mortar for ancient building color painting base course, porcine blood used in the form of a hydrogel is not only easier to be dispersed in hydrophobic tung oil than in liquid porcine blood but also the affinity between porcine blood gel and tung oil is enhanced. As constituent material dispersed in the composite mortar, the layered distribution of calcium carbonate in the porcine blood hydrogel may presumably be beneficial to reduce the internal stress of the composite mortar material.
The Impact of White Supremacy on First-Generation Mixed-Race Identity in Post-Apartheid South Africa
Authors: Metcalfe Jody
Published: March 2024

South African white supremacy has been shaped by over 400 years of settler colonialism and white minority apartheid rule to craft a pervasive and entrenched legacy of privilege and oppression in the post-apartheid context. This paper explores the constructions of white supremacy, specifically its role in shaping the perceptions of first-generation mixed-race identity in South Africa, through semi-structured, in-depth interviews. Through a critical race theory and an intersectional lens, this paper unpacks the personal, political, and social impact of white supremacist structures on the identity construction of first-generation mixed-race people in post-apartheid South Africa; specifically, societal- and self-perceptions of their identity within power structures with which they interact. Moreover, this paper aims to understand how first-generation mixed-race people understand their connections to white privilege. Ultimately this paper argues that although first-generation mixed-race people experience relative privilege, their access to white privilege and acceptance within structures of whiteness is always conditional.
Serum Urate as a Surrogate Outcome for Gout Flares: Where Do We Stand Today?
Authors: Stamp Lisa K. , Christensen Robin , Morillon Melanie B.
Published: March 2024

In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy.
Association between Workplace Bullying, Job Stress, and Professional Quality of Life in Nurses: A Systematic Review and Meta-Analysis
Authors: Galanis Petros , Moisoglou Ioannis , Katsiroumpa Aglaia , Mastrogianni Maria
Published: March 2024

Workplace bullying affects workers’ lives, causing several mental and physical health problems and job-related issues. Therefore, a summary of the evidence on the consequences of workplace bullying on workers’ lives is essential to improve working conditions. The literature lacks systematic reviews and meta-analyses on the association between workplace bullying and job stress and the professional quality of life of nurses. Thus, we aimed to quantitatively summarize the data on the association between workplace bullying, job stress, and professional quality of life. We performed our study in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The review protocol was registered with PROSPERO (CRD42024495948). We searched PubMed, Medline, Scopus, Cinahl, and Web of Science up to 4 January 2024. We calculated pooled correlation coefficients and 95% confidence intervals [CI]. We identified nine studies with a total of 3730 nurses. We found a moderate positive correlation between workplace bullying and job stress (pooled correlation coefficient = 0.34, 95% CI = 0.29 to 0.39). Moreover, a small negative correlation between workplace bullying and compassion satisfaction (pooled correlation coefficient = −0.28, 95% CI = −0.41 to −0.15) was identified. Additionally, our findings suggested a moderate positive correlation between workplace bullying and job burnout (pooled correlation coefficient = 0.43, 95% CI = 0.32 to 0.53) and secondary traumatic stress (pooled correlation coefficient = 0.36, 95% CI = 0.11 to 0.57). Our findings can help nursing managers and policy-makers to draw attention to workplace bullying by implementing effective interventions, so as to reduce the bullying of nurses.
The Effect of Salinity and Drought on the Essential Oil Yield and Quality of Various Plant Species of the Lamiaceae Family (Mentha spicata L., Origanum dictamnus L., Origanum onites L.)
Authors: Stefanakis Michalis K. , Giannakoula Anastasia E. , Ouzounidou Georgia , Papaioannou Charikleia , Lianopoulou Vaia , Philotheou-Panou Eleni
Published: March 2024

Mentha spicata L., Origanum dictamnus L., and Origanum onites L. are aromatic plants that produce very important essential oils. They are considered model plants with beneficial health properties due to their antioxidant content. Enhancing the yield while maintaining the quality of essential oil is of significant commercial importance. Salinization and drought cause various effects on the yield and quality of the bioactive constituents in essential oil. By assessing the response of these plants and their secondary metabolites accumulation to different salt stress and irrigation levels, this study aims to gain insights into how plants adapt to and cope with salinity and drought. A pot experiment was conducted in the spring of 2020 to assess the effect of salinity and drought stress on the growth and essential oils content of the three aromatic plant species mentioned above. The soil mixture used was perlite and peat in a ratio of 1:1:6, while four salinity treatments (25, 50, 100, and 150 mΜ NaCl) and two levels of irrigation were applied (100% and 50%). Salinity significantly affects total chlorophyll concentration especially in higher concentrations (100 and 150 mM) in M. spicata plants, especially under 50% soil water irrigation. Under the same conditions, M. spicata contained the higher proline concentration, which was significantly greater than that in O. dictamnus and O. onites. Similar variations of malondialdehyde and hydrogen hyperoxide were revealed among the three species, with significantly higher values in M. spicata when subjected to both excess salinity and drought conditions. The major compounds identified in M. spicata were carvone, in O. dictamnus carvacrol, and p-cymene and in O. onites carvacrol. It is important to highlight that O. onites had the highest concentration of essential oil, and that the concentration increased with the increase of NaCl. This suggests that the presence of NaCl in the soil may have a stimulating effect on the production of essential oil in O. onites. However, it is plausible that the stress caused by NaCl triggers a physiological response in O. onites, leading to increased production of essential oil. This could be a protective mechanism to enhance the plant’s resistance to the stressor. Overall, O. onites and O. dictamnus appeared to be more resistant to these stress conditions than M. spicata, since they maintained their growth and essential oil quality indicators at higher levels. These two species possess mechanisms that prevent or minimize lipid peroxidation, thus protecting their cell membranes and maintaining their ultrastructure integrity.
Safety and Efficacy of IL-12 Plasmid DNA Transfection into Pig Skin: Supportive Data for Human Clinical Trials on Gene Therapy and Vaccination
Authors: Lampreht Tratar Ursa , Jesenko Tanja , Omerzel Masa , Seliskar Alenka , Stupan Urban , Djokic Mihajlo , Sredensek Jerneja , Trotovsek Blaz , Sersa Gregor , Cemazar Maja
Published: March 2024

Gene electrotransfer (GET) of plasmids encoding interleukin 12 (IL-12) has already been used for the treatment of various types of tumors in human oncology and as an adjuvant in DNA vaccines. In recent years, we have developed a plasmid encoding human IL-12 (phIL12) that is currently in a phase I clinical study. The aim was to confirm the results of a non-clinical study in mice on pharmacokinetic characteristics and safety in a porcine model that better resembled human skin. The GET of phIL12 in the skin was performed on nine pigs using different concentrations of plasmid phIL12 and invasive (needle) or noninvasive (plate) types of electrodes. The results of our study demonstrate that the GET of phIL-12 with needle electrodes induced the highest expression of IL-12 at the protein level on day 7 after the procedure. The plasmid was distributed to all tested organs; however, its amount decreased over time and was at a minimum 28 days after GET. Based on plasmid copy number and expression results, together with blood analysis, we showed that IL-12 GET is safe in a porcine animal model. Furthermore, we demonstrated that pigs are a valuable model for human gene therapy safety studies.
Autoimmune Thyroiditis and Vitamin D
Authors: Durá-Travé Teodoro , Gallinas-Victoriano Fidel
Published: March 2024

Hashimoto’s thyroiditis (HT) is marked by self-tissue destruction as a consequence of an alteration in the adaptive immune response that entails the evasion of immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review of the relationship between vitamin D status and HT and the role of vitamin D supplementation in reducing HT risk by modulating the immune system. There is extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titers decreased significantly. Further knowledge of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases requires the execution of additional randomized, double-blind, placebo-controlled trials and longer follow-up periods.
RNA Expression of MMP12 Is Strongly Associated with Inflammatory Bowel Disease and Is Regulated by Metabolic Pathways in RAW 264.7 Macrophages
Authors: Arosa Laura , Camba-Gómez Miguel , Lorenzo-Martín Luis Francisco , Clavaín Laura , López Miguel , Conde-Aranda Javier
Published: March 2024

Macrophage metalloelastase or matrix metalloproteinase-12 (MMP12) is a macrophage-specific proteolytic enzyme involved in the physiopathology of many inflammatory diseases, including inflammatory bowel disease. Although previously published data suggested that the modulation of MMP12 in macrophages could be a determinant for the development of intestinal inflammation, scarce information is available on the mechanisms underlying the regulation of MMP12 expression in those phagocytes. Therefore, in this study, we aimed to delineate the association of MMP12 with inflammatory bowel disease and the molecular events leading to the transcriptional control of this metalloproteinase. For that, we used publicly available transcriptional data. Also, we worked with the RAW 264.7 macrophage cell line for functional experiments. Our results showed a strong association of MMP12 expression with the severity of inflammatory bowel disease and the response to relevant biological therapies. In vitro assays revealed that the inhibition of mechanistic target of rapamycin complex 1 (mTORC1) and the stimulation of the AMP-activated protein kinase (AMPK) signaling pathway potentiated the expression of Mmp12. Additionally, AMPK and mTOR required a functional downstream glycolytic pathway to fully engage with Mmp12 expression. Finally, the pharmacological inhibition of MMP12 abolished the expression of the proinflammatory cytokine Interleukin-6 (Il6) in macrophages. Overall, our findings provide a better understanding of the mechanistic regulation of MMP12 in macrophages and its relationship with inflammation.
Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer
Authors: Bailey Morgan , Morand Susan , Royfman Rachel , Lin Leslie , Singh Aditi , Stanbery Laura , Walter Adam , Hamouda Danae , Nemunaitis John
Published: March 2024

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi’s), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi’s have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.
The Role of Gut Microbiota in Neuromyelitis Optica Spectrum Disorder
Authors: Yao Shi-Qi , Yang Xiayin , Cen Ling-Ping , Tan Shaoying
Published: March 2024

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, disabling inflammatory disease of the central nervous system (CNS). Aquaporin-4 (AQP4)-specific T cells play a key role in the pathogenesis of NMOSD. In addition to immune factors, T cells recognizing the AQP4 epitope showed cross-reactivity with homologous peptide sequences in C. perfringens proteins, suggesting that the gut microbiota plays an integral role in the pathogenicity of NMOSD. In this review, we summarize research on the involvement of the gut microbiota in the pathophysiology of NMOSD and its possible pathogenic mechanisms. Among them, Clostridium perfringens and Streptococcus have been confirmed to play a role by multiple studies. Based on this evidence, metabolites produced by gut microbes, such as short-chain fatty acids (SCFAs), tryptophan (Trp), and bile acid (BA) metabolites, have also been found to affect immune cell metabolism. Therefore, the role of the gut microbiota in the pathophysiology of NMOSD is very important. Alterations in the composition of the gut microbiota can lead to pathological changes and alter the formation of microbiota-derived components and metabolites. It can serve as a biomarker for disease onset and progression and as a potential disease-modifying therapy.
Differential Mitochondrial, Oxidative Stress and Inflammatory Responses to SARS-CoV-2 Spike Protein Receptor Binding Domain in Human Lung Microvascular, Coronary Artery Endothelial and Bronchial Epithelial Cells
Authors: Kulkovienė Gabrielė , Narauskaitė Deimantė , Tunaitytė Agilė , Volkevičiūtė Augusta , Balion Zbigniev , Kutakh Olena , Gečys Dovydas , Kairytė Milda , Uldukytė Martyna , Stankevičius Edgaras , Jekabsone Aistė
Published: March 2024

Recent evidence indicates that the SARS-CoV-2 spike protein affects mitochondria with a cell type-dependent outcome. We elucidate the effect of the SARS-CoV-2 receptor binding domain (RBD) on the mitochondrial network and cristae morphology, oxygen consumption, mitoROS production, and inflammatory cytokine expression in cultured human lung microvascular (HLMVECs), coronary artery endothelial (HCAECs), and bronchial epithelial cells (HBECs). Live Mito Orange staining, STED microscopy, and Fiji MiNa analysis were used for mitochondrial cristae and network morphometry; an Agilent XFp analyser for mitochondrial/glycolytic activity; MitoSOX fluorescence for mitochondrial ROS; and qRT-PCR plus Luminex for cytokines. HLMVEC exposure to SARS-CoV-2 RBD resulted in the fragmentation of the mitochondrial network, mitochondrial swelling, increased cristae area, reduced cristae density, and suppressed mitochondrial oxygen consumption and glycolysis. No significant mitochondrial morphology or oxygen consumption changes were observed in HCAECs and HBECs. SARS-CoV-2 RBD induced mitoROS-mediated expression of cytokines GM-CSF and IL-1β in all three investigated cell types, along with IL-8 expression in both endothelial cell types. The findings suggest mitochondrial ROS control SARS-CoV-2 RBD-induced inflammation in HLMVECs, HCAECs, and HBECs, with the mitochondria of HLMVECs being more sensitive to SARS-CoV-2 RBD.
Effect of GnRH Active Immunisation on Reproductive Performance of Male Sprague Dawley Rats
Authors: Zhang Cheng-Qi , Li Shuang-Shuang , Hu Bo , Xu Li-Wen , Liu Jia-Jia , Sun Ya-Jie , Bai Xue
Published: March 2024

To investigate the effect of active immunisation with gonadotropin-releasing hormone (GnRH) on the reproductive function in male Sprague Dawley (SD) rats, 24 42-day-old rats were randomly assigned to treatment with GnRH6-MAP, GnRH-OVA, a surgical castration group, and a blank control group. Each rat in the treatment groups was intramuscularly injected at 6, 8, and 10 weeks of age. The serum concentrations of testosterone (T), follicle-stimulating hormone (FSH), luteinising hormone (LH), and anti-GnRH antibodies were determined using enzyme-linked immunosorbent assays. The results showed that active immunisation with recombinant GnRH6-MBP and GnRH-OVA significantly increased the serum levels of anti-GnRH antibodies and reduced the serum concentrations of testosterone compared to the black control. Eight weeks after immunisation, the rats’ testes were surgically removed for morphological evaluation, showing atrophy of the convoluted vasculature, relative emptying of the lumen, and insignificant differentiation of spermatogonial cells, which were increased in weight and volume compared with the blank control group. These findings indicated that active immunisation with GnRH can lead to testicular atrophy and reduce gonadal hormone concentrations, suggesting that GnRH is a highly effective immunogen.
Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance
Authors: Li Xi , Yang Yangjun , Shi Xiaoyu , Zhang Zhe , Ding Shuzhe
Published: March 2024

The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.