bluuebunny/crossref_metadata_2025 huggingface dataset:
Price Competition or Quality Competition? Evidence of Forest Products in Top Exporting Countries
Authors: Jiang Bo , Cai Wanhua , Dai Yongwu
Published: August 2023

Price competition and quality competition are the main ways to increase and maintain international competitiveness in the world. However, competitive strategies can vary significantly from product to product. With the utility function and trade gravity model as the research framework in this paper, we use the top 10 countries in terms of the trade volume of forest products from 2012 to 2021 as samples to systematically explore the differential impacts of price and quality on the international competitiveness of forest products. The results of the panel data model that show the regression coefficient of forest product price in terms of international competitiveness are significantly negative, while the regression coefficient of forest product quality is significantly positive, but the absolute value of the regression coefficient of product quality is higher than that of forest product price. Thus, the price and quality of forest products are key factors affecting international competitiveness in general, with the quality of forest products having a higher impact on international competitiveness than the price. However, a further analysis of different forest product categories and countries revealed significant differences in the significance and magnitude of price and quality impacts on international competitiveness. The quality of forest products contributes more to international competitiveness in Brazil, Canada, Germany, Russia, Sweden and the United States. Conversely, the price of forest products in China, Finland, Italy and Poland contributes more to international competitiveness. Therefore, an objective choice of price, quality or a quality:price ratio strategy, taking into account the industry and characteristics of forest products in each country, can contribute to the sustainable improvement of the international competitiveness of forest products.
Spot Market Cloud Orchestration Using Task-Based Redundancy and Dynamic Costing
Authors: O’Neill Vyas , Soh Ben
Published: August 2023

Cloud computing has become ubiquitous in the enterprise environment as its on-demand model realizes technical and economic benefits for users. Cloud users demand a level of reliability, availability, and quality of service. Improvements to reliability generally come at the cost of additional replication. Existing approaches have focused on the replication of virtual environments as a method of improving the reliability of cloud services. As cloud systems move towards microservices-based architectures, a more granular approach to replication is now possible. In this paper, we propose a cloud orchestration approach that balances the potential cost of failure with the spot market running cost, optimizing the resource usage of the cloud system. We present the results of empirical testing we carried out using a simulator to compare the outcome of our proposed approach to a control algorithm based on a static reliability requirement. Our empirical testing showed an improvement of between 37% and 72% in total cost over the control, depending on the specific characteristics of the cloud models tested. We thus propose that in clouds where the cost of failure can be reasonably approximated, our approach may be used to optimize the cloud redundancy configuration to achieve a lower total cost.
A Novel SDWSN-Based Testbed for IoT Smart Applications
Authors: Al-Hamid Duaa Zuhair , Karegar Pejman A. , Chong Peter Han Joo
Published: August 2023

Wireless sensor network (WSN) environment monitoring and smart city applications present challenges for maintaining network connectivity when, for example, dynamic events occur. Such applications can benefit from recent technologies such as software-defined networks (SDNs) and network virtualization to support network flexibility and offer validation for a physical network. This paper aims to present a testbed-based, software-defined wireless sensor network (SDWSN) for IoT applications with a focus on promoting the approach of virtual network testing and analysis prior to physical network implementation to monitor and repair any network failures. Herein, physical network implementation employing hardware boards such as Texas Instruments CC2538 (TI CC2538) and TI CC1352R sensor nodes is presented and designed based on virtual WSN- based clustering for stationary and dynamic networks use cases. The key performance indicators such as evaluating node (such as a gateway node to the Internet) connection capability based on packet drop and energy consumption virtually and physically are discussed. According to the test findings, the proposed software-defined physical network benefited from “prior-to-implementation” analysis via virtualization, as the performance of both virtual and physical networks is comparable.
Aquaporins Transcripts with Potential Prognostic Value in Pancreatic Cancer
Authors: Lopes Paula A. , Fonseca Elisabete , da Silva Inês V. , Vigia Emanuel , Paulino Jorge , Soveral Graça
Published: August 2023

Pancreatic cancer is anticipated to be the second leading cause of cancer-related death by 2030. Aquaporins (AQPs), a family of water channel proteins, have been linked to carcinogenesis. The aim of this study was to determine AQP gene expression in pancreatic cancer tissues and to validate aquaporins as possible diagnosis and/or prognosis genes. The relative gene expression levels of AQP1, AQP3, AQP5, and AQP9 were analyzed using real-time quantitative PCR (RT-qPCR) in 24 paired pancreatic tumors and adjacent healthy tissues according to variables such as age, gender, and tumor invasiveness and aggressiveness. AQPs transcripts were detected in both healthy and tumor tissues. While AQP1 was downregulated in the tumor samples, AQP3 was particularly overexpressed in low-grade invasive tumors. Interestingly, most of the strong positive Pearson correlation coefficients found between AQPs in healthy tissues were lost when analyzing the tumor tissues, suggesting disruption of the coordinated AQP-gene expression in pancreatic cancer.
Identifying Innate Resistance Hotspots for SARS-CoV-2 Antivirals Using In Silico Protein Techniques
Authors: Portelli Stephanie , Heaton Ruby , Ascher David B.
Published: August 2023

The development and approval of antivirals against SARS-CoV-2 has further equipped clinicians with treatment strategies against the COVID-19 pandemic, reducing deaths post-infection. Extensive clinical use of antivirals, however, can impart additional selective pressure, leading to the emergence of antiviral resistance. While we have previously characterized possible effects of circulating SARS-CoV-2 missense mutations on proteome function and stability, their direct effects on the novel antivirals remains unexplored. To address this, we have computationally calculated the consequences of mutations in the antiviral targets: RNA-dependent RNA polymerase and main protease, on target stability and interactions with their antiviral, nucleic acids, and other proteins. By analyzing circulating variants prior to antiviral approval, this work highlighted the inherent resistance potential of different genome regions. Namely, within the main protease binding site, missense mutations imparted a lower fitness cost, while the opposite was noted for the RNA-dependent RNA polymerase binding site. This suggests that resistance to nirmatrelvir/ritonavir combination treatment is more likely to occur and proliferate than that to molnupiravir. These insights are crucial both clinically in drug stewardship, and preclinically in the identification of less mutable targets for novel therapeutic design.
Behavioral and Cognitive Performance Following Exposure to Second-Hand Smoke (SHS) from Tobacco Products Associated with Oxidative-Stress-Induced DNA Damage and Repair and Disruption of the Gut Microbiome
Authors: Raber Jacob , Stagaman Keaton , Kasschau Kristin D. , Davenport Conor , Lopes Leilani , Nguyen Dennis , Torres Eileen Ruth , Sharpton Thomas J. , Kisby Glen
Published: August 2023

Exposure to second-hand Smoke (SHS) remains prevalent. The underlying mechanisms of how SHS affects the brain require elucidation. We tested the hypothesis that SHS inhalation drives changes in the gut microbiome, impacting behavioral and cognitive performance as well as neuropathology in two-month-old wild-type (WT) mice and mice expressing wild-type human tau, a genetic model pertinent to Alzheimer’s disease mice, following chronic SHS exposure (10 months to ~30 mg/m3). SHS exposure impacted the composition of the gut microbiome as well as the biodiversity and evenness of the gut microbiome in a sex-dependent fashion. This variation in the composition and biodiversity of the gut microbiome is also associated with several measures of cognitive performance. These results support the hypothesis that the gut microbiome contributes to the effect of SHS exposure on cognition. The percentage of 8-OHdG-labeled cells in the CA1 region of the hippocampus was also associated with performance in the novel object recognition test, consistent with urine and serum levels of 8-OHdG serving as a biomarker of cognitive performance in humans. We also assessed the effects of SHS on the percentage of p21-labeled cells, an early cellular marker of senescence that is upregulated in bronchial cells after exposure to cigarette smoke. Nuclear staining of p21-labeled cells was more prominent in larger cells of the prefrontal cortex and CA1 hippocampal neurons of SHS-exposed mice than in sham-exposed mice, and there was a significantly greater percentage of labelled cells in the prefrontal cortex and CA1 region of the hippocampus of SHS than air-exposed mice, suggesting that exposure to SHS may result in accelerated brain aging through oxidative-stress-induced injury.
Integrating Cultural Sites into the Sesia Val Grande UNESCO Global Geopark (North-West Italy): Methodologies for Monitoring and Enhancing Cultural Heritage
Authors: Guerini Michele , Khoso Rasool Bux , Negri Arianna , Mantovani Alizia , Storta Elena
Published: August 2023

UNESCO Global Geoparks are recognised in the scientific community for their exceptional geological significance, but their potential to embrace and preserve cultural heritage sites is underestimated. This study delves into a pioneering approach within the Sesia Val Grande UNESCO Global Geopark (NW Italy), examining the integration of culturally significant sites into conservation and promotion strategies. To achieve a successful integration, we adapted a methodology used for the identification and assessment of geosites, incorporating the criteria of cultural significance, to assess the value of 10 cultural sites within the geopark and compare the results with the assessment values of 10 geosites. Moreover, we submitted survey questionnaires to geopark tourists to understand their interest in visiting both geosites and cultural sites. The findings reveal the remarkable scientific, educational, and touristic values of these cultural sites, which constitute an important resource for the geopark, to be enhanced and protected together with the geosites. Interestingly, the higher scientific value of cultural sites corresponds to increased visitor interest, which is in contrast to the trend observed for geosites. Through this unified approach, the monitoring of cultural heritage within the geopark is simplified and improved, enabling a comprehensive inventory and efficient administration. Moreover, by aligning visitor interests with scientific value, the Sesia Val Grande Geopark can enhance conservation and sustainable tourism efforts.
Effects of Road Dust Particle Size on Mineralogy, Chemical Bulk Content, Pollution and Health Risk Analyses
Authors: Navarro-Ciurana Dídac , Corbella Mercè , Meroño Daniel
Published: August 2023

Because of the rising environmental and health concerns associated with atmospheric pollution caused by potentially toxic elements (PTEs), several road dust studies have been performed across the world in recent decades. This paper illustrates the effects of particle size on the PTE contents, mineralogical composition, environmental pollution and health risk assessments in road dust from Barcelona (Spain). The samples were sieved into five size fractions ranging from <45 to 500–800 µm. Although the major mineral contents (tectosilicates, phyllosilicates, and carbonates) were profuse in all fractions, the identified inhalable PTE particles (e.g., Fe, Cr, Cu, Zn, Ni, and REE), with size < 10 µm, were more pervasive in the finest fraction (<45 μm). This is consistent with the concentrations measured: the finest fractions were richer in PTEs than the coarser ones, resulting in a direct correlation with the enrichment factor (EFx), geo-accumulation (Igeo), and non-carcinogenic (HI) and carcinogenic (CRI) values. Igeo and EFx values can be appropriate tracers for some common elements (e.g., Zn, Sb, Sn, Cu, and Cr), but they do not seem adequate for anthropogenic particles accumulated at concentrations similar to the geogenic background. Overall, the HI and CRI values obtained in Barcelona were acceptable, reflecting no serious health impacts in the study area, except for Cr. Our results suggest that fine dust particles are a more suitable fraction to conduct pollution and health risk assessments than coarser ones, although the EFx, Igeo, HI, and CRI threshold values should be redefined in the future to include all emergent pollutants as well. In summary, monitoring programs should include at least the road dust evaluation of <45 µm particles, which can be performed with a simple sieving method, which is both time- and cost-effective.
What Is Wellbeing, and What Is Important for Wellbeing? Indigenous Voices from across Canada
Authors: Tsuji Stephen R. J. , Zuk Aleksandra M. , Solomon Andrew , Edwards-Wheesk Ruby , Ahmed Fatima , Tsuji Leonard J. S.
Published: August 2023

Indigenous peoples’ perceptions of wellbeing differ from non-Indigenous constructs. Thus, it is imperative to recognize that Indigenous peoples will conceptualize wellbeing from their perspectives and set their own wellbeing priorities. In keeping with this viewpoint, the aims of the present study were to conceptualize wellbeing and determine what was (and is) important for wellbeing from Canadian Indigenous peoples’ perspectives. In this paper, we take a partnership approach based on the elements of respect, equity, and empowerment. One primary data source and two existing data sources were examined and analyzed thematically utilizing a combination approach of deductive and inductive coding. Indigenous leadership and organizations viewed wellbeing holistically and conceptualized wellbeing multidimensionally. From across Canada, wellbeing was communicated as physical, economic, political, social, and cultural. The scaling of wellbeing represented a collectivist perspective, and land was the connecting thread between all types of wellbeing, being a place to practice cultural traditions, reassert one’s Indigenous identity, find solace, and pass on Indigenous knowledge and languages. Although wellbeing was discussed in the context of the individual, family, community, and nation, wellbeing was most often discussed at the cultural level by regional and national Indigenous leadership and organizations. Even in acknowledging the great cultural diversity among Canadian Indigenous nations, four concordant themes were identified regionally and nationally, with respect to what was important for cultural wellbeing: land and water, sustainability, and inherent obligations; being on the land, and indigenous languages and knowledge systems; sustainable development; and meaningful involvement in decision-making, and free, prior, and informed consent. Taking into account these themes is foundational for any interaction with Indigenous peoples, especially in the context of land, culture, and development. There needs to be a new beginning on the journey to reconciliation with land and cultural wellbeing at the forefront.
Sleep Time, Physical Activity, and Screen Time among Montana American Indian Youth
Authors: Grant Vernon , Gachupin Francine C.
Published: August 2023

The purpose of this study is to describe sleep, PA, and screen time behaviors among rural American Indian (AI) youth, stratified by sex and grade, to better understand how to address these health behaviors in AI youth. Body composition, a screen time survey, and demographic information were collected from 65 AI youth. Accelerometers were worn for 7 days. Sixty percent were overweight or obese. Sleep did not differ by sex or grade, with an actigraphy-based total sleep time (aTST) of 7.8 h per night. Boys had significantly more light PA (p = 0.002) and vigorous PA (p = 0.01) compared to girls. Screen time did differ by sex but not by grade, with girls in the sixth and seventh grades reporting more screen time than boys, but boys in the eighth grade reporting more screen time than girls. Despite sex differences in screen time, high levels of screen time and obesity and low levels of PA and sleep are a concern in this population.
The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats
Authors: Kraehling Jan R. , Benardeau Agnes , Schomber Tibor , Popp Laura , Vienenkoetter Julia , Ellinger-Ziegelbauer Heidrun , Pavkovic Mira , Hartmann Elke , Siudak Krystyna , Freyberger Alexius , Hagelschuer Ina , Mathar Ilka , Hueser Joerg , Hahn Michael G. , Geiss Volker , Eitner Frank , Sandner Peter
Published: August 2023

Chronic kidney disease (CKD) progression is associated with persisting oxidative stress, which impairs the NO-sGC-cGMP signaling cascade through the formation of oxidized and heme-free apo-sGC that cannot be activated by NO. Runcaciguat (BAY 1101042) is a novel, potent, and selective sGC activator that binds and activates oxidized and heme-free sGC and thereby restores NO-sGC-cGMP signaling under oxidative stress. Therefore, runcaciguat might represent a very effective treatment option for CKD/DKD. The potential kidney-protective effects of runcaciguat were investigated in ZSF1 rats as a model of CKD/DKD, characterized by hypertension, hyperglycemia, obesity, and insulin resistance. ZSF1 rats were treated daily orally for up to 12 weeks with runcaciguat (1, 3, 10 mg/kg/bid) or placebo. The study endpoints were proteinuria, kidney histopathology, plasma, urinary biomarkers of kidney damage, and gene expression profiling to gain information about relevant pathways affected by runcaciguat. Furthermore, oxidative stress was compared in the ZSF1 rat kidney with kidney samples from DKD patients. Within the duration of the 12-week treatment study, kidney function was significantly decreased in obese ZSF1 rats, indicated by a 20-fold increase in proteinuria, compared to lean ZSF1 rats. Runcaciguat dose-dependently and significantly attenuated the development of proteinuria in ZSF1 rats with reduced uPCR at the end of the study by −19%, −54%, and −70% at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo treatment. Additionally, average blood glucose levels measured as HbA1C, triglycerides, and cholesterol were increased by five times, twenty times, and four times, respectively, in obese ZSF1 compared to lean rats. In obese ZSF1 rats, runcaciguat reduced HbA1c levels by −8%, −34%, and −76%, triglycerides by −42%, −55%, and −71%, and cholesterol by −16%, −17%, and −34%, at 1, 3, and 10 mg/kg/bid, respectively, compared to placebo. Concomitantly, runcaciguat also reduced kidney weights, morphological kidney damage, and urinary and plasma biomarkers of kidney damage. Beneficial effects were accompanied by changes in gene expression that indicate reduced fibrosis and inflammation and suggest improved endothelial stabilization. In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061).
Metabolomics in Pulmonary Hypertension—A Useful Tool to Provide Insights into the Dark Side of a Tricky Pathology
Authors: Bassareo Pier Paolo , D’Alto Michele
Published: August 2023

Pulmonary hypertension (PH) is a multifaceted illness causing clinical manifestations like dyspnea, fatigue, and cyanosis. If left untreated, it often evolves into irreversible pulmonary arterial hypertension (PAH), leading to death. Metabolomics is a laboratory technique capable of providing insights into the metabolic pathways that are responsible for a number of physiologic or pathologic events through the analysis of a biological fluid (such as blood, urine, and sputum) using proton nuclear magnetic resonance spectroscopy or mass spectrometry. A systematic review was finalized according to the PRISMA scheme, with the goal of providing an overview of the research papers released up to now on the application of metabolomics to PH/PAH. So, eighty-five papers were identified, of which twenty-four concerning PH, and sixty-one regarding PAH. We found that, from a metabolic standpoint, the hallmarks of the disease onset and progression are an increase in glycolysis and impaired mitochondrial respiration. Oxidation is exacerbated as well. Specific metabolic fingerprints allow the characterization of some of the specific PH and PAH subtypes. Overall, metabolomics provides insights into the biological processes happening in the body of a subject suffering from PH/PAH. The disarranged metabolic pathways underpinning the disease may be the target of new therapeutic agents. Metabolomics will allow investigators to make a step forward towards personalized medicine.
NANOBODY® Molecule, a Giga Medical Tool in Nanodimensions
Authors: Kunz Sarah , Durandy Manon , Seguin Laetitia , Feral Chloe C.
Published: August 2023

Although antibodies remain the most widely used tool for biomedical research, antibody technology is not flawless. Innovative alternatives, such as Nanobody® molecules, were developed to address the shortcomings of conventional antibodies. Nanobody® molecules are antigen-binding variable-domain fragments derived from the heavy-chain-only antibodies of camelids (VHH) and combine the advantageous properties of small molecules and monoclonal antibodies. Nanobody® molecules present a small size (~15 kDa, 4 nm long and 2.5 nm wide), high solubility, stability, specificity, and affinity, ease of cloning, and thermal and chemical resistance. Recombinant production in microorganisms is cost-effective, and VHH are also building blocks for multidomain constructs. These unique features led to numerous applications in fundamental research, diagnostics, and therapy. Nanobody® molecules are employed as biomarker probes and, when fused to radioisotopes or fluorophores, represent ideal non-invasive in vivo imaging agents. They can be used as neutralizing agents, receptor-ligand antagonists, or in targeted vehicle-based drug therapy. As early as 2018, the first Nanobody®, Cablivi (caplacizumab), a single-domain antibody (sdAb) drug developed by French pharmaceutical giant Sanofi for the treatment of adult patients with acquired thrombocytopenic purpura (aTTP), was launched. Nanobody® compounds are ideal tools for further development in clinics for diagnostic and therapeutic purposes.
BRD4 as a Therapeutic Target in Pulmonary Diseases
Authors: Guo Xia , Olajuyin Ayobami , Tucker Torry A. , Idell Steven , Qian Guoqing
Published: August 2023

Bromodomain and extra-terminal domain (BET) proteins are epigenetic modulators that regulate gene transcription through interacting with acetylated lysine residues of histone proteins. BET proteins have multiple roles in regulating key cellular functions such as cell proliferation, differentiation, inflammation, oxidative and redox balance, and immune responses. As a result, BET proteins have been found to be actively involved in a broad range of human lung diseases including acute lung inflammation, asthma, pulmonary arterial hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Due to the identification of specific small molecular inhibitors of BET proteins, targeting BET in these lung diseases has become an area of increasing interest. Emerging evidence has demonstrated the beneficial effects of BET inhibitors in preclinical models of various human lung diseases. This is, in general, largely related to the ability of BET proteins to bind to promoters of genes that are critical for inflammation, differentiation, and beyond. By modulating these critical genes, BET proteins are integrated into the pathogenesis of disease progression. The intrinsic histone acetyltransferase activity of bromodomain-containing protein 4 (BRD4) is of particular interest, seems to act independently of its bromodomain binding activity, and has implication in some contexts. In this review, we provide a brief overview of the research on BET proteins with a focus on BRD4 in several major human lung diseases, the underlying molecular mechanisms, as well as findings of targeting BET proteins using pharmaceutical inhibitors in different lung diseases preclinically.
Comparative Study of Cytotoxicity and Antioxidant, Anti-Aging and Antibacterial Properties of Unfermented and Fermented Extract of Cornus mas L.
Authors: Zagórska-Dziok Martyna , Ziemlewska Aleksandra , Mokrzyńska Agnieszka , Nizioł-Łukaszewska Zofia , Sowa Ireneusz , Szczepanek Dariusz , Wójciak Magdalena
Published: August 2023

Due to the high demand for products that can help treat various skin conditions, the interest in plant extracts, which are a valuable source of phytochemicals, is constantly growing. In this work, the properties of extracts and ferments from Cornus mas L. and their potential use in cosmetic products were compared. For this purpose, their composition, antioxidant properties and cytotoxicity against skin cells, keratinocytes and fibroblasts were assessed in vitro. In addition, the ability to inhibit the activity of collagenase and elastase was compared, which enabled the assessment of their potential to inhibit skin aging. Microbiological analyses carried out on different bacterial strains were made in order to compare their antibacterial properties. The conducted analyses showed that both dogwood extract and ferment have antioxidant and anti-aging properties. In addition, they can have a positive effect on the viability of keratinocytes and fibroblasts and inhibit the proliferation of various pathogenic bacteria, which indicates their great potential as ingredients in skin care preparations. The stronger activity of the ferment compared to the extract indicates the legitimacy of carrying out the fermentation process of plant raw materials using kombucha in order to obtain valuable products for the cosmetics industry.
The Fibro-Inflammatory Response in the Glaucomatous Optic Nerve Head
Authors: Geiduschek Emma K. , McDowell Colleen M.
Published: August 2023

Glaucoma is a progressive disease and the leading cause of irreversible blindness. The limited therapeutics available are only able to manage the common risk factor of glaucoma, elevated intraocular pressure (IOP), indicating a great need for understanding the cellular mechanisms behind optic nerve head (ONH) damage during disease progression. Here we review the known inflammatory and fibrotic changes occurring in the ONH. In addition, we describe a novel mechanism of toll-like receptor 4 (TLR4) and transforming growth factor beta-2 (TGFβ2) signaling crosstalk in the cells of the ONH that contribute to glaucomatous damage. Understanding molecular signaling within and between the cells of the ONH can help identify new drug targets and therapeutics.
Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis
Authors: Strupp Christian , Corvaro Marco , Cohen Samuel M. , Corton J. Christopher , Ogawa Kumiko , Richert Lysiane , Jacobs Miriam N.
Published: August 2023

In contrast to genotoxic carcinogens, there are currently no internationally agreed upon regulatory tools for identifying non-genotoxic carcinogens of human relevance. The rodent cancer bioassay is only used in certain regulatory sectors and is criticized for its limited predictive power for human cancer risk. Cancer is due to genetic errors occurring in single cells. The risk of cancer is higher when there is an increase in the number of errors per replication (genotoxic agents) or in the number of replications (cell proliferation-inducing agents). The default regulatory approach for genotoxic agents whereby no threshold is set is reasonably conservative. However, non-genotoxic carcinogens cannot be regulated in the same way since increased cell proliferation has a clear threshold. An integrated approach for the testing and assessment (IATA) of non-genotoxic carcinogens is under development at the OECD, considering learnings from the regulatory assessment of data-rich substances such as agrochemicals. The aim is to achieve an endorsed IATA that predicts human cancer better than the rodent cancer bioassay, using methodologies that equally or better protect human health and are superior from the view of animal welfare/efficiency. This paper describes the technical opportunities available to assess cell proliferation as the central gateway of an IATA for non-genotoxic carcinogenicity.
Molecular Markers of Early Immune Response in Tuberculosis: Prospects of Application in Predictive Medicine
Authors: Diatlova Anastasiia , Linkova Natalia , Lavrova Anastasia , Zinchenko Yulia , Medvedev Dmitrii , Krasichkov Alexandr , Polyakova Victoria , Yablonskiy Piotr
Published: August 2023

Tuberculosis (TB) remains an important public health problem and one of the leading causes of death. Individuals with latent tuberculosis infection (LTBI) have an increased risk of developing active TB. The problem of the diagnosis of the various stages of TB and the identification of infected patients in the early stages has not yet been solved. The existing tests (the tuberculin skin test and the interferon-gamma release assay) are useful to distinguish between active and latent infections. But these tests cannot be used to predict the development of active TB in individuals with LTBI. The purpose of this review was to analyze the extant data of the interaction of M. tuberculosis with immune cells and identify molecular predictive markers and markers of the early stages of TB. An analysis of more than 90 sources from the literature allowed us to determine various subpopulations of immune cells involved in the pathogenesis of TB, namely, macrophages, dendritic cells, B lymphocytes, T helper cells, cytotoxic T lymphocytes, and NK cells. The key molecular markers of the immune response to M. tuberculosis are cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, IL-22b, IFNɣ, TNFa, and TGFß), matrix metalloproteinases (MMP-1, MMP-3, and MMP-9), and their inhibitors (TIMP-1, TIMP-2, TIMP-3, and TIMP-4). It is supposed that these molecules could be used as biomarkers to characterize different stages of TB infection, to evaluate the effectiveness of its treatment, and as targets of pharmacotherapy.
Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson’s Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique
Authors: Kawahata Ichiro , Sekimori Tomoki , Oizumi Hideki , Takeda Atsushi , Fukunaga Kohji
Published: August 2023

An increase in the global aging population is leading to an increase in age-related conditions such as dementia and movement disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The accurate prediction of risk factors associated with these disorders is crucial for early diagnosis and prevention. Biomarkers play a significant role in diagnosing and monitoring diseases. In neurodegenerative disorders like α-synucleinopathies, specific biomarkers can indicate the presence and progression of disease. We previously demonstrated the pathogenic impact of fatty acid-binding proteins (FABPs) in α-synucleinopathies. Therefore, this study investigated FABPs as potential biomarkers for Lewy body diseases. Plasma FABP levels were measured in patients with AD, PD, DLB, and mild cognitive impairment (MCI) and healthy controls. Plasma FABP3 was increased in all groups, while the levels of FABP5 and FABP7 tended to decrease in the AD group. Additionally, FABP2 levels were elevated in PD. A correlation analysis showed that higher FABP3 levels were associated with decreased cognitive function. The plasma concentrations of Tau, GFAP, NF-L, and UCHL1 correlated with cognitive decline. A scoring method was applied to discriminate between diseases, demonstrating high accuracy in distinguishing MCI vs. CN, AD vs. DLB, PD vs. DLB, and AD vs. PD. The study suggests that FABPs could serve as potential biomarkers for Lewy body diseases and aid in early disease detection and differentiation.
Anti-Inflammatory Effects of Spirodela polyrhiza (L.) SCHLEID. Extract on Contact Dermatitis in Mice—Its Active Compounds and Molecular Targets
Authors: Kim Kukhwa , Lee Daniel , Kim Han-Young , Kim Soyeon , Lyu Ji-Hyo , Park Sujung , Park Young-Chul , Kim Hyungwoo
Published: August 2023

Spirodela polyrhiza (L.) SCHLEID. has been used to treat epidemic fever, dysuria, and various skin ailments, such as measles eruptions, eczema, and pruritus, in China, Japan, and Korea. In this study, the active compounds in S. polyrhiza and their target genes were identified by network-based analysis. Moreover, the study evaluated the effects of a 70% ethanolic extract of S. polyrhiza (EESP) on skin lesions, histopathological changes, inflammatory cytokines, and chemokines in mice with contact dermatitis (CD) induced by 1-fluoro-2,4-dinitrobenzene (DNFB), and examined the inhibitory effects of EESP on mitogen-activated protein kinase (MAPK) signalling pathways. In our results, 14 active compounds and 29 CD-related target genes were identified. Among them, tumour necrosis factor (TNF) and interleukin 6 (IL-6) were identified as hub genes, and luteolin and apigenin showed a strong binding affinity with TNF (<−8 kcal/mol) and IL-6 (<−6 kcal/mol). Our in vivo studies showed that topical EESP ameliorated DNFB-induced skin lesions and histopathological abnormalities, and reduced the levels of TNF-α, interferon (IFN)-ɣ, IL-6, and monocyte chemotactic protein (MCP)-1 in inflamed tissues. In conclusion, our findings suggest the potential for dermatological applications of S. polyrhiza and suggest that its anti-dermatitis action is related to the inhibition of TNF and IL-6 by luteolin and luteolin glycosides.
Discovery of New Hydrazone-Thiazole Polyphenolic Antioxidants through Computer-Aided Design and In Vitro Experimental Validation
Authors: Marc Gabriel , Stana Anca , Tertiş Mihaela , Cristea Cecilia , Ciorîţă Alexandra , Drăgan Ștefan-Mihai , Toma Vlad-Alexandru , Borlan Raluca , Focșan Monica , Pîrnău Adrian , Vlase Laurian , Oniga Smaranda , Oniga Ovidiu
Published: August 2023

Oxidative stress is linked to a series of diseases; therefore, the development of efficient antioxidants might be beneficial in preventing or ameliorating these conditions. Based on the structure of a previously reported compound with good antioxidant properties and on computational studies, we designed several catechol derivatives with enhanced antioxidant potential. The compounds were synthesized and physicochemically characterized, and their antioxidant activity was assessed through different antiradical, electron transfer and metal ions chelation assays, their electrochemical behavior and cytotoxicity were studied. The results obtained in the in vitro experiments correlated very well with the in silico studies; all final compounds presented very good antioxidant properties, generally superior to those of the reference compounds used. Similarly, the results obtained from studying the compounds’ electrochemical behavior were in good agreement with the results of the antioxidant activity evaluation assays. Regarding the compounds’ cytotoxicity, compound 7b had a dose-dependent inhibitory effect against all cell lines. In conclusion, through computer-aided design, we developed several catechol thiazolyl-hydrazones with excellent antioxidant properties, of which compound 7b, with two catechol moieties in its structure, exhibited the best antioxidant activity.
Structural Space of the Duffy Antigen/Receptor for Chemokines’ Intrinsically Disordered Ectodomain 1 Explored by Temperature Replica-Exchange Molecular Dynamics Simulations
Authors: Kranjc Agata , Narwani Tarun Jairaj , Abby Sophie S. , de Brevern Alexandre G.
Published: August 2023

Plasmodium vivax malaria affects 14 million people each year. Its invasion requires interactions between the parasitic Duffy-binding protein (PvDBP) and the N-terminal extracellular domain (ECD1) of the host’s Duffy antigen/receptor for chemokines (DARC). ECD1 is highly flexible and intrinsically disordered, therefore it can adopt different conformations. We computationally modeled the challenging ECD1 local structure. With T-REMD simulations, we sampled its dynamic behavior and collected its most representative conformations. Our results suggest that most of the DARC ECD1 domain remains in a disordered state during the simulated time. Globular local conformations are found in the analyzed local free-energy minima. These globular conformations share an α-helix spanning residues Ser18 to Ser29 and in many cases they comprise an antiparallel β-sheet, whose β-strands are formed around residues Leu10 and Ala49. The formation of a parallel β-sheet is almost negligible. So far, progress in understanding the mechanisms forming the basis of the P. vivax malaria infection of reticulocytes has been hampered by experimental difficulties, along with a lack of DARC structural information. Our collection of the most probable ECD1 structural conformations will help to advance modeling of the DARC structure and to explore DARC–ECD1 interactions with a range of physiological and pathological ligands.
Bioinformatic Analysis of the CXCR2 Ligands in Cancer Processes
Authors: Korbecki Jan , Bosiacki Mateusz , Chlubek Dariusz , Baranowska-Bosiacka Irena
Published: August 2023

Human CXCR2 has seven ligands, i.e., CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8—chemokines with nearly identical properties. However, no available study has compared the contribution of all CXCR2 ligands to cancer progression. That is why, in this study, we conducted a bioinformatic analysis using the GEPIA, UALCAN, and TIMER2.0 databases to investigate the role of CXCR2 ligands in 31 different types of cancer, including glioblastoma, melanoma, and colon, esophageal, gastric, kidney, liver, lung, ovarian, pancreatic, and prostate cancer. We focused on the differences in the regulation of expression (using the Tfsitescan and miRDB databases) and analyzed mutation types in CXCR2 ligand genes in cancers (using the cBioPortal). The data showed that the effect of CXCR2 ligands on prognosis depends on the type of cancer. CXCR2 ligands were associated with EMT, angiogenesis, recruiting neutrophils to the tumor microenvironment, and the count of M1 macrophages. The regulation of the expression of each CXCR2 ligand was different and, thus, each analyzed chemokine may have a different function in cancer processes. Our findings suggest that each type of cancer has a unique pattern of CXCR2 ligand involvement in cancer progression, with each ligand having a unique regulation of expression.
Advances in Treatment of Dyslipidemia
Authors: Dybiec Jill , Baran Wiktoria , Dąbek Bartłomiej , Fularski Piotr , Młynarska Ewelina , Radzioch Ewa , Rysz Jacek , Franczyk Beata
Published: August 2023

Dyslipidemias have emerged as prevalent disorders among patients, posing significant risks for the development and progression of cardiovascular diseases. These conditions are characterized by elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). This review delves into the current treatment approach, focusing on equalizing these parameters while enhancing the overall quality of life for patients. Through an extensive analysis of clinical trials, we identify disorders that necessitate alternative treatment strategies, notably familial hypercholesterolemia. The primary objective of this review is to consolidate existing information concerning drugs with the potential to revolutionize dyslipidemia management significantly. Among these promising pharmaceuticals, we highlight alirocumab, bempedoic acid, antisense oligonucleotides, angiopoietin-like protein inhibitors, apolipoprotein C-III (APOC3) inhibitors, lomitapide, and cholesterol ester transfer protein (CETP) inhibitors. Our review demonstrates the pivotal roles played by each of these drugs in targeting specific parameters of lipid metabolism. We outline the future landscape of dyslipidemia treatment, envisaging a more tailored and effective therapeutic approach to address this widespread medical concern.
Pharmacological Inhibition of NHE1 Protein Increases White Matter Resilience and Neurofunctional Recovery after Ischemic Stroke
Authors: Metwally Shamseldin Ayman Hassan , Paruchuri Satya Siri , Yu Lauren , Capuk Okan , Pennock Nicholas , Sun Dandan , Song Shanshan
Published: August 2023

To date, recanalization interventions are the only available treatments for ischemic stroke patients; however, there are no effective therapies for reducing stroke-induced neuroinflammation. We recently reported that H+ extrusion protein Na+/H+ exchanger-1 (NHE1) plays an important role in stroke-induced inflammation and white matter injury. In this study, we tested the efficacy of two potent NHE1 inhibitors, HOE642 and Rimeporide, with a delayed administration regimen starting at 24 h post-stroke in adult C57BL/6J mice. Post-stroke HOE642 and Rimeporide treatments accelerated motor and cognitive function recovery without affecting the initial ischemic infarct, neuronal damage, or reactive astrogliosis. However, the delayed administration of NHE1 blockers after ischemic stroke significantly reduced microglial inflammatory activation while enhanced oligodendrogenesis and white matter myelination, with an increased proliferation and decreased apoptosis of the oligodendrocytes. Our findings suggest that NHE1 protein plays an important role in microglia-mediated inflammation and white matter damage. The pharmacological blockade of NHE1 protein activity reduced microglia inflammatory responses and enhanced oligodendrogenesis and white matter repair, leading to motor and cognitive function recovery after stroke. Our study reveals the potential of targeting NHE1 protein as a therapeutic strategy for ischemic stroke therapy.
Research Advances in the Role of the Tropomyosin Family in Cancer
Authors: Meng Yucheng , Huang Ke , Shi Mingxuan , Huo Yifei , Han Liang , Liu Bin , Li Yi
Published: August 2023

Cancer is one of the most difficult diseases for human beings to overcome. Its development is closely related to a variety of factors, and its specific mechanisms have been a hot research topic in the field of scientific research. The tropomyosin family (Tpm) is a group of proteins closely related to the cytoskeleton and actin, and recent studies have shown that they play an important role in various cancers, participating in a variety of biological activities, including cell proliferation, invasion, and migration, and have been used as biomarkers for various cancers. The purpose of this review is to explore the research progress of the Tpm family in tumorigenesis development, focusing on the molecular pathways associated with them and their relevant activities involved in tumors. PubMed and Web of Science databases were searched for relevant studies on the role of Tpms in tumorigenesis and development and the activities of Tpms involved in tumors. Data from the literature suggest that the Tpm family is involved in tumor cell proliferation and growth, tumor cell invasion and migration, tumor angiogenesis, tumor cell apoptosis, and immune infiltration of the tumor microenvironment, among other correlations. It can be used as a potential biomarker for early diagnosis, follow-up, and therapeutic response of some tumors. The Tpm family is involved in cancer in a close relationship with miRNAs and LncRNAs. Tpms are involved in tumor tissue invasion and migration as a key link. On this basis, TPM is frequently used as a biomarker for various cancers. However, the specific molecular mechanism of its involvement in cancer progression has not been explained clearly, which remains an important direction for future research.
Comprehensive Transcriptome and Metabolome Analyses Reveal Primary Molecular Regulation Pathways Involved in Peanut under Water and Nitrogen Co-Limitation
Authors: Ding Hong , Dai Liangxiang , Guo Qing , Chen Xiaoshu , Zhang Guanchu , Feng Hao , Qin Feifei , Gao Huayuan , Xu Yang , Zhang Zhimeng
Published: August 2023

The yield and quality of peanut (Arachis hypogaea L.), an oil crop planted worldwide, are often limited by drought stress (DS) and nitrogen (N) deficiency. To investigate the molecular mechanism by which peanut counteracts DS and N deficiency, we conducted comprehensive transcriptomic and metabolomic analyses of peanut leaves. Herein, 829 known differentially accumulated metabolites, 324 differentially expressed transcription factors, and 5294 differentially expressed genes (DEGs) were identified under different water and N conditions. The transcriptome analysis demonstrated that drought-related DEGs were predominantly expressed in “glycolysis/gluconeogenesis” and “glycerolipid metabolism”, while N-deficiency-related DEGs were mainly expressed in starch and sucrose metabolism, as well as in the biosynthesis of amino acid pathways. The biosynthesis, transport, and catabolism of secondary metabolites accounted for a large proportion of the 1317 DEGs present in water and N co–limitation. Metabolomic analysis showed that the metabolic accumulation of these pathways was significantly dependent on the stress conditions. Additionally, the roles of metabolites and genes in these pathways, such as the biosynthesis of amino acids and phenylpropanoid biosynthesis under different stress conditions, were discussed. The results demonstrated that different genes, metabolic pathways, and metabolites were related to DS and N deficiency. Thus, this study elucidates the metabolic pathways and functional genes that can be used for the improvement of peanut resistance to abiotic stress.
Significance of the cGAS-STING Pathway in Health and Disease
Authors: Zhou Jinglin , Zhuang Zhan , Li Jiamian , Feng Zhihua
Published: August 2023

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a significant role in health and disease. In this pathway, cGAS, one of the major cytosolic DNA sensors in mammalian cells, regulates innate immunity and the STING-dependent production of pro-inflammatory cytokines, including type-I interferon. Moreover, the cGAS–STING pathway is integral to other cellular processes, such as cell death, cell senescence, and autophagy. Activation of the cGAS–STING pathway by “self” DNA is also attributed to various infectious diseases and autoimmune or inflammatory conditions. In addition, the cGAS–STING pathway activation functions as a link between innate and adaptive immunity, leading to the inhibition or facilitation of tumorigenesis; therefore, research targeting this pathway can provide novel clues for clinical applications to treat infectious, inflammatory, and autoimmune diseases and even cancer. In this review, we focus on the cGAS–STING pathway and its corresponding cellular and molecular mechanisms in health and disease.