bluuebunny/crossref_metadata_2025 huggingface dataset:
RoGraphER: Enhanced Extraction of Chinese Medical Entity Relationships Using RoFormer Pre-Trained Model and Weighted Graph Convolution
Authors: Zhang Qinghui , Sun Yaya , Lv Pengtao , Lu Lei , Zhang Mengya , Wang Jinhui , Wan Chenxia , Wang Jingping
Published: July 2024

Unstructured Chinese medical texts are rich sources of entity and relational information. The extraction of entity relationships from medical texts is pivotal for the construction of medical knowledge graphs and aiding healthcare professionals in making swift and informed decisions. However, the extraction of entity relationships from these texts presents a formidable challenge, notably due to the issue of overlapping entity relationships. This study introduces a novel extraction model that leverages RoFormer’s rotational position encoding (RoPE) technique for an efficient implementation of relative position encoding. This approach not only optimizes positional information utilization but also captures syntactic dependency information by constructing a weighted adjacency matrix. During the feature fusion phase, the model employs an entity attention mechanism for a deeper integration of features, effectively addressing the challenge of overlapping entity relationships. Experimental outcomes demonstrate that our model achieves an F1 score of 83.42 on datasets featuring overlapping entity relations, significantly outperforming other baseline models.
TSTL-GNN: Graph-Based Two-Stage Transfer Learning for Timing Engineering Change Order Analysis Acceleration
Authors: Jiang Wencheng , Zhao Zhenyu , Luo Zhiyuan , Zhou Jie , Zhang Shuzheng , Hu Bo , Bian Peiyun
Published: July 2024

Timing Engineering Change Order (ECO) is time-consuming in IC design, requiring multiple rounds of timing analysis. Compared to traditional methods for accelerating timing analysis, which focus on a specific design, timing ECO requires higher accuracy and generalization because the design changes considerably after ECO. Additionally, there are challenges with slow acquisition of data for large designs and insufficient data for small designs. To solve these problems, we propose TSTL-GNN, a novel approach using two-stage transfer learning based on graph structures. Significantly, considering that delay calculation relies on transition time, we divide our model into two stages: the first stage predicts transition time, and the second stage predicts delay. Moreover, we employ transfer learning to transfer the model’s parameters and features from the first stage to the second due to the similar calculation formula for delay and transition time. Experiments show that our method has good accuracy on open-source and industrial applications with an average R2score/MAE of 0.9952/13.36, and performs well with data-deficient designs. Compared to previous work, our model reduce prediction errors by 37.1 ps on the modified paths, which are changed by 24.27% on average after ECO. The stable R2 score also confirms the generalization of our model. In terms of time cost, our model achieved results for path delays consuming up to 80 times less time compared to open-source tool.
Three-Coil Wireless Charging System Based on S-PS Topology
Authors: Yan Kai , Dang Ruirong , Wang Wenzhen
Published: July 2024

To protect the battery, radio energy transmission charging typically uses constant current (CC) charging before switching to constant voltage (CV) charging to enhance battery durability. This paper proposes adding an auxiliary clamp coil to the original circuit topology. The IPT battery charger designed with the auxiliary clamp coil can achieve both constant current (CC) and constant voltage (CV) outputs. The mutual inductance between the auxiliary clamp coil and the primary side coil greatly influences the output performance of the entire IPT system, so the auxiliary clamp coil should not be too large. To solve this problem, an S-S-PS circuit with secondary compensation topology in the secondary coil is proposed. This circuit topology reduces the size of the auxiliary clamp coil, allowing it to be placed in an optimal position. When the constant voltage output critical position is reached, the IPT system can still automatically, continuously, and smoothly switch between CC and CV modes. Consequently, this approach avoids increased cost consumption associated with detecting CC-CV switching thresholds, adding wireless transmission communication modules, real-time control of the power transmitter, and active protection of the circuit during constant current charging. Finally, a 48 V/2.5 A prototype was built to verify that the IPT system has CC-CV conversion functionality.
Fire Risk Reduction and Recover Energy Potential: A Disruptive Theoretical Optimization Model to the Residual Biomass Supply Chain
Authors: Bastos Tiago , Teixeira Leonor , Nunes Leonel J. R.
Published: July 2024

Rural fires have been a constant concern, with most being associated with land abandonment. However, some fires occur due to negligent attitudes towards fire, which is often used to remove agroforestry leftovers. In addition to the fire risk, this burning also represents a waste of the energy present in this residual biomass. Both rural fires and energy waste affect the three dimensions of sustainability. The ideal solution seems to be to use this biomass, avoiding the need for burning and recovering the energy potential. However, this process is strongly affected by logistical costs, making this recovery unfeasible. In this context, this study aims to propose an optimization model for this chain, focusing on the three dimensions of sustainability. The results of the present study comprise a summary of the current state of the art in supply-chain optimization, as well as a disruptive mathematical model to optimize the residual biomass supply chain. To achieve this objective, a literature review was carried out in the first phase, incorporating the specificities of the context under study to arrive at the final model. To conclude, this study provides a review covering several metaheuristics, including ant colony optimization, genetic algorithms, particle swarm optimization, and simulated annealing, which can be used in this context, adding another valuable input to the final discussion.
Feruloylation and Hydrolysis of Arabinoxylan Extracted from Wheat Bran: Effect on Dough Rheology and Microstructure
Authors: Pietiäinen Solja , Lee Youngsun , Jimenez-Quero Amparo , Katina Kati , Maina Ndegwa H. , Hansson Henrik , Moldin Annelie , Langton Maud
Published: July 2024

Feruloylated arabinoxylan (AX) is a potential health-promoting fiber ingredient that can enhance nutritional properties of bread but is also known to affect dough rheology. To determine the role of feruloylation and hydrolysis of wheat bran AX on dough quality and microstructure, hydrolyzed and unhydrolyzed AX fractions with low and high ferulic acid content were produced, and their chemical composition and properties were evaluated. These fractions were then incorporated into wheat dough, and farinograph measurements, large and small deformation measurements and dough microstructure were assessed. AX was found to greatly affect both fraction properties and dough quality, and this effect was modulated by hydrolysis of AX. These results demonstrated how especially unhydrolyzed fiber fractions produced stiff doughs with poor extensibility due to weak gluten network, while hydrolyzed fractions maintained a dough quality closer to control. This suggests that hydrolysis can further improve the baking properties of feruloylated wheat bran AX. However, no clear effects from AX feruloylation on dough properties or microstructure could be detected. Based on this study, feruloylation does not appear to affect dough rheology or microstructure, and feruloylated wheat bran arabinoxylan can be used as a bakery ingredient to potentially enhance the nutritional quality of bread.
Analytic Solution of the Time-Fractional Partial Differential Equation Using a Multi-G-Laplace Transform Method
Authors: Eltayeb Hassan
Published: July 2024

In several recent studies, many researchers have shown the advantage of fractional calculus in the production of particular solutions of a huge number of linear and nonlinear partial differential equations. In this research work, different theorems related to the G-double Laplace transform (DGLT) are proved. The solution of the system of time-fractional partial differential equations is addressed using a new analytical method. This technique is a combination of the multi-G-Laplace transform and decomposition methods (MGLTDM). Moreover, we discuss the convergence of this method. Two examples are provided to check the applicability and efficiency of our technique.
Perception and Experience of Independent Consultations in Primary Healthcare among Registered Nurses in Kazakhstan: A Qualitative Study
Authors: Dostanova Zhanar , Yermukhanova Lyudmila , Blaževičienė Aurelija , Baigozhina Zaure , Taushanova Maiya , Abdikadirova Indira , Sultanova Gulnar
Published: July 2024

(1) Background: The nursing profession has undergone a significant transformation not only in a formal context but also in terms of the increased educational competencies required of nurses and their preparedness to adapt to evolving roles and statuses. The aim of our study was to examine the experience of advanced practice nurses who conduct independent consultations on patients and to identify the main challenges they face in their practice. (2) Methods: We carried out 22 semi-structured interviews with nurses responsible for conducting independent consultations across three urban polyclinics located in Aktobe, Almaty, and Astana. All interviews were audio-recorded, transcribed verbatim, and subjected to qualitative content analysis. (3) Results: The content analysis revealed three main themes: “People awareness of the role of an independent nursing appointment”, “Adaptation of the work environment”, and “Confidence of nurses to provide independent services”. (4) Conclusions: Limited competency among nurses and the absence of quality metrics for autonomous nursing consultations present substantial obstacles to assessing and enhancing the quality of care delivered by nurses in their independent roles. Developing and implementing quality indicators for independent nursing appointment, as well as additional training within the framework of interprofessional continuous education for nurses, are important steps toward enhancing the effectiveness, safety, and accessibility of nursing care.
Essential Oils from Native Brazilian Plants of the Genus Eugenia as an Innovative and Sustainable Source of Active Ingredients for Food Systems and Human Health and Well-Being
Authors: Borsoi Felipe Tecchio , Possas Arícia , Pastore Glaucia Maria , Arruda Henrique Silvano
Published: July 2024

Brazil is home to some of the world’s greatest biodiversity, providing an immeasurable number of new opportunities and unexplored sources of native plants for the development of products, extracts, foods, and compounds of social and economic interest. Among these, plants of the genus Eugenia stand out because of the large number of species found in Brazilian territory, many of which are endemic and exclusive to Brazil. These plants have emerged as potential sources for obtaining essential oils with relevant biological activities. In this context, the present review provides an overview of essential oils derived from the main native plants of Brazilian socio-biodiversity from the genus Eugenia with food value (Eugenia stipitata, Eugenia dysenterica, Eugenia involucrata, Eugenia brasiliensis, Eugenia klotzschiana, Eugenia uniflora, and Eugenia pyriformis) and their phytochemical profile and health beneficial effects. The compiled data showed that the essential oils of these plants are composed mainly of sesquiterpenes and, in smaller quantities, monoterpenes and other compounds. These compounds contribute to different biological activities, including antimicrobial, antioxidant, anticancer, and antiparasitic effects. These findings demonstrate that the essential oils of Brazilian native plants of the genus Eugenia can be a promising raw material for active ingredients to develop innovative and sustainable food products, drugs, and cosmetics.
Mulching with Municipal Solid Waste (MSW) Compost Has Beneficial Side Effects on Vineyard Soil Compared to Mulching with Synthetic Films
Authors: Blanco Ileana , Cardinale Massimiliano , Domanda Corrado , Pappaccogli Gianluca , Romano Piergiorgio , Zorzi Gianni , Rustioni Laura
Published: July 2024

Municipal solid waste (MSW) compost represents a sustainable alternative to plastic film for mulching in viticulture. This study investigated the effects of MSW compost on vineyard soil properties, specifically focusing on side effects such as soil temperature and microbial decomposition activity, independently from its role in weed control. The experiment was conducted in a vineyard located in the Mediterranean region (Southern Italy), with six different mulching treatments: black polyethylene (PE) film, black and white biodegradable film, three different amounts of MSW compost (8, 15, and 22 kg plant−1), and a control without mulching. Weed growth was monitored to determine the optimal compost application amount. The 15 kg plant−1 treatment was selected for further analyses, as it did not significantly impact weed growth compared to the control. Results indicated that MSW compost mulching maintained lower soil temperatures compared to other treatments (up to 5 °C in the warmest hours) and reduced the amplitude of the thermal wave up to 50% compared to the non-mulched soil and even more compared to black film mulched soil, particularly during the warmest periods. This suggests that MSW compost can mitigate heat stress on plant roots, potentially enhancing plant resilience and preserving crop production also in stressful growing conditions. Microbial decomposition activity, assessed using the tea bag index, was higher in the MSW compost treatment during spring compared to the control, indicating temperature as a key driver for organic matter decomposition, but this effect disappeared during summer. These findings highlight the potential of MSW compost to support sustainable viticulture by reducing reliance on synthetic mulching materials and promoting environmental sustainability through the recycling of organic municipal waste.
Genome-Wide Identification and Characterization of Sucrose Metabolism Genes Involved in Actinidia rufa and Their Expression Profiling during the Fruit Developmental Stages
Authors: Jia Yun , Qiang Xu , Dong Pengbin , Ren Ting , Zhang Ying , Yang Yanci
Published: July 2024

Soluble sugars, as an indispensable source of energy, play crucial roles in plant growth and development. However, to date, scant information about the sucrose metabolism-related gene families is available in kiwifruit (Actinidia rufa Planch). Here, we systematically identified the members of various gene families encoding crucial enzymes or transporters involved in sucrose metabolism, re-analyzed their expression patterns under different fruit development stages, and determined the regulatory mechanism involving key transcription factors. A total of sixty-two genes from six gene families (thirty-one ArINVs, two ArSPPs, four ArSPSs, nine ArSUSs, six ArSUCs/SUTs, and ten ArSWEETs) were identified in the A. rufa genome. The characterization of these members, including gene structure, motifs, conserved domains, and cis-acting elements, were analyzed. Phylogenetic analysis revealed that these gene families could be categorized into six distinct subgroups. These six gene families have undergone strong purifying selection during domestication. In addition, expression analysis of the 62 genes indicated that differential expression patterns are highly regulated by developmental processes. Specifically, we identified 11 transcription factors that were rigorously correlated (r > 0.98) with key gene expression profiles. This represents a comprehensive analysis of the genes involved in sucrose metabolism in kiwifruit, which provides useful information for further functional analysis of these genes.
Comparative Analysis of Vegetative Development and Leaf Morpho-Anatomy in Three Taxa of Ornamental Alocasia (Araceae)
Authors: Krisantini  , Rahayu Megayani Sri , Kartika Juang Gema , Dinarti Diny , Putri Yunita Sulistyo , Matra Deden D. , Daawia  , Asih Ni Putu Sri , Fabillo Melodina
Published: July 2024

This study examines the growth patterns, leaf morpho-anatomical traits and physiological characteristics of three ornamental taxa of Alocasia: A. melo, A reginae and Alocasia × morfontanensis ‘Bambino’. Using optical and scanning electron microscopy, the research obtained anatomical details of the leaves. Alocasia × morfontanensis ‘Bambino’ exhibited the highest leaf growth rate among the taxa studied, showing significant leaf number increases from the 8th to the 12th week after planting. Alocasia melo produced 2–3 new basal shoots after 20 weeks, whereas the other two taxa did not produce any. Alocasia melo displayed the greatest relative water content and leaf thickness, while A. reginae showed the highest chlorophyll stability. This study also revealed variations in the adaxial and abaxial leaf color, stomatal width, epidermal thickness, and elemental composition among the taxa involved, with A. melo containing rhodium and high levels of calcium on their leaf surface. These findings contribute to the understanding of the Alocasia leaf morpho-anatomy and growth, which is useful for optimizing Alocasia cultivation and production across diverse ecosystems.
Economic Policy Uncertainty and Commercial Property Performance: An In-Depth Analysis of Rents and Capital Values
Authors: Ahiadu Albert Agbeko , Abidoye Rotimi Boluwatife , Yiu Tak Wing
Published: July 2024

Economic uncertainty has steadily increased in response to a series of unforeseen shocks, notably the Global Financial Crisis, Brexit, COVID-19, and the Russia–Ukraine war. This study examined the impact of economic uncertainty on rents and capital values in Australia’s office, retail, and industrial property sectors. The reactions of these performance indicators to national uncertainty shocks were assessed through reduced-form vector autoregressive (VAR) models, using quarterly data from 2001Q1 to 2022Q3. Overall, there is an inverse relationship between uncertainty and commercial property performance, with notable variations in magnitude and persistence across the different subsectors. Rents are more sensitive to external shocks across all three subsectors, highlighting their role as signals of short-term performance. Following one standard deviation shock in uncertainty, rents steadily declined for approximately three years in the office and retail subsectors. Industrial rents, however, exhibited muted reactions and recovered quicker, typically within five quarters. This resilience to external shocks displayed by the industrial subsector positions it as a compelling option for defensive investment strategies and portfolio diversification. Capital values are less reactive than rents, showing minimal responses to uncertainty shocks and little long-term persistence.
Exploring the Evolutionary History and Phylogenetic Relationships of Giant Reed (Arundo donax) through Comprehensive Analysis of Its Chloroplast Genome
Authors: Luo Lin , Qu Qi , Lin Hui , Chen Jiaming , Lin Zhanxi , Shao Ensi , Lin Dongmei
Published: July 2024

Giant reed (Arundo donax) is widely distributed across the globe and is considered an important energy crop. This study presents the first comprehensive analysis of the chloroplast genome of giant reed, revealing detailed characteristics of this species’ chloroplast genome. The chloroplast genome has a total length of 137,153 bp, containing 84 protein-coding genes, 38 tRNA genes, and 8 rRNA genes, with a GC content of 39%. Functional analysis indicates that a total of 45 photosynthesis-related genes and 78 self-replication-related genes were identified, which may be closely associated with its adaptability and growth characteristics. Phylogenetic analysis confirmed that Arundo donax cv. Lvzhou No.1 belongs to the Arundionideae clade and occupies a distinct evolutionary position compared to other Arundo species. The findings of this study not only enhance our understanding of the giant reed genome but also provide valuable genetic resources for its application in biotechnology, bioenergy crop development, and ecological restoration.
Gut Microbiota Signatures in Colorectal Cancer as a Potential Diagnostic Biomarker in the Future: A Systematic Review
Authors: Herlo Lucian-Flavius , Salcudean Andreea , Sirli Roxana , Iurciuc Stela , Herlo Alexandra , Nelson-Twakor Andreea , Alexandrescu Luana , Dumache Raluca
Published: July 2024

The gut microbiota has acquired significant attention in recent years for its potential as a diagnostic biomarker for colorectal cancer (CRC). In this literature review, we looked at the studies exploring alterations in gut microbiota composition associated with CRC, the potential mechanisms linking gut dysbiosis to CRC development, and the diagnostic approaches utilizing gut microbiota analysis. Our research has led to the conclusion that individuals with CRC often display alterations in their gut microbiota composition compared to healthy individuals. These alterations can include changes in the diversity, abundance, and type of bacteria present in the gut. While the use of gut microbiota as a diagnostic biomarker for CRC holds promise, further research is needed to validate its effectiveness and standardize testing protocols. Additionally, considerations such as variability in the microbiota composition among individuals and potential factors must be addressed before microbiota-based tests can be widely implemented in clinical practice.
An Adaptable Protocol to Generate a Murine Enteroid–Macrophage Co-Culture System
Authors: Hentschel Viktoria , Govindarajan Deepalakshmi , Seufferlein Thomas , Armacki Milena
Published: July 2024

Impairment of the intestinal epithelial barrier is frequently seen as collateral damage in various local and systemic inflammatory conditions. The inflammatory process is characterized by reciprocal interactions between the host intestinal epithelium and mucosal innate immune cells, e.g., macrophages. This article provides step-by-step instructions on how to set up a murine enteroid–macrophage co-culture by culturing cellular elements in proximity separated by a porous membrane. Unlike previously published co-culture systems, we have combined enteroids grown from C57BL6j mice with syngeneic bone marrow-derived macrophages to preclude potential allo-reactions between immune cells and epithelium. Transformation of intestinal crypts into proliferative enteroids was achieved by cultivation in Wnt3a-Noggin-R-Spondin-conditioned medium supplemented with ROCK inhibitor Y-27632. The differentiated phenotype was promoted by the use of the Wnt3-deprived EGF-Noggin-R-Spondin medium. The resulting co-culture of primary cells can be employed as a basic model to better understand the reciprocal relationship between intestinal epithelium and macrophages. It can be used for in vitro modelling of mucosal inflammation, mimicked by stimulation of macrophages either while being in co-culture or before being introduced into co-culture, to simulate enterogenic sepsis or systemic conditions affecting the intestinal tract.
The Effect of Broccoli Glucosinolates Hydrolysis Products on Botrytis cinerea: A Potential New Antifungal Agent
Authors: Román Juan , Lagos Ailine , Mahn Andrea , Quintero Julián
Published: July 2024

The present study investigates the interactions between eight glucosinolate hydrolysis products (GHPs) sourced from broccoli by-products and the detoxifying enzymes of Botrytis cinerea, namely eburicol 14-alpha-demethylase (CYP51) and glutathione-S-transferase (GST), through in silico analysis. Additionally, in vitro assays were conducted to explore the impact of these compounds on fungal growth. Our findings reveal that GHPs exhibit greater efficacy in inhibiting conidia germination compared to mycelium growth. Furthermore, the results demonstrate the antifungal activity of glucosinolate hydrolysis products derived from various parts of the broccoli plant, including inflorescences, leaves, and stems, against B. cinerea. Importantly, the results suggest that these hydrolysis products interact with the detoxifying enzymes of the fungus, potentially contributing to their antifungal properties. Extracts rich in GHPs, particularly iberin and indole-GHPs, derived from broccoli by-products emerge as promising candidates for biofungicidal applications, offering a sustainable and novel approach to plant protection by harnessing bioactive compounds from agricultural residues.
Martini 3 Coarse-Grained Model for the Cofactors Involved in Photosynthesis
Authors: Chiariello Maria Gabriella , Zarmiento-Garcia Rubi , Marrink Siewert-Jan
Published: July 2024

As a critical step in advancing the simulation of photosynthetic complexes, we present the Martini 3 coarse-grained (CG) models of key cofactors associated with light harvesting (LHCII) proteins and the photosystem II (PSII) core complex. Our work focuses on the parametrization of beta-carotene, plastoquinone/quinol, violaxanthin, lutein, neoxanthin, chlorophyll A, chlorophyll B, and heme. We derived the CG parameters to match the all-atom reference simulations, while structural and thermodynamic properties of the cofactors were compared to experimental values when available. To further assess the reliability of the parameterization, we tested the behavior of these cofactors within their physiological environments, specifically in a lipid bilayer and bound to photosynthetic complexes. The results demonstrate that our CG models maintain the essential features required for realistic simulations. This work lays the groundwork for detailed simulations of the PSII-LHCII super-complex, providing a robust parameter set for future studies.
Causal Relationship between Mitochondrial Biological Function and Periodontitis: Evidence from a Mendelian Randomization Study
Authors: Zhou Huan , Qi Yan-Xin , Cao Ruo-Yan , Zhang Xi-Xuan , Li Ang , Pei Dan-Dan
Published: July 2024

A growing number of studies indicate that mitochondrial dysfunction serves as a pathological mechanism for periodontitis. Therefore, this two-sample Mendelian randomization (MR) study was carried out to explore the causal associations between mitochondrial biological function and periodontitis, because the specific nature of this causal relationship remains inconclusive in existing MR studies. Inverse variance weighting, Mendelian randomization-Egger, weighted mode, simple mode, and weighted median analyses were performed to assess the causal relationships between the exposure factors and periodontitis. The results of the present study revealed a causal association between periodontitis and medium-chain specific acyl-CoA dehydrogenase (MCAD), malonyl-CoA decarboxylase (MLYCD), glutaredoxin 2 (Grx2), oligoribonuclease (ORN), and pyruvate carboxylase (PC). Notably, MCAD and MLYCD are causally linked to periodontitis, and serve as protective factors. However, Grx2, ORN, and PC function as risk factors for periodontitis. Our study established a causal relationship between mitochondrial biological function and periodontitis, and such insights may provide a promising approach for treating periodontitis via mitochondrial regulation.
Systemic Inflammatory Changes in Spinal Cord Injured Patients after Adding Aquatic Therapy to Standard Physiotherapy Treatment
Authors: Agulló-Ortuño María. Teresa , Romay-Barrero Helena , Lambeck Johan , Blanco-Calonge Juan M. , Arroyo-Fernández Rubén , Geigle Paula Richley , Menchero Raquel , Corral Gonzalo Melgar del , Martínez-Galán Inés
Published: July 2024

Spinal cord injury (SCI) is a severe medical condition resulting in substantial physiological and functional consequences for the individual. People with SCI are characterised by a chronic, low-grade systemic inflammatory state, which contributes to further undesirable secondary injuries. This study aimed to evaluate the effect of adding aquatic therapy to the standard physiotherapy treatment, implemented in two different schedules, on systemic inflammation in SCI patients. Additionally, the relationship between cytokine blood levels and changes in functionality (measured with the 6MWT, 10MWT, WISCI, BBS, and TUG tests) throughout the study was assessed. A quantitative multiplexed antibody assay was performed to measure the expression level of 20 pro- and anti-inflammatory cytokines in blood samples from SCI patients at three time points: baseline, week 6, and immediately post-intervention (week 12). This study identified a complex signature of five cytokines (IL-12p70, IL-8, MCP-1, IL-1α, and IP10) associated with the time course of the two physiotherapy programs. Two other cytokines (IL-4 and TNF-α) were also associated with the functional recovery of patients. These could be important indicators for SCI prognosis and provide a basis for developing novel targeted therapies.
Vasorelaxant and Hypotensive Effects of Galla chinensis in Rats
Authors: Shin Sujin , Park Junkyu , Choi Ho-Young , Bu Youngmin , Lee Kyungjin
Published: July 2024

Previous studies have revealed the medicinal and therapeutic effects of Galla chinensis. However, no studies have focused on the antihypertensive effects of G. chinensis. Therefore, we aimed to determine the vasorelaxant and hypotensive effects of G. chinensis 50% ethanolic extract (GCE). To evaluate the vascular relaxing effect of GCE, experiments were conducted using aortic segments dissected from Sprague Dawley rats. GCE showed a vasorelaxant effect via the nitric oxide/cyclic guanosine 3′,5′-monophosphate pathway, inhibiting Ca2+ channels, and activating K+ channels. The hypotensive effects of GCE were evaluated in spontaneously hypertensive rats (SHRs). The SHRs were randomly divided into a control group and orally administered GCE group (100 or 300 mg/kg). The systolic and diastolic blood pressure decreased significantly by −19.47 ± 4.58% and −31.14 ± 7.66% in the GCE 100 mg/kg group, and −21.64 ± 2.40% and −31.91 ± 5.75% in the GCE 300 mg/kg group at 4 h after administration. Considering its vasorelaxant and hypotensive effects, our results indicate that GCE may be a valuable solution for the control of hypertension. However, further studies on the long-term administration and toxicity of GCE are required.
Effect of Lanthanide Ions and Triazole Ligands on the Molecular Properties, Spectroscopy and Pharmacological Activity
Authors: Alcolea Palafox Mauricio , Belskaya Nataliya P. , Todorov Lozan T. , Hristova-Avakoumova Nadya G. , Kostova Irena P.
Published: July 2024

The effect of La, Ce, Pr and Nd ions on four Ln(ligand)3 complexes and at three DFT levels of calculation was analyzed. Four ligands were chosen, three of which were based on the 1,2,3-triazole ring. The DFT methods used were B3LYP, CAM-B3LYP and M06-2X. The relationships established were between the geometric parameters, atomic charges, HOMO-LUMO energies and other molecular properties. These comparisons and trends will facilitate the synthesis of new complexes by selecting the ligand and lanthanide ion best suited to the desired property of the complex. The experimental IR and Raman spectra of Ln(2b′)3 complexes where Ln = La, Ce, Pr, Nd, Sm, Gd, Dy, Ho and Er ions have been recorded and compared to know the effect of the lanthanide ion on the complex. The hydration in these complexes was also analyzed. Additionally, the effect of the type of coordination center on the ability of an Ln(ligand)3 complex to participate in electron exchange and hydrogen transfer was investigated using two in vitro model systems—DPPH and ABTS.
The Activin Branch Ligand Daw Regulates the Drosophila melanogaster Immune Response and Lipid Metabolism against the Heterorhabditis bacteriophora Serine Carboxypeptidase
Authors: Mallick Sreeradha , Kenney Eric , Eleftherianos Ioannis
Published: July 2024

Despite impressive advances in the broad field of innate immunity, our understanding of the molecules and signaling pathways that control the host immune response to nematode infection remains incomplete. We have shown recently that Transforming Growth Factor-β (TGF-β) signaling in the fruit fly Drosophila melanogaster is activated by nematode infection and certain TGF-β superfamily members regulate the D. melanogaster anti-nematode immune response. Here, we investigate the effect of an entomopathogenic nematode infection factor on host TGF-β pathway regulation and immune function. We find that Heterorhabditis bacteriophora serine carboxypeptidase activates the Activin branch in D. melanogaster adults and the immune deficiency pathway in Activin-deficient flies, it affects hemocyte numbers and survival in flies deficient for Activin signaling, and causes increased intestinal steatosis in Activin-deficient flies. Thus, insights into the D. melanogaster signaling pathways and metabolic processes interacting with H. bacteriophora pathogenicity factors will be applicable to entomopathogenic nematode infection of important agricultural insect pests and vectors of disease.
The Mechanism of Action of L-Tyrosine Derivatives against Chikungunya Virus Infection In Vitro Depends on Structural Changes
Authors: Loaiza-Cano Vanessa , Hernández-Mira Estiven , Pastrana-Restrepo Manuel , Galeano Elkin , Pardo-Rodriguez Daniel , Martinez-Gutierrez Marlen
Published: July 2024

Although the disease caused by chikungunya virus (CHIKV) is of great interest to public health organizations around the world, there are still no authorized antivirals for its treatment. Previously, dihalogenated anti-CHIKV compounds derived from L-tyrosine (dH-Y) were identified as being effective against in vitro infection by this virus, so the objective of this study was to determine the mechanisms of its antiviral action. Six dH-Y compounds (C1 to C6) dihalogenated with bromine or chlorine and modified in their amino groups were evaluated by different in vitro antiviral strategies and in silico tools. When the cells were exposed before infection, all compounds decreased the expression of viral proteins; only C4, C5 and C6 inhibited the genome; and C1, C2 and C3 inhibited infectious viral particles (IVPs). Furthermore, C1 and C3 reduce adhesion, while C2 and C3 reduce internalization, which could be related to the in silico interaction with the fusion peptide of the E1 viral protein. Only C3, C4, C5 and C6 inhibited IVPs when the cells were exposed after infection, and their effect occurred in late stages after viral translation and replication, such as assembly, and not during budding. In summary, the structural changes of these compounds determine their mechanism of action. Additionally, C3 was the only compound that inhibited CHIKV infection at different stages of the replicative cycle, making it a compound of interest for conversion as a potential drug.
Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies
Authors: Agosti Edoardo , Antonietti Sara , Ius Tamara , Fontanella Marco Maria , Zeppieri Marco , Panciani Pier Paolo
Published: July 2024

Gliomas’ aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells’ distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.
Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification
Authors: Dai Liujiang , Yu Pengfei , Fan Hongjie , Xia Wei , Zhao Yaopeng , Zhang Pengfei , Zhang John Z. H. , Zhang Haiping , Chen Yang
Published: July 2024

DNA-PKcs is a crucial protein target involved in DNA repair and response pathways, with its abnormal activity closely associated with the occurrence and progression of various cancers. In this study, we employed a deep learning-based screening and molecular dynamics (MD) simulation-based pipeline, identifying eight candidates for DNA-PKcs targets. Subsequent experiments revealed the effective inhibition of DNA-PKcs-mediated cell proliferation by three small molecules (5025-0002, M769-1095, and V008-1080). These molecules exhibited anticancer activity with IC50 (inhibitory concentration at 50%) values of 152.6 μM, 30.71 μM, and 74.84 μM, respectively. Notably, V008-1080 enhanced homology-directed repair (HDR) mediated by CRISPR/Cas9 while inhibiting non-homologous end joining (NHEJ) efficiency. Further investigations into the structure-activity relationships unveiled the binding sites and critical interactions between these small molecules and DNA-PKcs. This is the first application of DeepBindGCN_RG in a real drug screening task, and the successful discovery of a novel DNA-PKcs inhibitor demonstrates its efficiency as a core component in the screening pipeline. Moreover, this study provides important insights for exploring novel anticancer therapeutics and advancing the development of gene editing techniques by targeting DNA-PKcs.
Variation of Cyclodextrin (CD) Complexation with Biogenic Amine Tyramine: Pseudopolymorphs of β-CD Inclusion vs. α-CD Exclusion, Deep Atomistic Insights
Authors: Aree Thammarat
Published: July 2024

Tyramine (TRM) is a biogenic catecholamine neurotransmitter, which can trigger migraines and hypertension. TRM accumulated in foods is reduced and detected using additive cyclodextrins (CDs) while their association characteristics remain unclear. Here, single-crystal X-ray diffraction and density functional theory (DFT) calculation have been performed, demonstrating the elusive pseudopolymorphs in β-CD inclusion complexes with TRM base/HCl, β-CD·0.5TRM·7.6H2O (1) and β-CD·TRM HCl·4H2O (2) and the rare α-CD·0.5(TRM HCl)·10H2O (3) exclusion complex. Both 1 and 2 share the common inclusion mode with similar TRM structures in the round and elliptical β-CD cavities, belong to the monoclinic space group P21, and have similar herringbone packing structures. Furthermore, 3 differs from 2, as the smaller twofold symmetry-related, round α-CD prefers an exclusion complex with the twofold disordered TRM–H+ sites. In the orthorhombic P21212 lattice, α-CDs are packed in a channel-type structure, where the column-like cavity is occupied by disordered water sites. DFT results indicate that β-CD remains elliptical to suitably accommodate TRM, yielding an energetically favorable inclusion complex, which is significantly contributed by the β-CD deformation, and the inclusion complex of α-CD with the TRM aminoethyl side chain is also energetically favorable compared to the exclusion mode. This study suggests the CD implications for food safety and drug/bioactive formulation and delivery.
Discovery of Cell-Permeable Allosteric Inhibitors of Liver Pyruvate Kinase: Design and Synthesis of Sulfone-Based Urolithins
Authors: Iqbal Shazia , Islam Md. Zahidul , Ashraf Sajda , Kim Woonghee , AL-Sharabi Amal A. , Ozcan Mehmet , Hanashalshahaby Essam , Zhang Cheng , Uhlén Mathias , Boren Jan , Turkez Hasan , Mardinoglu Adil
Published: July 2024

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.
Impact of Different Anti-Hyperglycaemic Treatments on Bone Turnover Markers and Bone Mineral Density in Type 2 Diabetes Mellitus Patients: A Systematic Review and Meta-Analysis
Authors: Saadi Md Sadman Sakib , Das Rajib , Mullath Ullas Adhithya , Powell Diane E. , Wilson Emma , Myrtziou Ioanna , Rakieh Chadi , Kanakis Ioannis
Published: July 2024

Diabetic bone disease (DBD) is a frequent complication in patients with type 2 diabetes mellitus (T2DM), characterised by altered bone mineral density (BMD) and bone turnover marker (BTMs) levels. The impact of different anti-diabetic medications on the skeleton remains unclear, and studies have reported conflicting results; thus, the need for a comprehensive systematic review is of paramount importance. A systematic search was conducted in PubMed and the Cochrane Library. The primary outcomes assessed were changes in BMD in relation to different anatomical sites and BTMs, including mainly P1NP and CTX as well as OPG, OCN, B-ALP and RANK-L. Risk of bias was evaluated using the JADAD score. The meta-analysis of 19 randomised controlled trials comprising 4914 patients showed that anti-diabetic medications overall increased BMD at the lumbar spine (SMD: 0.93, 95% CI [0.13, 1.73], p = 0.02), femoral neck (SMD: 1.10, 95% CI [0.47, 1.74], p = 0.0007) and in total hip (SMD: 0.33, 95% CI [−0.25, 0.92], p = 0.27) in comparison with placebo, but when compared with metformin, the overall effect favoured metformin over other treatments (SMD: −0.23, 95% CI [−0.39, −0.07], p = 0.004). GLP-1 receptor agonists and insulin analogues seem to improve BMD compared to placebo, while SGLT2 inhibitors and thiazolidinediones (TZDs) showed no significant effect, although studies’ number cannot lead to safe conclusions. For BTMs, TZDs significantly increased P1NP levels compared to placebo. However, no significant differences were observed for CTX, B-ALP, OCN, OPG, and RANK-L between anti-diabetic drugs and metformin or placebo. High heterogeneity and diverse follow-up durations among studies were evident, which obscures the validity of the results. This review highlights the variable effects of anti-diabetic drugs on DBD in T2DM patients, emphasising the need for long-term trials with robust designs to better understand these relationships and inform clinical decisions.
Overexpression of BnaA10.WRKY75 Decreases Cadmium and Salt Tolerance via Increasing ROS Accumulation in Arabidopsis and Brassica napus L.
Authors: Ping Xiaoke , Ye Qianjun , Yan Mei , Wang Jia , Zhang Taiyuan , Chen Sheng , Siddique Kadambot H. M. , Cowling Wallace A. , Li Jiana , Liu Liezhao
Published: July 2024

Soil is indispensable for agricultural production but has been seriously polluted by cadmium and salt in recent years. Many crops are suffering from this, including rapeseed, the third largest global oilseed crop. However, genes simultaneously related to both cadmium and salt stress have not been extensively reported yet. In this study, BnaA10.WRKY75 was screened from previous RNA-seq data related to cadmium and salt stress and further analyses including sequence comparison, GUS staining, transformation and qRT-PCR were conducted to confirm its function. GUS staining and qRT-PCR results indicated BnaA10.WRKY75 was induced by CdCl2 and NaCl treatment. Sequence analysis suggested BnaA10.WRKY75 belongs to Group IIc of the WRKY gene family and transient expression assay showed it was a nuclear localized transcription factor. BnaA10.WRKY75-overexpressing Arabidopsis and rapeseed plants accumulated more H2O2 and O2− and were more sensitive to CdCl2 and NaCl treatment compared with untransformed plants, which may be caused by the downregulation of BnaC03.CAT2. Our study reported that BnaA10.WRKY75 increases sensitivity to cadmium and salt stress by disrupting the balance of reactive oxygen species both in Arabidopsis and rapeseed. The results support the further understanding of the mechanisms underlying cadmium and salt tolerance and provide BnaA10.WRKY75 as a valuable gene for rapeseed abiotic stress breeding.
Chemical Coaxing of Mesenchymal Stromal Cells by Drug Repositioning for Nestin Induction
Authors: Lim Sun-Ung , Lee Dae-Won , Kim Jung-Ho , Kang Young-Ju , Kim In-Yong , Oh Il-Hoan
Published: July 2024

Mesenchymal stromal cells (MSCs) display heterogeneity in origin and functional role in tissue homeostasis. Subsets of MSCs derived from the neural crest express nestin and serve as niches in bone marrow, but the possibility of coaxing MSCs into nestin-expresing cells for enhanced supportive activity is unclear. In this study, as an approach to the chemical coaxing of MSC functions, we screened libraries of clinically approved chemicals to identify compounds capable of inducing nestin expression in MSCs. Out of 2000 clinical compounds, we chose vorinostat as a candidate to coax the MSCs into neural crest-like fates. When treated with vorinostat, MSCs exhibited a significant increase in the expression of genes involved in the pluripotency and epithelial–mesenchymal transition (EMT), as well as nestin and CD146, the markers for pericytes. In addition, these nestin-induced MSCs exhibited enhanced differentiation towards neuronal cells with the upregulation of neurogenic markers, including SRY-box transcription factor 2 (Sox2), SRY-box transcription factor 10 (Sox10) and microtubule associated protein 2 (Map2) in addition to nestin. Moreover, the coaxed MSCs exhibited enhanced supporting activity for hematopoietic progenitors without supporting leukemia cells. These results demonstrate the feasibility of the drug repositioning of MSCs to induce neural crest-like properties through the chemical coaxing of cell fates.