bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response
Authors: Garcia-Vidal Edurne , Calba Ignasi , Riveira-Muñoz Eva , García Elisabet , Clotet Bonaventura , Serra-Mitjà Pere , Cabrera Cecilia , Ballana Ester , Badia Roger
Published: May 2024

The lung is prone to infections from respiratory viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). A challenge in combating these infections is the difficulty in targeting antiviral activity directly at the lung mucosal tract. Boosting the capability of the respiratory mucosa to trigger a potent immune response at the onset of infection could serve as a potential strategy for managing respiratory infections. This study focused on screening immunomodulators to enhance innate immune response in lung epithelial and immune cell models. Through testing various subfamilies and pathways of pattern recognition receptors (PRRs), the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family was found to selectively activate innate immunity in lung epithelial cells. Activation of NOD1 and dual NOD1/2 by the agonists TriDAP and M-TriDAP, respectively, increased the number of IL-8+ cells by engaging the NF-κB and interferon response pathways. Lung epithelial cells showed a stronger response to NOD1 and dual NOD1/2 agonists compared to control. Interestingly, a less-pronounced response to NOD1 agonists was noted in PBMCs, indicating a tissue-specific effect of NOD1 in lung epithelial cells without inducing widespread systemic activation. The specificity of the NOD agonist pathway was confirmed through gene silencing of NOD1 (siRNA) and selective NOD1 and dual NOD1/2 inhibitors in lung epithelial cells. Ultimately, activation induced by NOD1 and dual NOD1/2 agonists created an antiviral environment that hindered SARS-CoV-2 replication in vitro in lung epithelial cells.
Bilirubin Exerts Protective Effects on Alveolar Type II Pneumocytes in an In Vitro Model of Oxidative Stress
Authors: Endesfelder Stefanie , Schmitz Thomas , Bührer Christoph
Published: May 2024

Newborn infants face a rapid surge of oxygen and a more protracted rise of unconjugated bilirubin after birth. Bilirubin has a strong antioxidant capacity by scavenging free radicals, but it also exerts direct toxicity. This study investigates whether cultured rat alveolar epithelial cells type II (AEC II) react differently to bilirubin under different oxygen concentrations. The toxic threshold concentration of bilirubin was narrowed down by means of a cell viability test. Subsequent analyses of bilirubin effects under 5% oxygen and 80% oxygen compared to 21% oxygen, as well as pretreatment with bilirubin after 4 h and 24 h of incubation, were performed to determine the induction of apoptosis and the gene expression of associated transcripts of cell death, proliferation, and redox-sensitive transcription factors. Oxidative stress led to an increased rate of cell death and induced transcripts of redox-sensitive signaling pathways. At a non-cytotoxic concentration of 400 nm, bilirubin attenuated oxidative stress-induced responses and possibly mediated cellular antioxidant defense by influencing Nrf2/Hif1α- and NFκB-mediated signaling pathways. In conclusion, the study demonstrates that rat AEC II cells are protected from oxidative stress-induced impairment by low-dose bilirubin.
Whey Protein Isolate as a Substrate to Design Calendula officinalis Flower Extract Controlled-Release Materials
Authors: Stachowiak-Trojanowska Natalia , Walendziak Weronika , Douglas Timothy E. L. , Kozlowska Justyna
Published: May 2024

The use of natural active substances and the development of new formulations are promising directions in the cosmetic and pharmacy industries. The primary purpose of this research was the production of microparticles based on whey protein isolate (WPI) and calcium alginate (ALG) containing Calendula officinalis flower extract and their incorporation into films composed of gelatin, WPI, and glycerol. Both swollen and dry microparticles were studied by optical microscopy and their sizes were measured. Water absorption by the microparticles, their loading capacity, and the release profile of flower extract were also characterized. The films were analyzed by mechanical tests (Young’s modulus, tensile strength, elongation at break), swelling capacity, contact angle, and moisture content measurements. The presented data showed that the active ingredient was successfully enclosed in spherical microparticles and completely released after 75 min of incubation at 37 °C. The incorporation of the microparticles into polymer films caused a decrease in stiffness and tensile strength, simultaneously increasing the ductility of the samples. Moreover, the films containing microparticles displayed higher swelling ability and moisture content compared to those without them. Hence, the materials prepared in this study with Calendula officinalis flower extract encapsulated into polymeric microspheres can be a starting point for the development of new products intended for skin application; advantages include protection of the extract against external factors and a controlled release profile.
Comparison of Antimicrobial Properties of Graphene Oxide-Based Materials, Carbon Dots, and Their Combinations Deposited on Cotton Fabrics
Authors: Evseev Zakhar Ivanovich , Tarasova Lidia Andreevna , Vasilieva Fedora Dmitrievna , Egorova Marfa Nikitichna , Dmitriev Petr Stanislavovich , Akhremenko Yana Aleksandrovna , Smagulova Svetlana Afanasyevna
Published: May 2024

The rise in the antibiotic resistance of bacteria has increased scientific interest in the study of materials with unique mechanisms of antimicrobial action. This paper presents the results of studies on the antimicrobial activity of carbon materials and textiles decorated with them. A comparative analysis of the bactericidal and fungicidal activities of graphene oxide, electrochemically exfoliated multigraphene, carbon dots, and their combinations was performed. Microbiological studies on reference strains of E. coli, S. aureus, and C. albicans showed that graphene oxide inhibited growth with up to 98% efficiency. Electrochemically exfoliated multigraphene was less effective (up to 40%). This study found no significant antimicrobial activity of carbon dots and the combination of carbon dots with graphene oxide significantly weakened their effectiveness. However, the combination of electrochemically exfoliated multigraphene and carbon dots exhibits a synergistic effect (up to 76%). A study on the antimicrobial activity of decorated cotton textiles demonstrated the effectiveness of antimicrobial textiles with graphene oxide, electrochemically exfoliated multigraphene, and a combination of carbon dots with electrochemically exfoliated multigraphene.
CXCL8 Knockout: A Key to Resisting Pasteurella multocida Toxin-Induced Cytotoxicity
Authors: Yuan Jianlin , Zhao Qin , Li Jinfeng , Wen Yiping , Wu Rui , Zhao Shan , Lang Yi-Fei , Yan Qi-Gui , Huang Xiaobo , Du Senyan , Cao San-Jie
Published: May 2024

Pasteurella multocida, a zoonotic pathogen that produces a 146-kDa modular toxin (PMT), causes progressive atrophic rhinitis with severe turbinate bone degradation in pigs. However, its mechanism of cytotoxicity remains unclear. In this study, we expressed PMT, purified it in a prokaryotic expression system, and found that it killed PK15 cells. The host factor CXCL8 was significantly upregulated among the differentially expressed genes in a transcriptome sequencing analysis and qPCR verification. We constructed a CXCL8-knockout cell line with a CRISPR/Cas9 system and found that CXCL8 knockout significantly increased resistance to PMT-induced cell apoptosis. CXCL8 knockout impaired the cleavage efficiency of apoptosis-related proteins, including Caspase3, Caspase8, and PARP1, as demonstrated with Western blot. In conclusion, these findings establish that CXCL8 facilitates PMT-induced PK15 cell death, which involves apoptotic pathways; this observation documents that CXCL8 plays a key role in PMT-induced PK15 cell death.
Potential Role and Mechanism of Mulberry Extract in Immune Modulation: Focus on Chemical Compositions, Mechanistic Insights, and Extraction Techniques
Authors: Abbas Zaheer , Tong Yucui , Wang Junyong , Zhang Jing , Wei Xubiao , Si Dayong , Zhang Rijun
Published: May 2024

Mulberry is a rapidly growing plant that thrives in diverse climatic, topographical, and soil types, spanning temperature and temperate countries. Mulberry plants are valued as functional foods for their abundant chemical composition, serving as a significant reservoir of bioactive compounds like proteins, polysaccharides, phenolics, and flavonoids. Moreover, these compounds displayed potent antioxidant activity by scavenging free radicals, inhibiting reactive oxygen species generation, and restoring elevated nitric oxide production induced by LPS stimulation through the downregulation of inducible NO synthase expression. Active components like oxyresveratrol found in Morus demonstrated anti-inflammatory effects by inhibiting leukocyte migration through the MEK/ERK signaling pathway. Gallic and chlorogenic acids in mulberry leaves (ML) powder-modulated TNF, IL-6, and IRS1 proteins, improving various inflammatory conditions by immune system modulation. As we delve deeper into understanding its anti-inflammatory potential and how it works therapeutically, it is crucial to refine the extraction process to enhance the effectiveness of its bioactive elements. Recent advancements in extraction techniques, such as solid–liquid extraction, pressurized liquid extraction, superficial fluid extraction, microwave-assisted extraction, and ultrasonic-assisted extraction, are being explored. Among the extraction methods tested, including Soxhlet extraction, maceration, and ultrasound-assisted extraction (UAE), UAE demonstrated superior efficiency in extracting bioactive compounds from mulberry leaves. Overall, this comprehensive review sheds light on the potential of mulberry as a natural immunomodulatory agent and provides insights into its mechanisms of action for future research and therapeutic applications.
Tissue Elasticity as a Diagnostic Marker of Molecular Mutations in Morphologically Heterogeneous Colorectal Cancer
Authors: Plekhanov Anton A. , Kozlov Dmitry S. , Shepeleva Anastasia A. , Kiseleva Elena B. , Shimolina Liubov E. , Druzhkova Irina N. , Plekhanova Maria A. , Karabut Maria M. , Gubarkova Ekaterina V. , Gavrina Alena I. , Krylov Dmitry P. , Sovetsky Alexander A. , Gamayunov Sergey V. , Kuznetsova Daria S. , Zaitsev Vladimir Y. , Sirotkina Marina A. , Gladkova Natalia D.
Published: May 2024

The presence of molecular mutations in colorectal cancer (CRC) is a decisive factor in selecting the most effective first-line therapy. However, molecular analysis is routinely performed only in a limited number of patients with remote metastases. We propose to use tissue stiffness as a marker of the presence of molecular mutations in CRC samples. For this purpose, we applied compression optical coherence elastography (C-OCE) to calculate stiffness values in regions corresponding to specific CRC morphological patterns (n = 54). In parallel to estimating stiffness, molecular analysis from the same zones was performed to establish their relationships. As a result, a high correlation between the presence of KRAS/NRAS/BRAF driver mutations and high stiffness values was revealed regardless of CRC morphological pattern type. Further, we proposed threshold stiffness values for label-free targeted detection of molecular alterations in CRC tissues: for KRAS, NRAS, or BRAF driver mutation—above 803 kPa (sensitivity—91%; specificity—80%; diagnostic accuracy—85%), and only for KRAS driver mutation—above 850 kPa (sensitivity—90%; specificity—88%; diagnostic accuracy—89%). To conclude, C-OCE estimation of tissue stiffness can be used as a clinical diagnostic tool for preliminary screening of genetic burden in CRC tissues.
Linking Variability in Phytochemical Composition with Safety Profile of Thymus carnosus Boiss. Extracts: Effect of Major Compounds and Evaluation of Markers of Oxidative Stress and Cell Death
Authors: Martins-Gomes Carlos , Nunes Fernando M. , Silva Amélia M.
Published: May 2024

Natural products are generally considered safe for human consumption, but this classification is often based on ethnobotanical surveys or their use in traditional medicine over a long period of time. However, edaphoclimatic factors are known to produce different chemotypes, which may affect the safety profile and bioactivities, and are not commonly considered for plants exploited as crops worldwide. Thymus carnosus Boiss., a thyme species with various health-promoting effects, has potential pharmaceutical applications, but edaphoclimatic factors were found to significantly impact its phytochemical composition. Thus, we aimed to assess the safety profile of T. carnosus extracts obtained from plants harvested in two locations over three consecutive years and to establish an association with specific components, an essential study in the search for new sources of nutraceuticals. Thus, the antiproliferative effect of an aqueous decoction (AD), hydroethanolic (HE) extracts, and major extracts’ components of T. carnosus was evaluated on intestinal (Caco-2) and hepatic (HepG2) cell models, revealing effects dependent on extract type, cell line, and tested compounds. Flavonoids induced different cytotoxic patterns, which could be attributed to molecular structural differences. Flow cytometry analysis showed apoptosis and necrosis induction, mediated by the modulation of intracellular reactive oxygen species and mitochondrial membrane potential, effects that were dependent on the cell line and phytochemical composition and on the synergism between extracts components, rather than on the activity of an isolated compound. While ursolic acid was the component with the strongest impact on the difference between extraction methods, flavonoids assumed a pivotal role in the response of different cell lines to the extracts. We report for the first time, for Thymus spp. extracts, that variations in the phytochemical composition clearly influence the cellular response, thus highlighting the need for extract standardization for medicinal applications.
In Silico Search for Drug Candidates Targeting the PAX8–PPARγ Fusion Protein in Thyroid Cancer
Authors: Sakaguchi Kaori , Okiyama Yoshio , Tanaka Shigenori
Published: May 2024

The PAX8/PPARγ rearrangement, producing the PAX8–PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble-docking-based compound screening. Specifically, we investigated the pocket structure that should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand-binding pocket on the PPARγ side of the PPFP is similar to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to the PPFP for 97 drug or drug-like compounds registered in the DrugBank database with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics Poisson–Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.
Mitigation of Breast Cancer Cells’ Invasiveness via Down Regulation of ETV7, Hippo, and PI3K/mTOR Pathways by Vitamin D3 Gold-Nanoparticles
Authors: Roy Moumita , Hussain Fazle
Published: May 2024

Metastasis in breast cancer is the major cause of death in females (about 30%). Based on our earlier observation that Vitamin D3 downregulates mTOR, we hypothesized that Vitamin D3 conjugated to gold nanoparticles (VD3-GNPs) reduces breast cancer aggressiveness by downregulating the key cancer controller PI3K/AKT/mTOR. Western blots, migration/invasion assays, and other cell-based, biophysical, and bioinformatics studies are used to study breast cancer cell aggressiveness and nanoparticle characterization. Our VD3-GNP treatment of breast cancer cells (MCF-7 and MDA-MB-231) significantly reduces the aggressiveness (cancer cell migration and invasion rates > 45%) via the simultaneous downregulation of ETV7 and the Hippo pathway. Consistent with our hypothesis, we, indeed, found a downregulation of the PI3K/AKT/mTOR pathway. It is surprising that the extremely low dose of VD3 in the nano formulation (three orders of magnitude lower than in earlier studies) is quite effective in the alteration of cancer invasiveness and cell signaling pathways. Clearly, VD3-GNPs are a viable candidate for non-toxic, low-cost treatment for reducing breast cancer aggressiveness.
Electro-Metabolic Coupling of Cumulus–Oocyte Complex
Authors: Del Bianco Diletta , Gentile Rosaria , Sallicandro Luana , Biagini Andrea , Quellari Paola Tiziana , Gliozheni Elko , Sabbatini Paola , Ragonese Francesco , Malvasi Antonio , D’Amato Antonio , Baldini Giorgio Maria , Trojano Giuseppe , Tinelli Andrea , Fioretti Bernard
Published: May 2024

Oocyte–cumulus cell interaction is essential for oocyte maturation and competence. The bidirectional crosstalk network mediated by gap junctions is fundamental for the metabolic cooperation between these cells. As cumulus cells exhibit a more glycolytic phenotype, they can provide metabolic substrates that the oocyte can use to produce ATP via oxidative phosphorylation. The impairment of mitochondrial activity plays a crucial role in ovarian aging and, thus, in fertility, determining the success or failure of assisted reproductive techniques. This review aims to deepen the knowledge about the electro-metabolic coupling of the cumulus–oocyte complex and to hypothesize a putative role of potassium channel modulators in order to improve fertility, promote intracellular Ca2+ influx, and increase the mitochondrial biogenesis and resulting ATP levels in cumulus cells.
Metabolic and Transcriptomic Profile Revealing the Differential Accumulating Mechanism in Different Parts of Dendrobium nobile
Authors: Zhao Ruoxi , Yan Shou , Hu Yadong , Rao Dan , Li Hongjie , Chun Ze , Zheng Shigang
Published: May 2024

Dendrobium nobile is an important orchid plant that has been used as a traditional herb for many years. For the further pharmaceutical development of this resource, a combined transcriptome and metabolome analysis was performed in different parts of D. nobile. First, saccharides, organic acids, amino acids and their derivatives, and alkaloids were the main substances identified in D. nobile. Amino acids and their derivatives and flavonoids accumulated strongly in flowers; saccharides and phenols accumulated strongly in flowers and fruits; alkaloids accumulated strongly in leaves and flowers; and a nucleotide and its derivatives and organic acids accumulated strongly in leaves, flowers, and fruits. Simultaneously, genes for lipid metabolism, terpenoid biosynthesis, and alkaloid biosynthesis were highly expressed in the flowers; genes for phenylpropanoids biosynthesis and flavonoid biosynthesis were highly expressed in the roots; and genes for other metabolisms were highly expressed in the leaves. Furthermore, different members of metabolic enzyme families like cytochrome P450 and 4-coumarate-coA ligase showed differential effects on tissue-specific metabolic accumulation. Members of transcription factor families like AP2-EREBP, bHLH, NAC, MADS, and MYB participated widely in differential accumulation. ATP-binding cassette transporters and some other transporters also showed positive effects on tissue-specific metabolic accumulation. These results systematically elucidated the molecular mechanism of differential accumulation in different parts of D. nobile and enriched the library of specialized metabolic products and promising candidate genes.
A Pilot Study to Investigate Peripheral Low-Level Chronic LPS Injection as a Model of Neutrophil Activation in the Periphery and Brain in Mice
Authors: Aries Michelle , Cook Makayla , Hensley-McBain Tiffany
Published: May 2024

Lipopolysaccharide-induced (LPS) inflammation is used as model to understand the role of inflammation in brain diseases. However, no studies have assessed the ability of peripheral low-level chronic LPS to induce neutrophil activation in the periphery and brain. Subclinical levels of LPS were injected intraperitoneally into mice to investigate its impacts on neutrophil frequency and activation. Neutrophil activation, as measured by CD11b expression, was higher in LPS-injected mice compared to saline-injected mice after 4 weeks but not 8 weeks of injections. Neutrophil frequency and activation increased in the periphery 4–12 h and 4–8 h after the fourth and final injection, respectively. Increased levels of G-CSF, TNFa, IL-6, and CXCL2 were observed in the plasma along with increased neutrophil elastase, a marker of neutrophil extracellular traps, peaking 4 h following the final injection. Neutrophil activation was increased in the brain of LPS-injected mice when compared to saline-injected mice 4–8 h after the final injection. These results indicate that subclinical levels of peripheral LPS induces neutrophil activation in the periphery and brain. This model of chronic low-level systemic inflammation could be used to understand how neutrophils may act as mediators of the periphery–brain axis of inflammation with age and/or in mouse models of neurodegenerative or neuroinflammatory disease.
Leveraging the Fragment Molecular Orbital and MM-GBSA Methods in Virtual Screening for the Discovery of Novel Non-Covalent Inhibitors Targeting the TEAD Lipid Binding Pocket
Authors: Kim Jongwan , Jin Haiyan , Kim Jinhyuk , Cho Seon Yeon , Moon Sungho , Wang Jianmin , Mao Jiashun , No Kyoung Tai
Published: May 2024

The Hippo pathway controls organ size and homeostasis and is linked to numerous diseases, including cancer. The transcriptional enhanced associate domain (TEAD) family of transcription factors acts as a receptor for downstream effectors, namely yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which binds to various transcription factors and is essential for stimulated gene transcription. YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival. TEAD1–4 overexpression has been observed in different cancers in various tissues, making TEAD an attractive target for drug development. The central drug-accessible pocket of TEAD is crucial because it undergoes a post-translational modification called auto-palmitoylation. Crystal structures of the C-terminal TEAD complex with small molecules are available in the Protein Data Bank, aiding structure-based drug design. In this study, we utilized the fragment molecular orbital (FMO) method, molecular dynamics (MD) simulations, shape-based screening, and molecular mechanics–generalized Born surface area (MM-GBSA) calculations for virtual screening, and we identified a novel non-covalent inhibitor—BC-001—with IC50 = 3.7 μM in a reporter assay. Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC50 of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications.
Biopolymer Drug Delivery Systems for Oromucosal Application: Recent Trends in Pharmaceutical R&D
Authors: Dubashynskaya Natallia V. , Petrova Valentina A. , Skorik Yury A.
Published: May 2024

Oromucosal drug delivery, both local and transmucosal (buccal), is an effective alternative to traditional oral and parenteral dosage forms because it increases drug bioavailability and reduces systemic drug toxicity. The oral mucosa has a good blood supply, which ensures that drug molecules enter the systemic circulation directly, avoiding drug metabolism during the first passage through the liver. At the same time, the mucosa has a number of barriers, including mucus, epithelium, enzymes, and immunocompetent cells, that are designed to prevent the entry of foreign substances into the body, which also complicates the absorption of drugs. The development of oromucosal drug delivery systems based on mucoadhesive biopolymers and their derivatives (especially thiolated and catecholated derivatives) is a promising strategy for the pharmaceutical development of safe and effective dosage forms. Solid, semi-solid and liquid pharmaceutical formulations based on biopolymers have several advantageous properties, such as prolonged residence time on the mucosa due to high mucoadhesion, unidirectional and modified drug release capabilities, and enhanced drug permeability. Biopolymers are non-toxic, biocompatible, biodegradable and may possess intrinsic bioactivity. A rational approach to the design of oromucosal delivery systems requires an understanding of both the anatomy/physiology of the oral mucosa and the physicochemical and biopharmaceutical properties of the drug molecule/biopolymer, as presented in this review. This review summarizes the advances in the pharmaceutical development of mucoadhesive oromucosal dosage forms (e.g., patches, buccal tablets, and hydrogel systems), including nanotechnology-based biopolymer nanoparticle delivery systems (e.g., solid lipid particles, liposomes, biopolymer polyelectrolyte particles, hybrid nanoparticles, etc.).
Novel C3-Methylene-Bridged Indole Derivatives with and without Substituents at N1: The Influence of Substituents on Their Hemolytic, Cytoprotective, and Antimicrobial Activity
Authors: Babijczuk Karolina , Berdzik Natalia , Nowak Damian , Warżajtis Beata , Rychlewska Urszula , Starzyk Justyna , Mrówczyńska Lucyna , Jasiewicz Beata
Published: May 2024

Alkaloids are natural compounds useful as scaffolds for discovering new bioactive molecules. This study utilized alkaloid gramine to synthesize two groups of C3-substituted indole derivatives, which were either functionalized at N1 or not. The compounds were characterized by spectroscopic methods. The protective effects of the new compounds against in vitro oxidative hemolysis induced by standard oxidant 2,2′-azobis(2-amidinopropane dihydro chloride (AAPH) on human erythrocytes as a cell model were investigated. Additionally, the compounds were screened for antimicrobial activity. The results indicated that most of the indole derivatives devoid of the N1 substitution exhibited strong cytoprotective properties. The docking studies supported the affinities of selected indole-based ligands as potential antioxidants. Furthermore, the derivatives obtained exhibited potent fungicidal properties. The structures of the eight derivatives possessing indole moiety bridged to the imidazole-, benzimidazole-, thiazole-, benzothiazole-, and 5-methylbenzothiazoline-2-thiones were determined by X-ray diffraction. The C=S bond lengths in the thioamide fragment pointed to the involvement of zwitterionic structures of varying contribution. The predominance of zwitterionic mesomers may explain the lack of cytoprotective properties, while steric effects, which limit multiple the hydrogen-bond acceptor properties of a thione sulfur, seem to be responsible for the high hemolytic activity.
Structural Models for a Series of Allosteric Inhibitors of IGF1R Kinase
Authors: Verma Jyoti , Vashisth Harish
Published: May 2024

The allosteric inhibition of insulin-like growth factor receptor 1 kinase (IGF1RK) is a potential strategy to overcome selectivity barriers for targeting receptor tyrosine kinases. We constructed structural models of a series of 12 indole-butyl-amine derivatives that have been reported as allosteric inhibitors of IGF1RK. We further studied the dynamics and interactions of each inhibitor in the allosteric pocket via all-atom explicit-solvent molecular dynamics (MD) simulations. We discovered that a bulky carbonyl substitution at the R1 indole ring is structurally unfavorable for inhibitor binding in the IGF1RK allosteric pocket. Moreover, we found that the most potent derivative (termed C11) acquires a distinct conformation: forming an allosteric pocket channel with better shape complementarity and interactions with the receptor. In addition to a hydrogen-bonding interaction with V1063, the cyano derivative C11 forms a stable hydrogen bond with M1156, which is responsible for its unique binding conformation in the allosteric pocket. Our findings show that the positioning of chemical substituents with different pharmacophore features at the R1 indole ring influences molecular interactions and binding conformations of indole-butyl-amine derivatives and, hence, dramatically affects their potencies. Our results provide a structural framework for the design of allosteric inhibitors with improved affinities and specificities against IGF1RK.
Comparison of Synthetic Pathways for Obtaining Fluorescent Nanomaterials Based on Halloysite and Carbon Dots for Potential Biological Sensing
Authors: Massaro Marina , Cinà Giuseppe , Cavallaro Giuseppe , Lazzara Giuseppe , Silvestri Alessandro , Barbosa Raquel de Melo , Sànchez-Espejo Rita , Viseras-Iborra César , Notarbartolo Monica , Riela Serena
Published: May 2024

Recently, fluorescent sensors have gained considerable attention due to their high sensitivity, low cost and noninvasiveness. Among the different materials that can be used for this purpose, carbon dots (CDs) represent valuable candidates for applications in sensing. These, indeed, are easily synthesized, show high quantum yield and are highly biocompatible. However, it was pointed out that the photoluminescence properties of these nanomaterials are strictly dependent on the synthetic and purification methods adopted. The presence of halloysite nanotubes (HNTs), a natural, low cost and biocompatible clay mineral, has been found to be efficient in obtaining small and highly monodispersed CDs without long and tedious purification techniques. Herein, we report the comparison of synthetic pathways for obtaining halloysite-N-doped CDs (HNTs-NCDs) that could be used in biological sensing. One was based on the synthesis of N-doped CDs by a bottom-up approach on HNTs’ surface by a MW pyrolysis process; the other one was based on the post-modification of pristine N-doped CDs with halloysite derivatives. The evaluation of the best synthetic route was performed by different physico-chemical techniques. It was found that the bottom-up approach led to the formation of N-doped CDs with different functional groups onto the HNTs’ surface. This evidence was also translated in the different fluorescence quantum yields and the existence of several functional groups in the obtained materials was investigated by potentiometric titrations. Furthermore, the ability of the synthesized nanomaterials as sensors for Fe3+ ions detection was assessed by spectroscopic measurements, and the cellular uptake was verified by confocal/fluorescence microscopies as well.
Fuzzy Integrated Delphi-ISM-MICMAC Hybrid Multi-Criteria Approach to Optimize the Artificial Intelligence (AI) Factors Influencing Cost Management in Civil Engineering
Authors: Hu Hongxia , Jiang Shouguo , Goswami Shankha Shubhra , Zhao Yafei
Published: May 2024

This research paper presents a comprehensive study on optimizing the critical artificial intelligence (AI) factors influencing cost management in civil engineering projects using a multi-criteria decision-making (MCDM) approach. The problem addressed revolves around the need to effectively manage costs in civil engineering endeavors amidst the growing complexity of projects and the increasing integration of AI technologies. The methodology employed involves the utilization of three MCDM tools, specifically Delphi, interpretive structural modeling (ISM), and Cross-Impact Matrix Multiplication Applied to Classification (MICMAC). A total of 17 AI factors, categorized into eight broad groups, were identified and analyzed. Through the application of different MCDM techniques, the relative importance and interrelationships among these factors were determined. The key findings reveal the critical role of certain AI factors, such as risk mitigation and cost components, in optimizing the cost management processes. Moreover, the hierarchical structure generated through ISM and the influential factors identified via MICMAC provide insights for prioritizing strategic interventions. The implications of this study extend to informing decision-makers in the civil engineering domain about effective strategies for leveraging AI in their cost management practices. By adopting a systematic MCDM approach, stakeholders can enhance project outcomes while optimizing resource allocation and mitigating financial risks.
Mosquitoes (Diptera: Culicidae) of Poland: An Update of Species Diversity and Current Challenges
Authors: Jawień Piotr , Pfitzner Wolf Peter , Schaffner Francis , Kiewra Dorota
Published: May 2024

This article presents the current state of knowledge of mosquito species (Diptera: Culicidae) occurring in Poland. In comparison to the most recently published checklists (1999 and 2007), which listed 47 mosquito species, four species (Aedes japonicus, Anopheles daciae, Anopheles hyrcanus, and Anopheles petragnani) are added to the Polish fauna. Our new checklist of Polish mosquito fauna includes 51 species of mosquitoes from five genera: Aedes (30), Anopheles (8), Coquillettidia (1), Culiseta (7), and Culex (5). Aspects of the ecology and biology of the Polish mosquito fauna, with particular emphasis on newly recorded species, are discussed.
Influence of Vineyard Inter-Row Management on Grapevine Leafhoppers and Their Natural Enemies
Authors: Cargnus Elena , Kiaeian Moosavi Seyedeh Fatemeh , Frizzera Davide , Floreani Chiara , Zandigiacomo Pietro , Bigot Giovanni , Mosetti Davide , Pavan Francesco
Published: May 2024

Inter-row management in vineyards can influence the abundance of grapevine pests and their natural enemies. In 2013–2015, in a vineyard in northeastern Italy, the influence of two vineyard inter-row management strategies (i.e., alternate mowing, AM, and periodical tillage, PT) on the population dynamics of grapevine leafhoppers Hebata vitis and Zygina rhamni and their natural enemies, the mymarid Anagrus atomus and spiders (Araneae), and other hymenopteran parasitoids, were studied with different survey approaches. The infestations of both leafhoppers were lower in AM than PT due to the reduced leafhopper oviposition and higher nymph mortality in AM. This occurred although leafhopper egg parasitization by A. atomus was greater in PT than AM according to a density-dependent relationship with the leafhopper egg amount. Hymenopteran parasitoids other than A. atomus were the most abundant in AM, probably due to the higher availability of nectar and pollen than in PM. The significantly higher population densities of hunting spiders in AM than PT can be associated with the higher predation of leafhopper nymphs. Therefore, the study demonstrated that the alternate mowing of vineyard inter-rows enhances the abundance of natural enemies, such as spiders and hymenopteran parasitoids, and can contribute to grapevine leafhopper pest control.
Allochthonous Trichoderma Isolates Boost Atractylodes lancea Herb Quality at the Cost of Rhizome Growth
Authors: Li Kuo , Lin Huaibin , Guo Xiuzhi , Wang Sheng , Wang Hongyang , Wang Tielin , Peng Zheng , Wang Yuefeng , Guo Lanping
Published: May 2024

Atractylodes lancea is a perennial herb whose rhizome (AR) is a valuable traditional Chinese medicine with immense market demand. The cultivation of Atractylodes lancea faces outbreaks of root rot and deterioration in herb quality due to complex causes. Here, we investigated the effects of Trichoderma spp., well-known biocontrol agents and plant-growth-promoters, on ARs. We isolated Trichoderma strains from healthy ARs collected in different habitats and selected three T. harzianum strains (Th2, Th3 and Th4) with the strongest antagonizing effects on root rot pathogens (Fusarium spp.). We inoculated geo-authentic A. lancea plantlets with Th2, Th3 and Th4 and measured the biomass and quality of 70-day-old ARs. Th2 and Th3 promoted root rot resistance of A. lancea. Th2, Th3 and Th4 all boosted AR quality: the concentration of the four major medicinal compounds in ARs (atractylon, atractylodin, hinesol and β-eudesmol) each increased 1.6- to 18.2-fold. Meanwhile, however, the yield of ARs decreased by 0.58- to 0.27-fold. Overall, Th3 dramatically increased the quality of ARs at a relatively low cost, namely lower yield, showing great potential for practical application. Our results showed selectivity between A. lancea and allochthonous Trichoderma isolates, indicating the importance of selecting specific microbial patches for herb cultivation.
Automated 3-D Computer-Aided Measurement of the Bony Orbit: Evaluation of Correlations among Volume, Depth, and Surface Area
Authors: Kontio Risto , Wilkman Tommy , Mesimäki Karri , Chepurnyi Yurii , Asikainen Antti , Haapanen Aleksi , Poutala Arto , Mikkonen Marko , Slobodianiuk Alina , Kopchak Andrii
Published: May 2024

(1)The study aimed to measure the depth, volume, and surface area of the intact human orbit by applying an automated method of CT segmentation and to evaluate correlations among depth, volume, and surface area. Additionally, the relative increases in volume and surface area in proportion to the diagonal of the orbit were assessed. (2) CT data from 174 patients were analyzed. A ball-shaped mesh consisting of tetrahedral elements was inserted inside orbits until it encountered the bony boundaries. Orbital volume, area depth, and their correlations were measured. For the validation, an ICC was used. (3) The differences between genders were significant (p < 10−7) but there were no differences between sides. When comparing orbit from larger to smaller, a paired sample t-test indicated a significant difference in groups (p < 10−10). A simple linear model (Volume~1 + Gender + Depth + Gender:Depth) revealed that only depth had a significant effect on volume (p < 10−19). The ICCs were 1.0. (4) Orbital volume, depth, and surface area measurements based on an automated CT segmentation algorithm demonstrated high repeatability and reliability. Male orbits were always larger on average by 14%. There were no differences between the sides. The volume and surface area ratio did not differ between genders and was approximately 0.75.
Segmental Mandibulectomy and Mandibular Reconstruction with Fibula-Free Flap Using a 3D Template
Authors: Tatti Melania , Carta Filippo , Bontempi Mauro , Deriu Sara , Mariani Cinzia , Marrosu Valeria , Foddis Emanuele , Gerosa Clara , Marongiu Giuseppe , Saba Luca , Figus Andrea , Pau Massimiliano , Leban Bruno , Puxeddu Roberto
Published: May 2024

Introduction: The present study evaluates the influence of virtual surgical planning with a preoperative 3D resin model on aesthetic and functional outcomes in patients treated by segmental mandibulectomy and reconstruction with fibula-free flap for oral cancer. Methods: All consecutive patients who underwent segmental mandibulectomy and mandibular reconstruction with a fibula-free flap using a 3D template at our department from January 2021 to January 2023 were included in the study. “Patients control” were patients treated by reconstruction with a fibula-free flap without using a 3D template. Three-dimensional modeling was performed by converting from preoperative computed tomography to a stereolithography format to obtain the resin 3D models. Qualitative analysis of anatomical and aesthetic results consisted of the evaluation of the patients’ aesthetic and functional satisfaction and the symmetry of the mandibular contour observed at clinical examination. Quantitative analysis was based on the assessment of the accuracy and precision of the reconstruction by comparing preoperative and postoperative computed tomograms as objective indicators. Results: Seven patients (five males and two females, mean age of 65.1 years) were included in the study. All patients showed a symmetric mandibular contour based on the clinical examination. After recovery, six patients (85.7%) considered themselves aesthetically satisfied. The quantitative analysis (assessed in six/seven patients) showed that the mean difference between preoperative and postoperative intercondylar distance, intergonial angle distance, anteroposterior dimension, and gonial angle improved in the 3D template-assisted group. Conclusion: The 3D-printed template for mandibular reconstruction with microvascular fibula-free flap can improve aesthetic outcomes in comparison with standard approaches.
Identifying Suitable Patients for Overcoming Androgen Deprivation Monotherapy in De Novo Metastatic Hormone-Sensitive Prostate Cancer
Authors: Lee Donghyun , Lim Bumjin , Nguyen Tuan Thanh , Choi Se Young
Published: May 2024

Background: Although metastatic hormone-sensitive prostate cancer (mHSPC) treatments have evolved, androgen deprivation therapy (ADT) remains a widely used regimen. Therefore, this study sought patients who did not progress to castration-resistant prostate cancer (CRPC) but received ADT monotherapy and factors affecting overall survival (OS) in de novo mHSPC. Methods: De novo mHSPC patients who received ADT treatment were included. ADT included luteinizing hormone-releasing hormone agonists with or without anti-androgen. The total cohort was divided into two groups relative to CRPC progression within two years. Logistic analysis was used to identify factors that did not progress CRPC within two years. Cox regression was used to assess the independent predictors for OS. Results: The total cohort was divided into the no-CRPC within two years group (n = 135) and the CRPC within two years group (n = 126). Through multivariate logistic analysis, the life expectancy (odds ratio [OR] 0.95, 95% CI 0.91–0.99, p = 0.014) and Gleason scores (≥9 vs. ≤8; OR 0.43, 95% CI 0.24–0.75, p = 0.003) were associated with the group without castration-resistant prostate cancer progression within two years. The multivariate Cox model revealed that life expectancy (hazard ratio [HR] 0.951, 95% CI 0.904–0.999, p = 0.0491), BMI (HR 0.870, 95% CI 0.783–0.967, p = 0.0101), and CCI (≥2 vs. <2; HR 2.018, 95% CI 1.103–3.693, p = 0.0227) were significant predictive factors for OS. Conclusions: Patients with long life expectancy and a Gleason score of 9 or more were more likely to develop mCRPC while alive. Patients with short life expectancy, low BMI, and worsening comorbidity were more likely to die before progressing to CRPC. Although intensified treatment is essential for oncologic outcomes in mHSPC, shared decision making is integral for patients who may not benefit from this treatment.
Clinical Outcome of Colorectal Cancer Patients with Concomitant Hypertension: A Systematic Review and Meta-Analysis
Authors: Sur Daniel , Coroama Constantin Ionut , Audisio Alessandro , Fazio Roberta , Coroama Maria , Lungulescu Cristian Virgil
Published: May 2024

Background: Arterial hypertension is regarded as a possible biomarker of treatment efficacy in colorectal cancer. Also, extended anti-angiogenic use in the metastatic treatment of the colorectal neoplasm may result in elevated blood pressure. We carried out a systematic review and meta-analysis to assess the clinical outcome of colorectal cancer patients with concomitant hypertension (HTN). Methods: We conducted a systematic search on Embase, Web of Science, Scopus, PubMed (Medline), the Cochrane Library, and CINAHL from inception until October 2023 for articles that addressed the relationship between HTN and progressive free survival (PFS), overall survival (OS), and overall response rate (ORR) for the first and second line of systemic therapy in patients with metastatic colorectal cancer. Results: Eligibility criteria were met by 16 articles out of 802 screened studies. Pooled analysis showed that HTN was associated with significantly improved PFS (HR: 0.507, 95% CI: 0.460–0.558, p ≤ 0.001) and OS (HR: 0.677, 95% CI: 0.592–0.774, p ≤ 0.001) in patients with metastatic colorectal cancer. In addition, the pooled RR of HTN for the ORR (RR: 1.28, 95% CI: 1.108–1.495, p = 0.001) suggests that HTN could be a predictive factor of ORR in patients with metastatic colorectal cancer. Conclusions: Elevated blood pressure is associated with better clinical outcomes in patients with metastatic colorectal cancer.
Integration of Smart Home and Building Automation Systems in Virtual Reality and Robotics-Based Technological Environment for Neurorehabilitation: A Pilot Study Protocol
Authors: Federico Sara , Zitti Mirko , Regazzetti Martina , Dal Pozzo Enrico , Cieślik Błażej , Pomella Alberto , Stival Francesca , Pirini Marco , Pregnolato Giorgia , Kiper Pawel
Published: May 2024

Technological innovation has revolutionized healthcare, particularly in neurological rehabilitation, where it has been used to address chronic conditions. Smart home and building automation (SH&BA) technologies offer promising solutions for managing chronic disabilities associated with such conditions. This single group, pre-post longitudinal pilot study, part of the H2020 HosmartAI project, aims to explore the integration of smart home technologies into neurorehabilitation. Eighty subjects will be enrolled from IRCCS San Camillo Hospital (Venice, Italy) and will receive rehabilitation treatment through virtual reality (VR) and robotics devices for 15 h per day, 5 days a week for 3 weeks in the HosmartAI Room (HR), equipped with SH&BA devices measuring the environment. The study seeks to optimize patient outcomes and refine rehabilitation practices. Findings will be disseminated through peer-reviewed publications and scientific meetings, contributing to advancements in neurological rehabilitation and guiding future research.
Enhancing Interaction between Lanthanum Manganese Cobalt Oxide and Carbon Black through Different Approaches for Primary Zn–Air Batteries
Authors: García-Rodríguez Mario , Flores-Lasluisa Jhony X. , Cazorla-Amorós Diego , Morallón Emilia
Published: May 2024

Due to the need for decarbonization in energy generation, it is necessary to develop electrocatalysts for the oxygen reduction reaction (ORR), a key process in energy generation systems such as fuel cells and metal–air batteries. Perovskite–carbon material composites have emerged as active and stable electrocatalysts for the ORR, and the interaction between both components is a crucial aspect for electrocatalytic activity. This work explores different mixing methods for composite preparation, including mortar mixing, ball milling, and hydrothermal and thermal treatments. Hydrothermal treatment combined with ball milling resulted in the most favorable electrocatalytic performance, promoting intimate and extensive contact between the perovskite and carbon material and improving electrocatalytic activity. Employing X-ray photoelectron spectroscopy (XPS), an increase in the number of M-O-C species was observed, indicating enhanced interaction between the perovskite and the carbon material due to the adopted mixing methods. This finding was further corroborated by temperature-programmed reduction (TPR) and temperature-programmed desorption (TPD) techniques. Interestingly, the ball milling method results in similar performance to the hydrothermal method in the zinc–air battery and, thus, is preferable because of the ease and straightforward scalability of the preparation process.