bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges
Authors: Meira Débora Dummer , de Castro e Caetano Maria Clara , Casotti Matheus Correia , Zetum Aléxia Stefani Siqueira , Gonçalves André Felipe Monteiro , Moreira André Rodrigues , de Oliveira Augusto Henrique , Pesente Fellipe , Santana Gabriel Mendonça , de Almeida Duque Daniel , Pereira Gierleson Santos Cangussu , de Castro Giulia de Souza Cupertino , Pavan Isabele Pagani , Chagas João Pedro Sarcinelli , Bourguignon José Henrique Borges , de Oliveira Juliana Ribeiro , Barbosa Karen Ruth Michio , Altoé Lorena Souza Castro , Louro Luana Santos , Merigueti Luiza Poppe , Alves Lyvia Neves Rebello , Machado Marlon Ramos Rosado , Roque Maria Luísa Rodrigues Oliveira , Prates Pedro Santana , de Paula Segáua Sayuri Honorio , dos Santos Uchiya Taissa , Louro Thomas Erik Santos , Daleprane Vinicius Eduardo , Guaitolini Yasmin Moreto , Vicente Creuza Rachel , dos Reis Trabach Raquel Silva , de Araújo Bruno Cancian , dos Santos Eldamária de Vargas Wolfgramm , de Paula Flávia , Lopes Tiago José S. , de Carvalho Elizeu Fagundes , Louro Iúri Drumond
Published: October 2023

Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.
Weathering Effects on Engineering Geological Properties of Trachydacitic Volcanic Rocks from the Monte Amiata (Southern Tuscany, Italy)
Authors: D’Addario Enrico , Giorgetti Giovanna , Magrini Claudia , Disperati Leonardo
Published: October 2023

Variability in lithology and weathering degree affects physical and mechanical properties of rocks. In this study, we investigated the relationships between weathering degree and engineering geological properties of trachydacitic volcanic rocks from Monte Amiata (central Italy) by coupling field and laboratory analyses. We collected in situ Schmidt hammer tests in the field. We evaluated weathering quantifying the percentage of secondary minerals through thermal analysis in the laboratory. We also determined dry density (ρd), specific gravity of solids (Gs), porosity (n) and two-dimensional (2D) porosity as resulted from scanning electron microscopy investigations. The results of our study indicate a negative linear correlation between Schmidt hammer rebound values and secondary mineral percentage. This correlation provides a tool to quantitatively estimate the deterioration of rock uniaxial compressive strength (UCS) as weathering increases. Moreover, thermal analysis turned out to be a quantitative and reproducible method to evaluate weathering degree of magmatic rocks.
The Toynbee Affair at 100: The Birth of ‘World History’ and the Long Shadow of the Interwar Liberal Imaginaire
Authors: Dubnov Arie M.
Published: October 2023

Functioning as “precedent” and “templates” for future transfers, the Greco-Turkish population exchange and the Lausanne Treaty) are undoubtedly events of world-historical significance. But they are also crucial in the genesis of the subfield of historical research we now call “World History”: they provided the backdrop against which Arnold Joseph Toynbee (1889–1975) began sketching his magnum opus, A Study of History and developed the foundations of this subfield of history writing. This article revisits the so-called “Toynbee Affair” and places it in its intellectual and political contexts. First, it revisits the British classicist scholarship that provided the backdrop and initial inspiration for Toynbee as it shifted its gaze from ancient Rome to Greece, which was put forward as a better model for foreign and imperial policy. Next, it examines Toynbee’s wartime activities and shows that his attitudes towards the new states of Central Europe were based on principles that often stood in tension with his activities and views connected to the Middle East. During these years, Toynbee was an active participant in a discourse concerning the need to manage “mixed populations,” which moved to the forefront of a new form of internationalism, while also exposed to the writings of authors such as Oswald Spengler and Frederick J. Teggart, who pushed him to advance a new type of historiography. Third, the article looks at the uneven reception of Toynbee’s ideas after 1945, including his views on the US, the “Muslim civilization,” and his controversial views on Jews and the politics of the Middle East. The article concludes by arguing that his views, which rested on a deep suspicion of liminal hybridity or cultural mestizos, failed to transcend the basic logic of separation developed in Lausanne. Entirely on the contrary: Toynbee’s story offers us a case in which we can recognize the making of the interwar “cultural imaginaire” and “reinvention of differences,” which continues shaping our view of “the West’s” supposed borders to this day.
Does Family Ownership Moderate the Relationship between Board Diversity and the Financial Performance of Saudi-Listed Firms
Authors: Bazhair Ayman Hassan , Sulimany Hamid Ghazi H
Published: October 2023

This paper explores the moderating role of family ownership in the relationship between board diversity and financial performance. The study sampled data of 98 Saudi non-financial companies from 2012 to 2021. The data were analysed using fixed effect regression, while a generalised method of moments (GMM) was employed for a robustness test. The empirical evidence suggests that board gender may not have much relevance in enhancing the financial performance of Saudi firms. In contrast, the research findings emphasised that coupled with stringent monitoring from family ownership, foreign directorship, CEO tenure, and board financial expertise may serve as crucial control mechanisms that can minimise agency costs, leading to higher financial performance. This research modelled how the interaction between family ownership and board diversity attributes may determine financial performance. Hence, the study contributes to the body of knowledge by unveiling a more robust control governance mechanism, particularly in developing economies with ineffective markets for corporate controls.
Development of an Algorithm to Evaluate the Quality of Geolocated Addresses in Urban Areas
Authors: Sierra Requena Rafael , Martínez-Llario José Carlos , Lorenzo-Sáez Edgar , Coll-Aliaga Eloína
Published: October 2023

The spatial and semantic data of geographic addresses are extremely important for citizens, governments, and companies. The addresses can georeference environmental, economic, security, health, and demographic parameters in urban areas. Additionally, address components can be used by users to locate any point of interest (POI) with location-based systems (LBSs). For this reason, errors in address data can affect the geographic location of events, map representations, and spatial analyses. Thus, this paper presents the development of an algorithm for evaluating the quality of semantic and geographic information in any geospatial address dataset. The reference datasets are accessible using open data platforms or spatial data infrastructure (SDI) and volunteered geographic information (VGI), and both have been compared with commercial datasets using geocoding web services. Address quality analysis was developed using several open-source data science code libraries combined with spatial databases and geographic information systems. In addition, the quality of geographic addresses was evaluated by carrying out normalized tests in accordance with International Geospatial Standards (ISO 19157). Finally, this methodology assesses the quality of authorized and VGI address datasets that can be used for geocoding any relevant information in specific urban areas.
Analytical Ultracentrifugation Detects Quaternary Rearrangements and Antibody-Induced Conformational Selection of the SARS-CoV-2 Spike Trimer
Authors: Guerrini Giuditta , Mehn Dora , Fumagalli Francesco , Gioria Sabrina , Pedotti Mattia , Simonelli Luca , Bianchini Filippo , Robbiani Davide F. , Varani Luca , Calzolai Luigi
Published: October 2023

Analytical ultracentrifugation (AUC) analysis shows that the SARS-CoV-2 trimeric Spike (S) protein adopts different quaternary conformations in solution. The relative abundance of the “open” and “close” conformations is temperature-dependent, and samples with different storage temperature history have different open/close distributions. Neutralizing antibodies (NAbs) targeting the S receptor binding domain (RBD) do not alter the conformer populations; by contrast, a NAb targeting a cryptic conformational epitope skews the Spike trimer toward an open conformation. The results highlight AUC, which is typically applied for molecular mass determination of biomolecules as a powerful tool for detecting functionally relevant quaternary protein conformations.
miR-124 and VAMP3 Act Antagonistically in Human Neuroblastoma
Authors: Zhang Xiaoxiao , Yang Chengyong , Meng Zhen , Zhong Huanhuan , Hou Xutian , Wang Fenfen , Lu Yiping , Guo Jingjing , Zeng Yan
Published: October 2023

Neuroblastoma (NB) is the most common extracranial solid tumor that affects developing nerve cells in the fetus, infants, and children. miR-124 is a microRNA (miRNA) enriched in neuronal tissues, and VAMP3 (vesicle-associated membrane protein 3) has been reported to be an miR-124 target, although the relationship between NB and miR-124 or VAMP3 is unknown. Our current work identified that miR-124 levels are high in NB cases and that elevated miR-124 correlates with worse NB outcomes. Conversely, depressed VAMP3 correlates with worse NB outcomes. To investigate the mechanisms by which miR-124 and VAMP3 regulate NB, we altered miR-124 or VAMP3 expression in human NB cells and observed that increased miR-124 and reduced VAMP3 stimulated cell proliferation and suppressed apoptosis, while increased VAMP3 had the opposite effects. Genome-wide mRNA expression analyses identified gene and pathway changes which might explain the NB cell phenotypes. Together, our studies suggest that miR-124 and VAMP3 could be potential new markers of NB and targets of NB treatments.
Evaluation of Antibacterial Activity against Nosocomial Pathogens of an Enzymatically Derived α-Aminophosphonates Possessing Coumarin Scaffold
Authors: Kowalczyk Paweł , Koszelewski Dominik , Brodzka Anna , Kramkowski Karol , Ostaszewski Ryszard
Published: October 2023

The purpose of the present study was to evaluate the synergistic effect of two important pharmacophores, coumarin and α-amino dimethyl phosphonate moieties, on antimicrobial activity against selected strains of multidrug-resistant nosocomial pathogenic bacteria. The previously developed enzyme-catalysed Kabachnik–Fields protocol allowed us to obtain the studied compounds with high yields which were free from metal impurities. The structure–activity relationship revealed that inhibitory activity is strongly related to the presence of the trifluoromethyl group (CF3−) in the coumarin scaffold. MIC and MBC studies carried out on six selected pathogenic bacterial strains (Gram-positive pathogenic Staphylococcus aureus (ATCC 23235) strain, as well as on Gram-negative Acinetobacter baumannii (ATCC 17978), Pseudomonas aeruginosa (ATCC 15442), Enterobacter cloacae (ATCC 49141), Porphyromonas gingivalis (ATCC 33277), and Treponema denticola (ATCC 35405)) have shown that tested compounds show a strong bactericidal effect at low concentrations. Among all agents investigated, five exhibit higher antimicrobial activity than those observed for commonly used antibiotics. It should be noted that all the compounds tested showed very high activity against S. aureus, which is the main source of nosocomial infections that cause numerous fatalities. Furthermore, we have shown that the studied coumarin-based α-aminophosphonates, depending on their structural characteristics, are non-selective and act efficiently against various Gram-positive and Gram-negative pathogens, which is of great importance for hospitalised patients.
Exploring the Cellular and Molecular Mechanism of Discoidin Domain Receptors (DDR1 and DDR2) in Bone Formation, Regeneration, and Its Associated Disease Conditions
Authors: Mariadoss Arokia Vijaya Anand , Wang Chau-Zen
Published: October 2023

The tyrosine kinase family receptor of discoidin domain receptors (DDR1 and DDR2) is known to be activated by extracellular matrix collagen catalytic binding protein receptors. They play a remarkable role in cell proliferation, differentiation, migration, and cell survival. DDR1 of the DDR family regulates matrix-metalloproteinase, which causes extracellular matrix (ECM) remodeling and reconstruction during unbalanced homeostasis. Collagenous-rich DDR1 triggers the ECM of cartilage to regenerate the cartilage tissue in osteoarthritis (OA) and temporomandibular disorder (TMD). Moreover, DDR2 is prominently present in the fibroblasts, smooth muscle cells, myofibroblasts, and chondrocytes. It is crucial in generating and breaking collagen vital cellular activities like proliferation, differentiation, and adhesion mechanisms. However, the deficiency of DDR1 rather than DDR2 was detrimental in cases of OA and TMDs. DDR1 stimulated the ECM cartilage and improved bone regeneration. Based on the above information, we made an effort to outline the advancement of the utmost promising DDR1 and DDR2 regulation in bone and cartilage, also summarizing their structural, biological activity, and selectivity.
Assessing Drug Administration Techniques in Zebrafish Models of Neurological Disease
Authors: Chaoul Victoria , Dib Emanuel-Youssef , Bedran Joe , Khoury Chakib , Shmoury Omar , Harb Frédéric , Soueid Jihane
Published: October 2023

Neurological diseases, including neurodegenerative and neurodevelopmental disorders, affect nearly one in six of the world’s population. The burden of the resulting deaths and disability is set to rise during the next few decades as a consequence of an aging population. To address this, zebrafish have become increasingly prominent as a model for studying human neurological diseases and exploring potential therapies. Zebrafish offer numerous benefits, such as genetic homology and brain similarities, complementing traditional mammalian models and serving as a valuable tool for genetic screening and drug discovery. In this comprehensive review, we highlight various drug delivery techniques and systems employed for therapeutic interventions of neurological diseases in zebrafish, and evaluate their suitability. We also discuss the challenges encountered during this process and present potential advancements in innovative techniques.
The cGAS/STING/IFN-1 Response in Squamous Head and Neck Cancer Cells after Genotoxic Challenges and Abrogation of the ATR-Chk1 and Fanconi Anemia Axis
Authors: Zahnreich Sebastian , El Guerzyfy Soumia , Kaufmann Justus , Schmidberger Heinz
Published: October 2023

Locally advanced head and neck squamous cell carcinomas (HNSCC) are often refractory to platinum-based radiochemotherapy and new immuno-oncological strategies. To stimulate immunogenic antitumor responses in HNSCC patients, we investigated the cGAS/STING/IFN-1 signaling pathway after genotoxic treatments and concomitant abrogation of the DNA damage response (DDR). For this purpose, FaDu and UM-SCC1 cells were exposed to X-rays or cisplatin and treated with an ATR or Chk1 inhibitor, or by Fanconi anemia gene A knockout (FANCA ko). We assessed clonogenic survival, cell cycle regulation, micronuclei, free cytosolic double-stranded DNA, and the protein expression and activity of the cGAS/STING/IFN-1 pathway and related players. Cell survival, regulation of G2/M arrest, and formation of rupture-prone cGAS-positive micronuclei after genotoxic treatments were most affected by ATR inhibition and FANCA ko. In UM-SCC-1 cells only, 8 Gy X-rays promoted IFN-1 expression unaltered by abrogation of the DDR or concomitant increased TREX1 expression. At a higher dose of 20 Gy, this effect was observed only for concurrent Chk1- or ATR-inhibition. FANCA ko or cisplatin treatment was ineffective in this regard. Our observations open new perspectives for the enhancement of cGAS/STING/IFN-1-mediated antitumor immune response in HNSCC by hypofractionated or stereotactic radiotherapy concepts in multimodal settings with immuno-oncological strategies.
ADP-Ribosylation Factor 6 Pathway Acts as a Key Executor of Mesenchymal Tumor Plasticity
Authors: Hashimoto Ari , Hashimoto Shigeru
Published: October 2023

Despite the “big data” on cancer from recent breakthroughs in high-throughput technology and the development of new therapeutic modalities, it remains unclear as to how intra-tumor heterogeneity and phenotypic plasticity created by various somatic abnormalities and epigenetic and metabolic adaptations orchestrate therapy resistance, immune evasiveness, and metastatic ability. Tumors are formed by various cells, including immune cells, cancer-associated fibroblasts, and endothelial cells, and their tumor microenvironment (TME) plays a crucial role in malignant tumor progression and responses to therapy. ADP-ribosylation factor 6 (ARF6) and AMAP1 are often overexpressed in cancers, which statistically correlates with poor outcomes. The ARF6-AMAP1 pathway promotes the intracellular dynamics and cell-surface expression of various proteins. This pathway is also a major target for KRAS/TP53 mutations to cooperatively promote malignancy in pancreatic ductal adenocarcinoma (PDAC), and is closely associated with immune evasion. Additionally, this pathway is important in angiogenesis, acidosis, and fibrosis associated with tumor malignancy in the TME, and its inhibition in PDAC cells results in therapeutic synergy with an anti-PD-1 antibody in vivo. Thus, the ARF6-based pathway affects the TME and the intrinsic function of tumors, leading to malignancy. Here, we discuss the potential mechanisms of this ARF6-based pathway in tumorigenesis, and novel therapeutic strategies.
Role of Biomaterials in the Development of Epithelial Support in 3D In Vitro Airway Epithelium Development: A Systematic Review
Authors: Nashihah Ab Karim , Muhammad Firdaus Fairuz Izan , Fauzi Mh. Busra , Mobarak Nadhratun Naiim , Lokanathan Yogeswaran
Published: October 2023

Respiratory diseases have a major impact on global health. The airway epithelium, which acts as a frontline defence, is one of the most common targets for inhaled allergens, irritants, or micro-organisms to enter the respiratory system. In the tissue engineering field, biomaterials play a crucial role. Due to the continuing high impact of respiratory diseases on society and the emergence of new respiratory viruses, in vitro airway epithelial models with high microphysiological similarities that are also easily adjustable to replicate disease models are urgently needed to better understand those diseases. Thus, the development of biomaterial scaffolds for the airway epithelium is important due to their function as a cell-support device in which cells are seeded in vitro and then are encouraged to lay down a matrix to form the foundations of a tissue for transplantation. Studies conducted in in vitro models are necessary because they accelerate the development of new treatments. Moreover, in comparatively controlled conditions, in vitro models allow for the stimulation of complex interactions between cells, scaffolds, and growth factors. Based on recent studies, the biomaterial scaffolds that have been tested in in vitro models appear to be viable options for repairing the airway epithelium and avoiding any complications. This review discusses the role of biomaterial scaffolds in in vitro airway epithelium models. The effects of scaffold, physicochemical, and mechanical properties in recent studies were also discussed.
Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA
Authors: Di Costanzo Assunta , Indolfi Ciro , Franzone Anna , Esposito Giovanni , Spaccarotella Carmen Anna Maria
Published: October 2023

To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85–90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.
Drug-Tolerant Mycobacterium tuberculosis Adopt Different Survival Strategies in Alveolar Macrophages of Patients with Pulmonary Tuberculosis
Authors: Ufimtseva Elena G. , Eremeeva Natalya I.
Published: October 2023

The rapid spread of drug-resistant M. tuberculosis (Mtb) strains and the phenomenon of phenotypic tolerance to drugs present challenges toward achieving the goal of tuberculosis (TB) elimination worldwide. By using the ex vivo cultures of alveolar macrophages obtained from lung tissues of TB patients after intensive antimicrobial chemotherapy before surgery, different subpopulations of multidrug-tolerant Mtb with a spectrum of phenotypic and growth features were identified in the same TB lesions. Our results are indicative of not only passive mechanisms generating nonheritable resistance of Mtb to antibiotics, which are associated mainly with a lack of Mtb growth, but also some active mechanisms of Mtb persistence, such as cell wall and metabolic pathway remodeling. In one of the subpopulations, non-acid-fast Mtb have undergone significant reprogramming with the restoration of acid-fastness, lipoarabinomannan expression and replication in host cells of some patients after withdrawal of anti-TB drugs. Our data indicate the universal stress protein Rv2623 as a clinically relevant biomarker of Mtb that has lost acid-fastness in human lungs. The studies of Mtb survival, persistence, dormancy, and resumption and the identification of biomarkers characterizing these phenomena are very important concerning the development of vaccines and drug regimens with individualized management of patients for overcoming the resistance/tolerance crisis in anti-TB therapy.
Channeling the Natural Properties of Sindbis Alphavirus for Targeted Tumor Therapy
Authors: Pampeno Christine , Hurtado Alicia , Opp Silvana , Meruelo Daniel
Published: October 2023

Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies that support the targeted delivery of Sindbis vectors to tumor cells, highlighting their effectiveness in expressing tumor-associated antigens and immunomodulating proteins. Among the various alphavirus vectors developed for cancer therapy, Sindbis-vector-based imaging studies have been particularly extensive. Imaging modalities that enable the in vivo localization of Sindbis vectors within lymph nodes and tumors are discussed. The correlation between laminin receptor expression, tumorigenesis, and Sindbis virus infection is examined. Additionally, we present alternative entry receptors for Sindbis and related alphaviruses, such as Semliki Forest virus and Venezuelan equine encephalitis virus. The review also discusses cancer treatments that are based on the alphavirus vector expression of anti-tumor agents, including tumor-associated antigens, cytokines, checkpoint inhibitors, and costimulatory immune molecules.
Enhancing Giardicidal Activity and Aqueous Solubility through the Development of “RetroABZ”, a Regioisomer of Albendazole: In Vitro, In Vivo, and In Silico Studies
Authors: Martínez-Conde Carlos , Colín-Lozano Blanca , Gutiérrez-Hernández Abraham , Hernández-Núñez Emanuel , Yépez-Mulia Lilián , Colorado-Pablo Luis Fernando , Aguayo-Ortiz Rodrigo , Escalante Jaime , Rivera-Leyva Julio C. , Sánchez-Carranza Jessica Nayelli , Barbosa-Cabrera Elizabeth , Navarrete-Vazquez Gabriel
Published: October 2023

Parasitic diseases, including giardiasis caused by Giardia lamblia (G. lamblia), present a considerable global health burden. The limited effectiveness and adverse effects of current treatment options underscore the necessity for novel therapeutic compounds. In this study, we employed a rational design strategy to synthesize retroalbendazole (RetroABZ), aiming to address the limitations associated with albendazole, a commonly used drug for giardiasis treatment. RetroABZ exhibited enhanced in vitro activity against G. lamblia trophozoites, demonstrating nanomolar potency (IC50 = 83 nM), outperforming albendazole (189 nM). Moreover, our in vivo murine model of giardiasis displayed a strong correlation, supporting the efficacy of RetroABZ, which exhibited an eleven-fold increase in potency compared to albendazole, with median effective dose (ED50) values of 5 µg/kg and 55 µg/kg, respectively. A notable finding was RetroABZ’s significantly improved water solubility (245.74 µg/mL), representing a 23-fold increase compared to albendazole, thereby offering potential opportunities for developing derivatives that effectively target invasive parasites. The molecular docking study revealed that RetroABZ displays an interaction profile with tubulin similar to albendazole, forming hydrogen bonds with Glu198 and Cys236 of the β-tubulin. Additionally, molecular dynamics studies demonstrated that RetroABZ has a greater number of hydrophobic interactions with the binding site in the β-tubulin, due to the orientation of the propylthio substituent. Consequently, RetroABZ exhibited a higher affinity compared to albendazole. Overall, our findings underscore RetroABZ’s potential as a promising therapeutic candidate not only for giardiasis but also for other parasitic diseases.
New Facets of DNA Double Strand Break Repair: Radiation Dose as Key Determinant of HR versus c-NHEJ Engagement
Authors: Mladenov Emil , Mladenova Veronika , Stuschke Martin , Iliakis George
Published: October 2023

Radiation therapy is an essential component of present-day cancer management, utilizing ionizing radiation (IR) of different modalities to mitigate cancer progression. IR functions by generating ionizations in cells that induce a plethora of DNA lesions. The most detrimental among them are the DNA double strand breaks (DSBs). In the course of evolution, cells of higher eukaryotes have evolved four major DSB repair pathways: classical non-homologous end joining (c-NHEJ), homologous recombination (HR), alternative end-joining (alt-EJ), and single strand annealing (SSA). These mechanistically distinct repair pathways have different cell cycle- and homology-dependencies but, surprisingly, they operate with widely different fidelity and kinetics and therefore contribute unequally to cell survival and genome maintenance. It is therefore reasonable to anticipate tight regulation and coordination in the engagement of these DSB repair pathway to achieve the maximum possible genomic stability. Here, we provide a state-of-the-art review of the accumulated knowledge on the molecular mechanisms underpinning these repair pathways, with emphasis on c-NHEJ and HR. We discuss factors and processes that have recently come to the fore. We outline mechanisms steering DSB repair pathway choice throughout the cell cycle, and highlight the critical role of DNA end resection in this process. Most importantly, however, we point out the strong preference for HR at low DSB loads, and thus low IR doses, for cells irradiated in the G2-phase of the cell cycle. We further explore the molecular underpinnings of transitions from high fidelity to low fidelity error-prone repair pathways and analyze the coordination and consequences of this transition on cell viability and genomic stability. Finally, we elaborate on how these advances may help in the development of improved cancer treatment protocols in radiation therapy.
Multi-Method Quantification of Acetyl-Coenzyme A and Further Acyl-Coenzyme A Species in Normal and Ischemic Rat Liver
Authors: Tokarska-Schlattner Malgorzata , Zeaiter Nour , Cunin Valérie , Attia Stéphane , Meunier Cécile , Kay Laurence , Achouri Amel , Hiriart-Bryant Edwige , Couturier Karine , Tellier Cindy , El Harras Abderrafek , Elena-Herrmann Bénédicte , Khochbin Saadi , Le Gouellec Audrey , Schlattner Uwe
Published: October 2023

Thioesters of coenzyme A (CoA) carrying different acyl chains (acyl-CoAs) are central intermediates of many metabolic pathways and donor molecules for protein lysine acylation. Acyl-CoA species largely differ in terms of cellular concentrations and physico-chemical properties, rendering their analysis challenging. Here, we compare several approaches to quantify cellular acyl-CoA concentrations in normal and ischemic rat liver, using HPLC and LC-MS/MS for multi-acyl-CoA analysis, as well as NMR, fluorimetric and spectrophotometric techniques for the quantification of acetyl-CoAs. In particular, we describe a simple LC-MS/MS protocol that is suitable for the relative quantification of short and medium-chain acyl-CoA species. We show that ischemia induces specific changes in the short-chain acyl-CoA relative concentrations, while mild ischemia (1–2 min), although reducing succinyl-CoA, has little effects on acetyl-CoA, and even increases some acyl-CoA species upstream of the tricarboxylic acid cycle. In contrast, advanced ischemia (5–6 min) also reduces acetyl-CoA levels. Our approach provides the keys to accessing the acyl-CoA metabolome for a more in-depth analysis of metabolism, protein acylation and epigenetics.
Anti-Inflammatory and Antioxidant Activities of Lipophilic Fraction from Liriope platyphylla Seeds Using Network Pharmacology, Molecular Docking, and In Vitro Experiments
Authors: Truong Van-Long , Bae Yeon-Ji , Rarison Razanamanana H. G. , Bang Ji-Hong , Park So-Yoon , Jeong Woo-Sik
Published: October 2023

Antioxidant and anti-inflammatory mechanisms counteract the pathogenesis of chronic diseases, such as diabetes, aging, and cancer. Therefore, enhancing antioxidant and anti-inflammatory functions may help manage these pathological conditions. This study aimed to assess the antioxidant and anti-inflammatory potentials of lipophilic fraction of Liriope platyphylla seeds (LLPS) using network pharmacology, molecular docking, and in vitro experiments. Here GC–MS analysis tentatively identified forty-three lipophilic compounds in LLPS. LLPS exhibited powerful antioxidant activity, according to the results from chemical-based antioxidant assays on DPPH, ABTS+, superoxide anion, hydrogen peroxide, nitric oxide, and hydroxyl radicals scavenging, lipid peroxidation, reducing antioxidant powers, and total antioxidant capacity. Additionally, LLPS enhanced cellular antioxidant capacity by inhibiting reactive oxygen species formation and elevating antioxidant enzyme levels, including catalase and heme oxygenase-1. Moreover, LLPS attenuated inflammatory response by reducing nitric oxide secretion and downregulating the expression of inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1β in lipopolysaccharide-treated macrophages. Network pharmacology and molecular docking analyses showed that key compounds in LPPS, particularly phytosterols and fatty acid esters, exerted antioxidant and anti-inflammatory properties through regulating NFKB1, PTGS1, PTGS2, TLR4, PRKCA, PRKCD, KEAP1, NFE2L2, and NR1l2. Overall, these data suggest that LLPS may be a potential antioxidant and anti-inflammatory agent for developing functional foods.
Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency: Family Impact and Perspectives
Authors: Crawford Sarah , Sablon Elizabeth , Ali Nadia , Rosen Ami R. , Hall Patricia L. , Neira Fresneda Juanita
Published: October 2023

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD) is a fatty acid oxidation disorder characterized by the decreased ability of the enzyme very-long-chain acyl-CoA dehydrogenase to break down fatty acids with 14 to 20-long carbon chains. The resulting clinical manifestations are variable in severity and include hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. Treatment can consist of limiting the dietary intake of long-chain fatty acids, the prevention of fasting, and the supplementation of medium-chain fats. This study, conducted in the context of a 5-year long-term follow-up on VLCADD, evaluates how the diagnosis of this fatty acid disorder impacts the family, specifically as it relates to the medical diet and barriers to care. Caregivers (n = 10) of individuals with VLCADD responded to a survey about how VLCADD potentially impacts their family. The review included the clinical outcomes of the patients (n = 11), covering instances of rhabdomyolysis, cardiomyopathy, and hospitalizations related to VLCADD. Families affected by VLCADD experience barriers to care, including difficulties with finances, ability to work, and access to nutrition.
Systematic Comparison of Sensor Signals for Pump Operating Points Estimation Using Convolutional Neural Network
Authors: Ma Hanbing , Kirschner Oliver , Riedelbauch Stefan
Published: October 2023

The head and flow rate of a pump characterize the pump performance, which help determine whether maintenance is needed. In the proposed method, instead of a traditional flowmeter and manometer, the operating points are identified using data collected from accelerometers and microphones. The dataset is created from a test rig consisting of a standard centrifugal water pump and measurement system. After implementing preprocessing techniques and Convolutional Neural Networks (CNNs), the trained models are obtained and evaluated. The influence of the sensor location and the performance of different signals or signal combinations are investigated. The proposed method achieves a mean relative error of 7.23% for flow rate and 2.37% for head with the best model. By employing two data augmentation techniques, performance is further improved, resulting in a mean relative error of 3.55% for flow rate and 1.35% for head with the sliding window technique.
The Effect of Serotonin Transmission on Depressive and Insomnia Symptoms in Inflammatory Bowel Diseases
Authors: Sochal Marcin , Witkowska Alicja , Binienda Agata , Gabryelska Agata , Białasiewicz Piotr , Fichna Jakub , Talar-Wojnarowska Renata , Małecka-Wojciesko Ewa
Published: October 2023

The serotonergic pathway may impact the pathogenesis and the course of inflammatory bowel diseases (IBDs). The aim of this study was to investigate the relationship between 5-HT, the serotonin transporter (SERT), and the clinical course of the disease with the occurrence of sleep and mood disorders. Participants completed sleep questionnaires and the Beck Depression Inventory (BDI). Serum 5-HT, SERT protein expression, and mRNA levels were quantified. Additionally, patients treated with anti-TNF therapy were examined before and after treatment. In this study, 77 patients with IBD and 41 healthy controls (HCs) were enrolled and 24 of them were treated with anti-TNF therapy. Patients with IBD had higher 5-HT levels and SERT protein expression than the HCs, but not mRNA SERT levels (p = 0.015, p = 0.001, p = 0.069, respectively). Similar results were obtained for patients in the active state of the disease compared to the non-active state. There was a positive relationship between insomnia severity and SERT protein expression. BDI did not correlate with serotonin or SERT. After anti-TNF therapy, only 5-HT levels were decreased. 5-HT and SERT protein are overexpressed in active IBD and may represent a candidate for novel disease activity biomarkers. The correlation between the SERT protein level and the severity of insomnia symptoms might be among the underlying biochemical factors of sleep disturbances. Anti-TNF treatment might contribute to the reduction in 5-HT levels.
A Case of Giant Goiter Associated with Airway Stenosis Caused by Long-Term Intravenous Epoprostenol Therapy for Idiopathic Pulmonary Arterial Hypertension
Authors: Nishiura Kazuto , Nakazato Kazuhiko , Yokokawa Tetsuro , Suzuki Yoshinori , Kurosawa Yuta , Wada Kento , Shimizu Takeshi , Oikawa Masayoshi , Kobayashi Atsushi , Sugimoto Koichi , Shakespear Norshalena , Hashimoto Yuko , Takeishi Yasuchika
Published: October 2023

Idiopathic pulmonary arterial hypertension is a progressive and life-threatening disease with pulmonary vasculature remodeling, leading to right-sided heart failure. Epoprostenol (prostaglandin I2) is highly recommended for patients with severe pulmonary arterial hypertension (PAH) categorized by the World Health Organization as functional class III or IV. It has been reported that prostaglandin I2 analogs can cause thyroid gland swelling and abnormal thyroid function. A 34-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension and started receiving continuous intravenous epoprostenol. Three years after starting epoprostenol, she began complaining of neck swelling and was diagnosed with Graves’ disease. The patient’s thyroid function was controlled by thiamazole and levothyroxine; nevertheless, her thyroid gland enlargement worsened as the epoprostenol dose was titrated. After 20 years, she developed respiratory failure with a giant goiter leading to airway stenosis, and she passed away. The pathological autopsy confirmed a massive goiter associated with hyperthyroidism and airway stenosis. We experienced a case of idiopathic pulmonary hypertension with a giant goiter and airway stenosis after long-term intravenous epoprostenol therapy.
The Effects of Pilates Exercise Training Combined with Walking on Cardiorespiratory Fitness, Functional Capacity, and Disease Activity in Patients with Non-Radiologically Confirmed Axial Spondylitis
Authors: Zaggelidou Eleni , Theodoridou Athina , Michou Vassiliki , Gika Helen , Panayiotou George , Dimitroulas Theodoros , Kouidi Evangelia
Published: October 2023

The objective of the study was to examine the effects of Pilates exercise training combined with walking on cardiorespiratory fitness, functional capacity, and disease activity in patients with non-radiologically confirmed axial spondylitis (nr-axSpA). Thirty patients with nr-axSpA (seven women (90%), with a mean age of 46.07 ± 10.48 years old and C-reactive protein (CRP) 2.26 ± 2.14 mg/L) were randomly divided into two groups: A (n1 = 15 patients) and B (n2 = 15 patients). Group A followed a 6-month home-based Pilates exercise training program, while Group B remained untrained until the end of the study. A cardiopulmonary exercise test (CPET), timed up and go test (TUG), five times sit-to-stand test (5×STS), sit-and-reach test (SR), back scratch test for the right (BSR) and the left arm (BSL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Ankylosing Spondylitis Disease Activity Score (ASDAS) were applied to all patients, both at the beginning and at the end of the study. After 6 months, Group A showed higher values in exercise time by 37.41% (p = 0.001), higher peak oxygen uptake (VO2peak) by 25.41% (p = 0.01), a higher ratio between oxygen uptake and maximum heart rate (VO2/HRmax) by 14.83% (p = 0.04), and higher SR by 18.70% (p = 0.007), while lower values were observed in TUG by 24.32% (p = 0.001), 5×STS by 12.13% (p = 0.001), BASDAI score by 20.00% (p = 0.04) and ASDAS score by 23.41% (p = 0.03), compared to Group B. Furthermore, linear regression analysis showed a positive correlation in Group A between BASDAI and 5×STS (r = 0.584, p = 0.02), BASDAI and TUG (r = 0.538, p = 0.03), and ASDAS and 5×STS (r = 0.538, p = 0.03), while a negative correlation was found between BASDAI and VO2peak (r = −0.782, p < 0.001), ASDAS and SR (r = −0.548, p = 0.03), and ASDAS and VO2peak (r = −0.659, p = 0.008). To sum up, cardiorespiratory fitness, functional capacity, and disease activity improved after a long-term Pilates exercise training program in patients with nr-axSpA.
Multi-Scale Drivers of Land-Use Changes at Farm Level II: Application of Conceptual Framework in the Salinity Intrusion Zone of the Vietnamese Mekong Delta and Cross-Case Comparison with the Highly Flooded Zone
Authors: Le Thuy Ngan , Bregt Arnold K. , van Halsema Gerardo E. , Hellegers Petra J. G. J. , Ngo Thi Thu Trang
Published: October 2023

Frequent drought and worsening salinity intrusion challenge future land uses and livelihoods in the Vietnamese Mekong Delta. The central government is, therefore, formulating a new strategy premised on adaption to natural environmental dynamics. For an achievable strategy that bridges the gap between plans and practice, it is important to understand what drives land-use changes at the farm level. Previous research developed and applied a multi-scale drivers framework in the highly flooded zone of the delta. The current study uses that same framework to investigate the land-use history and drivers of change in the salinity intrusion zone of this delta from 1975 to 2016. We interviewed 32 farmers in Tra Vinh Province and used transcript analysis to quantify the influence of the drivers that the farmers mentioned. We then compared the drivers of land-use change with those found earlier in the highly flooded zone. Results show more diversification of land uses and land-use changes in the salinity intrusion zone. Farmers here followed three main pathways: rice intensification, integrated farming of rice and vegetables/aquaculture, or intensive shrimp farming. Land-use changes were conditional on the regional infrastructure construction to preserve freshwater conditions. However, household-scale drivers, especially natural and financial assets, were most frequently mentioned. Socio-economic context also emerged as an important driver, particularly trends and pressures from the community and markets.
Research on the Service Condition Monitoring Method of Rolling Bearings Based on Isomorphic Data Fusion
Authors: Zhang Yanfei , Liu Yang , Yang Mingqi , Feng Xiaoyang , Zhu Qianxiang , Kong Lingfei
Published: October 2023

In order to solve the problem that it is difficult for a single sensor to accurately characterize the running state of rotating bearings under complex working conditions, this paper proposes a data-level fusion method based on multi-source isomorphic sensors to monitor spindle bearings. First, new vibration signals in the X,Y,Z direction were obtained through the process of decomposing, de-noise, and reconstructing. Second, the PCA algorithm was used to select the time-domain and frequency-domain features of the vibration signals, construct the feature matrix, and perform dimensionality reduction in the feature matrix. Finally, the entropy weight method was introduced to obtain the initial weights of the three directions as the inputs of the adaptive function. The chaotic particle swarm optimization algorithm proposed in this paper helps particles jump out of the local optimum. Chaotic mapping is used to initialize the velocity and position of the particles, which calculates globally optimal weights in three directions. In order to extract bearing signal features more accurately and efficiently, a DenseNet and Transformer (DAT) feature extraction model is proposed to deal with the complex changes and noise interference of bearing signals. Through the open data set of Jiangnan University and the data collected by our own experimental platform, the maximum accuracy of the DAT model was verified to be 100%.
Conceptual Design and Numerical Validation of a Carbon-Based Ink Injector
Authors: Ortega-Gutiérrez Arleth , Escobar-Flores Job Eli , Grave-Capistrán Mario Alberto , López-Perrusquia Noé , Doñu-Ruiz Marco Antonio , Oropeza-Osornio Armando , Torres-SanMiguel Christopher René
Published: October 2023

This paper shows the design of an injector, using carbon nanotubes as inkjet material, implemented in a 3D printer. According to the available literature, few injectors are capable of depositing material. Due to the lack of information, the central part of this research is to develop a suitable device for ink injection that is capable of applying the Fused Deposition Modeling (FDM) method to print nanomaterial ink. The injector was designed using a CAD program based on an open-source desktop 3D printer, which allows it to be modified according to the needs of the injector. This prototype was manufactured in aluminum alloy 7075T6. Computational fluid dynamics (CFD) were carried out to analyze the behavior of the fluid when it passes through the injector, obtaining parameters such as pressure, velocity, and vorticity. An experimental matrix of the injector operation was carried out to achieve an adequate printing speed. The results show that the optimum speed was 250 ms, considering that a temperature of 100 °C is needed in the heated bed to dry the ink so that it does not undergo expansion.
Honeycomb Column Thin-Walled Structure Design and Mechanical Properties of Ti Alloy Fabricated through Selective Laser Melting
Authors: Zhang Shenghua , Shi Jingshuai , Liu Bin , Li Zhonghua
Published: October 2023

A honeycomb column thin-walled structure (HCTS) was designed and the relative density was calculated for numerical simulation. The HCTS samples were fabricated via selective laser melting (SLM). The numerical simulation and a three-point bending test were conducted to evaluate the mechanical properties of the HCTS made of Ti6Al4V. The findings of the numerical simulation demonstrated that the HCTS had a stronger resistance to deformation and a maximum loading force 30% higher than the equivalent solid thin-walled structure (ESTS). The mechanical performance of the HCTS as determined by the three-point bending test was mostly comparable with the numerical simulation. The maximum loading force of the experimental HCTS050-E thin-walled structure was 1200 N higher than that of HCTS050-S. The numerical simulation can provide theoretical guidance for the SLM processing of HCTSs.