bluuebunny/crossref_metadata_2025 huggingface dataset:
Formation of Hydroxyapatite-Based Hybrid Materials in the Presence of Platelet-Poor Plasma Additive
Authors: Glazov Ilya E. , Krut’ko Valentina K. , Safronova Tatiana V. , Sazhnev Nikita A. , Kil’deeva Natalia R. , Vlasov Roman A. , Musskaya Olga N. , Kulak Anatoly I.
Published: July 2023

Biomaterials based on hydroxyapatite with controllable composition and properties are promising in the field of regenerative bone replacement. One approach to regulate the phase composition of the materials is the introduction of biopolymer-based additives into the synthesis process. The purpose of present study was to investigate the formation of hydroxyapatite-based hybrid materials in the presence of 6–24% platelet-poor plasma (PPP) additive, at a [Ca2+]/[PO43−] ratio of 1.67, pH 11, and varying maturing time from 4 to 9 days. The mineral component of the materials comprised 53% hydroxyapatite/47% amorphous calcium phosphate after 4 days of maturation and 100% hydroxyapatite after 9 days of maturation. Varying the PPP content between 6% and 24% brought about the formation of materials with rather defined contents of amorphous calcium phosphate and biopolymer component and the desired morphology, ranging from typical apatitic conglomerates to hybrid apatite-biopolymer fibers. The co-precipitated hybrid materials based on hydroxyapatite, amorphous calcium phosphate, and PPP additive exhibited increased solubility in SBF solution, which defines their applicability for repairing rhinoplastic defects.
A Spider-Joint-like Bionic Actuator with an Approximately Triangular Prism Shape
Authors: Jiang Xiaomao , Yang Jun , Zeng Le , Huang Changyang
Published: July 2023

The unique drive principle and strong manipulation ability of spider legs have led to several bionic robot designs. However, some parameters of bionic actuators still need to be improved, such as torque. Inspired by the hydraulic drive principle of spider legs, this paper describes the design of a bionic actuator characterized by the use of air pressure on each surface and its transmittance in the direction of movement, achieving a torque amplification effect. The produced torque is as high as 4.78 N m. In addition, its torque characteristics during folding motions are similar to those during unfolding motions, showing that the bionic actuator has stable bidirectional drive capability.
The Influence of Relational Benefits on Behavioral Intention and the Moderating Role of Habit: A Study in a Personal Service Business
Authors: Karami Mohammad , Eyüpoğlu Şerife Zihni , Ertugan Ahmet
Published: July 2023

The intention to repurchase is a key component in relationship marketing. However, minimal attention has been paid to how customers’ habitual behavior moderates the relationship between customers’ evaluation of benefits received from a service provider and the intention to revisit, specifically in a personal service business where customer-service provider interactions likely constitute the core of a sustainable relationship. To address this gap, the current study proposes and tests a comprehensive model to advance the theory of relationship marketing (RM) and additionally contributes to social exchange theory (SET), as well as the theory of repurchase decision making (TRD), in the business service context. Structural equation modeling (SEM) was employed to examine the relationships of the research model. Based on data collected from 482 customers on their perceptions of hairstylists, the empirical findings revealed that relational benefits significantly affect post-experience behavior, satisfaction, trust, and relationship commitment, and subsequently boost the intention to revisit. Furthermore, habit as an unconscious factor moderates the paths between revisiting intention and its determinants. Although several limitations exist, the findings practically and theoretically contribute to the literature on relationship marketing.
Repair Bond Strength of Two Shadeless Resin Composites Bonded to Various CAD-CAM Substrates with Different Surface Treatments
Authors: AlOtaibi AlFulwah A. , Taher Nadia M.
Published: July 2023

This study compared the repair bond strength values of two single-shade composite resins bonded to different computer-aided design and computer-aided manufacturing (CAD-CAM) substrates with different surface treatments. A total of 80 slice-shaped specimens were fabricated using two CAD-CAM materials: Lava Ultimate and VitaEnamic. The substrates were thermocycled and then, based on the surface treatment, each substrate material was subdivided into four groups: the air abrasion group (APA), the hydrofluoric-acid-etched group (HF) and two silicon carbide ground groups (SiCr). All of the groups received silane followed by Single Bond Universal Adhesive application prior to being repaired with a resin composite of a smaller disc shape. All the specimens were thermocycled prior to shear bond strength testing and subsequent failure analyses. Statistical analyses were conducted, and the level of statistical significance was set at 0.05. A comparison of the mean values showed a highly statistically significant difference among the eight groups. The highest value of mean shear bond strength was associated with Lava Ultimate substrates repaired using the Charisma Diamond ONE composite after APA surface treatment (36.7 ± 1.99). Meanwhile, the lowest value was recorded for the Vita Enamic group repaired using the OMNICHROMA composite after SiCr surface treatment (17.8 ± 1.6). The failure analysis revealed that cohesive failure in the substrate was the most predominant. Within the limitations of this study, Charisma Diamond ONE showed better bond strength values compared to Omnichroma. Meanwhile, APA is recommended for improved bond strength in repairs of Lava Ultimate restorations.
Determinants of the European Sovereign Debt Crisis: Application of Logit, Panel Markov Regime Switching Model and Self Organizing Maps
Authors: Allegret Jean-Pierre , Cergibozan Raif
Published: July 2023

The study aims to empirically identify the determinants of the debt crisis that occurred within the framework of 15 core EU member countries (EU-15). Contrary to previous empirical studies that tend to use event-based crisis indicators, our study develops a continuous fiscal stress index to identify the debt crises in the EU-15 and employs three different estimation techniques, namely self-organizing map, multivariate logit and panel Markov regime switching models. Our estimation results show first that the study correctly identifies the time and the length of the debt crisis in each EU-15-member country. Empirical results then indicate, via three different models, that the debt crisis in the EU-15 is the consequence of deterioration of both financial and macroeconomic variables such as nonperforming loans over total loans, GDP growth, unemployment rates, primary balance over GDP, and cyclically adjusted balance over GDP. Furthermore, variables measuring governance quality, such as voice and accountability, regulatory quality, and government effectiveness, also play a significant role in the emergence and the duration of the debt crisis in the EU-15.
The Danube Delta: The Achilles Heel of Danube River–Danube Delta–Black Sea Region Fish Diversity under a Black Sea Impact Scenario Due to Sea Level Rise—A Prospective Review
Authors: Bănăduc Doru , Afanasyev Sergey , Akeroyd John Robert , Năstase Aurel , Năvodaru Ion , Tofan Lucica , Curtean-Bănăduc Angela
Published: July 2023

The Danube Delta is one of Earth’s biodiversity hotspots and includes many endemic, rare, and important species of both major conservation and economic value. This unique complex of ecosystems also plays a key role for Danube River and Black Sea fish fauna through its role as a natural safe buffer, shelter, feeding, reproduction, and smooth transitional area for a large number of fish species. Climate change is inducing a progressive sea level rise in the Black Sea, a fact that is expected to impact the delta’s key complex and dynamic habitats, biocoenoses, and associated biota, and last but not least the key taxonomic group, namely, fish. Around one-third of the fish species of this delta will be greatly affected, sometimes negatively, by this climate change scenario, another one-third to a lesser extent, and the final one-third not at all. The ecological positive feedback of fish can stimulate environmental change and is expected to be responsible for changes within Danube Delta ecosystems, and also for the near Danube River and Black Sea diverse matrix of aquatic and semi-aquatic ecosystems. Sea level rise in the Black Sea is considered to have been one of the main stress factors of the Danube Delta fish fauna in the past, and is likely to be the case in the future. In this spatio-temporal dynamic context, for the fish species under threat and risk, in situ-adapted management measures are highly required. The current work brings for the first time such a prospective knowledge about the potential impact on Danube River–Danube Delta–Black Sea coast fish diversity in the potential climate change–sea level rise scenario.
Transcriptome-Based Analysis of the Liver Response Mechanism of Black Porgy (Acanthopagrus schlegelii) to Stocking Density
Authors: Zhou Tangjian , Jia Chaofeng , Meng Qian , Xu Dafeng , Zhang Zhiwei , Zhu Fei , Zhao Yonglei , Sun Ruijian , Yang Yunxia , Chen Shuyin
Published: July 2023

Long-term high stocking density often brings negative effects such as decreased body weight, decreased immunity, and increased mortality to cultured fish, while the effects of short-term stocking are relatively less studied. In this experiment, we characterized spatial and temporal gene expression in black porgy (Acanthopagrus schlegelii) liver by establishing two stocking density groups—high (H: 26.5 kg/m3) and low (L: 2.95 kg/m3)—and conducting transcriptome sequencing before collecting liver samples at two time points: 6 h (AL and AH) and 60 d (CL and CH) into the culture trial. There were 648 and 550 differentially expressed genes (DEGs) in the AL-vs-AH and CL-vs-CH groups, respectively. The DEGs in the AL-vs-AH group were significantly enriched in steroid biosynthesis, terpenoid backbone biosynthesis, the PPAR signaling pathway, proteasome, aminoacyl-tRNA biosynthesis, and ribosome biogenesis in eukaryotes. The DEGs in the CL-vs-CH group were more significantly enriched in lipid metabolism-related pathways, such as the PPAR signaling pathway, fatty acid metabolism, and cholesterol metabolism. In addition, immune-related pathways such as the phagosome and complement and coagulation cascades were also enriched in the CL-vs-CH group. The expression changes concerning the DEGs in each group were further analyzed. The DEGs related to steroid synthesis, protein synthesis, and the degradation pathways were down-regulated, but immune-related genes were generally up-regulated in the AH group. The DEGs related to lipid synthesis were significantly up-regulated in the CH group, but the DEGs related to lipid consumption and utilization were down-regulated. The expression of immune-related DEGs was also negatively affected in the CH group. These results suggest that acute and chronic crowding stress affects lipid metabolism and immune regulation in the liver of black porgy. Acute stress particularly affected hepatic protein metabolism, while chronic stress showed more effects on hepatic lipid metabolism. The results of this study provide a theoretical basis for understanding the effects of high stocking densities upon black porgy and may also provide a reference for crowding stress regulation studies in other fish species.
Bacterial Co-Infection as a Potential Threat to Farmed Flathead Grey Mullet (Mugil cephalus): Phenotypic and Molecular Diagnosis, Histopathology, Immunity Response, and In Vitro Antibacterial Evaluation
Authors: Elbahnaswy Samia , Elshopakey Gehad E. , Shakweer Medhat S. , Eldessouki Elsayed A. A. , Abdelwarith Abdelwahab A. , Younis Elsayed M. , Davies Simon J. , El-Son Mai A. M.
Published: July 2023

Vibrio alginolyticus, Vibrio chlorea, and Enterococcus cloacae were the main bacterial pathogens investigated during recurrent episodes of mortalities among farmed flathead grey mullet (Mugil cephalus) in the Bahar El-Baqar area, Sharqia governorate, Egypt, during the summer season in 2021. Nevertheless, the contamination of water with heavy metals was evaluated. In this study, a total number of sixty moribund and freshly dead Mugil cephalus were examined clinically and upon post-mortem. Then, the bacterial isolates were subjected to bacteriological phenotypic examination, 16S rRNA gene sequencing, and antibiotic sensitivity testing. Histopathological screening and the immunity response of naturally infected M. cephalus were also implemented. In areas where bacterial strains were recovered in a high percentage, water contamination with Cu, Fe, and Ni was higher than the permissible limit. The results showed a high similarity (99–100%) to Vibrio and E. cloacae strains using phylogenetic analysis of 16S rRNA. Most isolates exhibited sensitivity to florfenicol, ciprofloxacin, and norfloxacin, while they were resistant to erythromycin and amoxicillin. Hemorrhage, oedema, hemosiderosis, and melanomacrophage activation in most affected tissues of infected M. cephalus were detected by light microscopy. Nevertheless, higher levels of AST and ALT, as well as serum inflammatory markers, CRP, and lysozyme activity, were shown in infected fish. There were higher MDA levels, along with a reduction of GSH, SOD, and catalase, in the gills and brain of infected M. cephalus, compared to the control fish. Our obtained data confirmed the high prevalence of Vibrio serovars and E. cloacae in infected grey mullets, describing their histopathological alterations, higher inflammatory response, and oxidative stress impact. These results could be useful indicators for understanding the pathogenesis of these pathogens in correlation with water parameter deterioration. Thus, the emergence of Vibrio and E. cloacae species in this study threatens the brackish water aquaculture industry in Egypt and poses a public health concern.
Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
Authors: Ormazabal Maximiliano Emanuel , Pavan Eleonora , Vaena Emilio , Ferino Dania , Biasizzo Jessica , Mucci Juan Marcos , Serra Fabrizio , Cifù Adriana , Scarpa Maurizio , Rozenfeld Paula Adriana , Dardis Andrea Elena
Published: July 2023

Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD.
Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank
Authors: Cañadas-Garre Marisa , Kunzmann Andrew T. , Anderson Kerry , Brennan Eoin P. , Doyle Ross , Patterson Christopher C. , Godson Catherine , Maxwell Alexander P. , McKnight Amy Jayne
Published: July 2023

Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC). CUBN-rs1801239 and DDR1-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables.
LncRNA 220: A Novel Long Non-Coding RNA Regulates Autophagy and Apoptosis in Kupffer Cells via the miR-5101/PI3K/AKT/mTOR Axis in LPS-Induced Endotoxemic Liver Injury in Mice
Authors: Yang Ying , Tian Tian , Li Shan , Li Nanhong , Luo Haihua , Jiang Yong
Published: July 2023

Sepsis is a severe medical condition distinguished by immune systematic dysfunction and multiple organic injury, or even failure, resulting from an acute systemic inflammatory response. Acute liver injury (ALI) could be considered as a notable inflammatory outcome of sepsis. Studies have demonstrated the essential roles played by long non-coding RNAs (lncRNAs) in mediating the processes of various diseases, including their ability to engage in interactions with microRNAs (miRNAs) as complexes of competing endogenous RNA (ceRNA) to modulate signaling pathways. In this study, a newly discovered lncRNA, named 220, was identified to function in regulating autophagy and apoptosis in Kupffer cells treated with lipopolysaccharide (LPS). This was achieved through sponging miR-5101 as a ceRNA complex, as identified via high-throughput sequencing. The expression of 220 was found to be significantly different in the hepatic tissues of endotoxemic mice that were treated with LPS for 8 h, ultimately modulating the ALI process. Our studies have collectively demonstrated that 220 is a novel regulator that acts on LPS-induced autophagy and apoptosis in Kupffer cells, thereby mediating the ALI process induced by LPS. Furthermore, the validation of our findings using clinical databases suggests that 220 could potentially serve as a molecular target of clinical, diagnostic, and therapeutic significance in septic liver injury.
In Vitro Evaluation of the Antiamoebic Activity of Kaempferol against Trophozoites of Entamoeba histolytica and in the Interactions of Amoebae with Hamster Neutrophils
Authors: Levaro-Loquio David , Serrano-Luna Jesús , Velásquez-Torres Maritza , Higuera-Martínez Germán , Arciniega-Martínez Ivonne Maciel , Reséndiz-Albor Aldo Arturo , Pérez-Vielma Nadia Mabel , Pacheco-Yépez Judith
Published: July 2023

Entamoeba histolytica (E. histolytica) is a parasite in humans that provokes amoebiasis. The most employed drug is metronidazole (MTZ); however, some studies have reported that this drug induces genotoxic effects. Therefore, it is necessary to explore new compounds without toxicity that can eliminate E. histolytica. Flavonoids are polyphenolic compounds that have demonstrated inhibition of growth and dysregulation of amoebic proteins. Despite the knowledge acquired to date, action mechanisms are not completely understood. The present work evaluates the effect of kaempferol against E. histolytica trophozoites and in the interactions with neutrophils from hamster, which is a susceptibility model. Our study demonstrated a significant reduction in the amoebic viability of trophozoites incubated with kaempferol at 150 μM for 90 min. The gene expression analysis showed a significant downregulation of Pr (peroxiredoxin), Rr (rubrerythrin), and TrxR (thioredoxin reductase). In interactions with amoebae and neutrophils for short times, we observed a reduction in ROS (reactive oxygen species), NO (nitric oxide), and MPO (myeloperoxidase) neutrophil activities. In conclusion, we confirmed that kaempferol is an effective drug against E. histolytica through the decrease in E. histolytica antioxidant enzyme expression and a regulator of several neutrophil mechanisms, such as MPO activity and the regulation of ROS and NO.
Investigating the Crime Scene—Molecular Signatures in Inflammatory Bowel Disease
Authors: Andersen Vibeke , Bennike Tue B. , Bang Corinna , Rioux John D. , Hébert-Milette Isabelle , Sato Toshiro , Hansen Axel K. , Nielsen Ole H.
Published: July 2023

Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life.
Transcription Factor Nrf2 Modulates Lipopolysaccharide-Induced Injury in Bovine Endometrial Epithelial Cells
Authors: Song Pengjie , Liu Chen , Sun Mingkun , Liu Jianguo , Lin Pengfei , Chen Huatao , Zhou Dong , Tang Keqiong , Wang Aihua , Jin Yaping
Published: July 2023

Endometritis in high-yield dairy cows adversely affects lactation length, milk quality, and the economics of dairy products. Endoplasmic reticulum stress (ERS) in bovine endometrial epithelial cells (BEECs) occurs as a consequence of diverse post-natal stressors, and plays a key role in a variety of inflammatory diseases. Nuclear-factor-erythroid-2-related factor 2 (Nrf2) is an important protective regulatory factor in numerous inflammatory responses. However, the mechanism by which Nrf2 modulates inflammation by participating in ERS remains unclear. The objective of the present study was to explore the role of Nrf2 in lipopolysaccharide (LPS)-induced injury to BEECs and to decipher the underlying molecular mechanisms of this injury. The expression of Nrf2- and ERS-related genes increased significantly in bovine uteri with endometritis. Isolated BEECs were treated with LPS to stimulate the inflammatory response. The expression of Nrf2 was significantly higher in cells exposed to LPS, which also induced ERS in BEECs. Activation of Nrf2 led to enhanced expression of the genes for the inflammation markers TNF-α, p65, IL-6, and IL-8 in BEECs. Moreover, stimulation of Nrf2 was accompanied by activation of ERS. In contrast, Nrf2 knockdown reduced the expression of TNF-α, p65, IL-6, and IL-8. Additionally, Nrf2 knockdown decreased expression of ERS-related genes for the GRP78, PERK, eIF2α, ATF4, and CHOP proteins. Collectively, our findings demonstrate that Nrf2 and ERS are activated during inflammation in BEECs. Furthermore, Nrf2 promotes the inflammatory response by activating the PERK pathway in ERS and inducing apoptosis in BEECs.
Genome-Wide Identification and Analysis of the Plant Cysteine Oxidase (PCO) Gene Family in Brassica napus and Its Role in Abiotic Stress Response
Authors: Bian Xiaohua , Cao Yifan , Zhi Ximin , Ma Ni
Published: July 2023

Plant Cysteine Oxidase (PCO) is a plant O2-sensing enzyme catalyzing the oxidation of cysteine to Cys-sulfinic acid at the N-termini of target proteins. To better understand the Brassica napus PCO gene family, PCO genes in B. napus and related species were analyzed. In this study, 20, 7 and 8 PCO genes were identified in Brassica napus, Brassica rapa and Brassica oleracea, respectively. According to phylogenetic analysis, the PCOs were divided into five groups: PCO1, PCO2, PCO3, PCO4 and PCO5. Gene organization and motif distribution analysis suggested that the PCO gene family was relatively conserved during evolution. According to the public expression data, PCO genes were expressed in different tissues at different developmental stages. Moreover, qRT-PCR data showed that most of the Bna/Bra/BoPCO5 members were expressed in leaves, roots, flowers and siliques, suggesting an important role in both vegetative and reproductive development. Expression of BnaPCO was induced by various abiotic stress, especially waterlogging stress, which was consistent with the result of cis-element analysis. In this study, the PCO gene family of Brassicaceae was analyzed for the first time, which contributes to a comprehensive understanding of the origin and evolution of PCO genes in Brassicaceae and the function of BnaPCO in abiotic stress responses.
Serotonin Transporter Activity in Mouse Oocytes Is a Positive Indicator of Follicular Growth and Oocyte Maturity
Authors: Alyoshina Nina M. , Tkachenko Maria D. , Nikishina Yulia O. , Nikishin Denis A.
Published: July 2023

Serotonin (5-hydroxytryptamine, 5-HT) is known to be a regulator of oocyte maturation in a large number of animal species. In maturing mammalian oocytes, the accumulation of exogenous, maternal serotonin occurs due to the activity of the membrane transporter SERT. In this work, we investigated how SERT activity in oocytes correlates with indicators of follicular selection and oocyte maturity. An immunohistochemical study showed that the difference in the 5-HT intake activity in oocytes does not correlate with the marker of apoptosis in follicular cells, but positively correlates with markers of follicular growth, such as granulosa proliferation and follicle size. Functional analysis of oocytes at different stages of maturation showed that the expression and activity of SERT increases with oocyte maturation. An in vivo experiment on administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) for 7 days showed a significant decrease in the content of serotonin in both growing GV-oocytes and ovulated mature MII-oocytes. The data obtained clearly indicate that the mechanism of specific membrane transport of serotonin normally ensures the accumulation of serotonin in maturing oocytes, and can be considered as a promising positive marker of their mature status.
Fascin-1 in Cancer Cell Metastasis: Old Target-New Insights
Authors: Sarantelli Eleonora , Mourkakis Apostolis , Zacharia Lefteris C. , Stylianou Andreas , Gkretsi Vasiliki
Published: July 2023

As metastasis is responsible for most cancer-related deaths, understanding the cellular and molecular events that lead to cancer cell migration and invasion will certainly provide insights into novel anti-metastatic therapeutic targets. Fascin-1 is an actin-bundling protein fundamental to all physiological or pathological processes that require cell migration. It is responsible for cross-linking actin microfilaments during the formation of actin-rich cellular structures at the leading edge of migrating cells such as filopodia, lamellipodia and invadopodia. While most epithelial tissues express low levels of Fascin-1, it is dramatically elevated in the majority of cancers and its expression has been associated with more aggressive disease and decreased overall survival. Hence, it has been proposed as a potential anti-cancer target. In the present review, we studied recent literature with regard to Fascin-1 expression in different cancers, its role in altering the mechanical properties of cancer cells, promoting cancer cell migration, invasion and metastasis and the effect of its inhibition, via various pharmacological inhibitors, in eliminating metastasis in vitro and/or in vivo. Recent studies corroborate the notion that Fascin-1 is critically involved in metastasis and prove that it is a valuable anti-metastatic target that is worth investigating further.
Synergistic Effects of Vitis vinifera L. and Centella asiatica against CCl4-Induced Liver Injury in Mice
Authors: Munakarmi Suvesh , Gurau Yamuna , Shrestha Juna , Risal Prabodh , Park Ho Sung , Lee Geum-Hwa , Jeong Yeon Jun
Published: July 2023

Liver injury can be acute or chronic, resulting from a variety of factors, including viral hepatitis, drug overdose, idiosyncratic drug reaction, or toxins, while the progression of pathogenesis in the liver rises due to the involvement of numerous cytokines and growth factor mediators. Thus, the identification of more effective biomarker-based active phytochemicals isolated from medicinal plants is a promising strategy to protect against CCl4-induced liver injury. Vitis vinifera L. (VE) and Centella asiatica (CE) are well-known medicinal plants that possess anti-inflammatory and antioxidant properties. However, synergism between the two has not previously been studied. Here, we investigated the synergistic effects of a V. vinifera L. (VE) leaf, C. asiatica (CE) extract combination (VCEC) against CCl4-induced liver injury. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 mL/kg). VCEC was administered orally for three consecutive days at various concentrations (100 and 200 mg/kg) prior to CCl4 injection. The extent of liver injury and the protective effects of VCEC were evaluated by biochemical analysis and histopathological studies. Oxidative stress was evaluated by measuring malondialdehyde (MDA) and glutathione (GSH) levels and Western blotting. VCEC treatment significantly reduced serum transaminase levels (AST and ALT), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by VCEC treatment by reducing cleaved caspase-3 and Bcl2-associated X protein (Bax). VCEC-treated mice significantly restored cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in CCl4-treated mice. In addition, VCEC downregulated overexpression of proinflammatory cytokines and hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4-mediated apoptosis. Collectively, VCEC exhibited synergistic protective effects against liver injury through its antioxidant, anti-inflammatory, and antiapoptotic ability against oxidative stress, inflammation, and apoptosis. Therefore, VCEC appears promising as a potential therapeutic agent for CCl4-induced acute liver injury in mice.
Genetic Abnormalities in Extramedullary Multiple Myeloma
Authors: McAvera Roisin , Quinn John , Murphy Philip , Glavey Siobhan
Published: July 2023

Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. The role of genomics in MM has been studied extensively; however, much less is known about the genetic background of EMD. Recently there has been an increased focus on driver events for the establishment of distant EMD sites. Generally, high-risk cytogenetic abnormalities and gene signatures are associated with EMD, alongside mutations in RAS signalling pathways. More recently, changes in epigenetic regulation have also been documented, specifically the hypermethylation of DNA promoter regions. Therefore, the focus of this review is to summarize and discuss what is currently known about the genetic background of EMD in MM.
Profiling Chemobiological Connection between Natural Product and Target Space Based on Systematic Analysis
Authors: Wang Disheng , Li Xue , Miao Yicheng , Zhang Qiang
Published: July 2023

Natural products provide valuable starting points for new drugs with unique chemical structures. Here, we retrieve and join the LOTUS natural product database and ChEMBL interaction database to explore the relations and rhythm between chemical features of natural products and biotarget spaces. Our analysis revealed relations between the biogenic pathways of natural products and species taxonomy. Nitrogen-containing natural products were more likely to achieve high activity and have a higher potential to become candidate compounds. An apparent trend existed in the target space of natural products originating from different biological sources. Highly active alkaloids were more related to targets of neurodegenerative or neural diseases. Oligopeptides and polyketides were mainly associated with protein phosphorylation and HDAC receptors. Fatty acids readily intervened in various physiological processes involving prostanoids and leukotrienes. We also used FusionDTA, a deep learning model, to predict the affinity between all LOTUS natural products and 622 therapeutic drug targets, exploring the potential target space for natural products. Our data exploration provided a global perspective on the gaps in the chemobiological space of natural compounds through systematic analysis and prediction of their target space, which can be used for new drug design or natural drug repurposing.
Impact of the Protein Environment on Two-Photon Absorption Cross-Sections of the GFP Chromophore Anion Resolved at the XMCQDPT2 Level of Theory
Authors: Aslopovsky Vladislav R. , Scherbinin Andrei V. , Kleshchina Nadezhda N. , Bochenkova Anastasia V.
Published: July 2023

The search for fluorescent proteins with large two-photon absorption (TPA) cross-sections and improved brightness is required for their efficient use in bioimaging. Here, we explored the impact of a single-point mutation close to the anionic form of the GFP chromophore on its TPA activity. We considered the lowest-energy transition of EGFP and its modification EGFP T203I. We focused on a methodology for obtaining reliable TPA cross-sections for mutated proteins, based on conformational sampling using molecular dynamics simulations and a high-level XMCQDPT2-based QM/MM approach. We also studied the numerical convergence of the sum-over-states formalism and provide direct evidence for the applicability of the two-level model for calculating TPA cross-sections in EGFP. The calculated values were found to be very sensitive to changes in the permanent dipole moments between the ground and excited states and highly tunable by internal electric field of the protein environment. In the case of the GFP chromophore anion, even a single hydrogen bond was shown to be capable of drastically increasing the TPA cross-section. Such high tunability of the nonlinear photophysical properties of the chromophore anions can be used for the rational design of brighter fluorescent proteins for bioimaging using two-photon laser scanning microscopy.
Pulmonary Sarcoidosis: Experimental Models and Perspectives of Molecular Diagnostics Using Quantum Dots
Authors: Linkova Natalia , Diatlova Anastasiia , Zinchenko Yulia , Kornilova Anastasiia , Snetkov Petr , Morozkina Svetlana , Medvedev Dmitrii , Krasichkov Alexandr , Polyakova Victoria , Yablonskiy Piotr
Published: July 2023

Sarcoidosis is a complex inflammatory multisystem disease of unknown etiology that is characterised by epithelioid cell granulomatous lesions affecting various organs, mainly the lungs. In general, sarcoidosis is asymptomatic, but some cases result in severe complications and organ failure. So far, no accurate and validated modelling for clinical and pathohistological manifestations of sarcoidosis is suggested. Moreover, knowledge about disease-specific diagnostic markers for sarcoidosis is scarce. For instance, pulmonary granulomatosis is associated with the upregulated production of proinflammatory molecules: TNF-α, IL-6, CXCL1, CCL2, CCL18, CD163, serum angiotensin-converting enzyme (sACE), lysozyme, neopterin, and serum amyloid A (SAA). Quantum dots (QDs) are widely applied for molecular diagnostics of various diseases. QDs are semiconductor nanoparticles of a few nanometres in size, made from ZnS, CdS, ZnSe, etc., with unique physical and chemical properties that are useful for the labelling and detection in biological experiments. QDs can conjugate with various antibodies or oligonucleotides, allowing for high-sensitivity detection of various targets in organs and cells. Our review describes existing experimental models for sarcoidosis (in vitro, in vivo, and in silico), their advantages and restrictions, as well as the physical properties of quantum dots and their potential applications in the molecular diagnostics of sarcoidosis. The most promising experimental models include mice with TSC2 deletion and an in silico multiscale computational model of sarcoidosis (SarcoidSim), developed using transcriptomics and flow cytometry of human sarcoid biopsies. Both models are most efficient to test different candidate drugs for sarcoidosis.
CDX-585, a Bispecific Antibody with Dual Targeting of ILT4 and PD-1 Checkpoint Pathways
Authors: Murphy Michael B. , Vitale Laura , Xia Shukai , Peng Zeyu , O’Neill Thomas , Lillquist Jay , Wasiuk Anna , Weidlick Jeff , Widger Jenifer , Mills-Chen Laura , Crocker Andrea , Patterson Colleen , Boyer James , Baronas April R. , Chen Mingjiu , Davis Hugh M. , Ma Mark , Goldstein Joel , Thomas Lawrence J. , Alvarado Diego , Marsh Henry C. , Keler Tibor
Published: July 2023

Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed on myeloid cells. Recent studies combining ILT4 suppression with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade have shown promising signs of activity in immune checkpoint inhibitor refractory patients. We theorized that coupling ILT4 and PD-1/PD-L1 blockade in a bispecific antibody (bsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced bridging of APCs to T cells. To test this approach, we developed CDX-585, a tetravalent ILT4xPD-1 IgG1-scFv bsAb from novel PD-1 and ILT-4 mAbs. CDX-585 is a potent antagonist of both PD-1 and ILT4. CDX-585 promotes M1 macrophage polarization and enhances pro-inflammatory cytokine secretion in response to lipopolysaccharide or CD40 agonist mAb treatment. In mixed lymphocyte reaction (MLR) assays, CDX-585 is more potent than the combination of parental antibodies. In a humanized NCG mouse SK-MEL-5 tumor model, CDX-585 exhibits greater antitumor activity than the combination of parental mAbs. A pilot study of CDX-585 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-585 effectively combines ILT4 and the PD-1 blockade into one molecule that is more potent than the combination of the parental antibodies, providing the rationale to advance this bsAb into clinical studies.
Power-Based Side-Channel Attacks on Program Control Flow with Machine Learning Models
Authors: Robins Andey , Olguin Stone , Brown Jarek , Carper Clay , Borowczak Mike
Published: July 2023

The control flow of a program represents valuable and sensitive information; in embedded systems, this information can take on even greater value as the resources, control flow, and execution of the system have more constraints and functional implications than modern desktop environments. Early works have demonstrated the possibility of recovering such control flow through power-based side-channel attacks in tightly constrained environments; however, they relied on meaningful differences in computational states or data dependency to distinguish between states in a state machine. This work applies more advanced machine learning techniques to state machines which perform identical operations in all branches of control flow. Complete control flow is recovered with 99% accuracy even in situations where 97% of work is outside of the control flow structures. This work demonstrates the efficacy of these approaches for recovering control flow information; continues developing available knowledge about power-based attacks on program control flow; and examines the applicability of multiple standard machine learning models to the problem of classification over power-based side-channel information.
Study on Morphology, Microstructure and Properties of 6063-T6 Aluminum Alloy Joints in MIG Welding
Authors: Cui Shuwan , Yu Yunhe , Ma Rong , Tian Fuyuan , Pang Shuwen
Published: July 2023

In this paper, a metal inert gas (MIG) shielded welding method was used for high-quality welding of 6063-T6 aluminum alloy sheet with a thickness of 2.5 mm. The welding process of MIG welding was accurately simulated and the welding temperature field and thermal cycle curve were calculated using a combination of Gaussian body heat source and double ellipsoidal heat source. As the welding current increased from 75 A to 90 A, the reinforcing phase precipitated under the microstructure of the joint gradually became larger and re-solidified into the body, resulting in a reduction in mechanical properties. When the welding current is 85 A, the pitting resistance of weld forming and weld area reaches its optimum. At this time, the tensile strength of the joint is up to 110.9 MPa, the elongation is up to 16.3% and the Vickers Microhardness is up to 46.9 HV.
Effects of Homogenization Heat Treatment on the Fe Micro-Segregation in Ti-1023 Titanium Alloy
Authors: Tong Jian-Bo , Zhang Chao-Jie , Chen Jun-Shu , Yan Meng-Qi , Xu Rui-Lin , Huang Li-Jun
Published: July 2023

The segregation of the Fe element in Ti-10V-2Fe-3Al titanium alloy (Ti-1023) can lead to the generation of beta flecks, which seriously affects the performance of Ti-1023 products. During the heat treatment (HT) process at a high temperature, the Fe element in Ti-1023 ingots will migrate, making its distribution more uniform and reducing the segregation index. In this paper, the control of Fe micro-segregation in Ti-1023 ingots by homogenization HT was investigated. Firstly, dissection sampling and SEM-EDS analysis methods were used to study the distribution pattern of the Fe element in the equiaxed grains in the core of Ti-1023 ingots. It was found that the Fe content in the grain gradually increased along with the radial direction from the core to the grain boundary. Then, the homogenization HT experiments and numerical simulations of Ti-1023 at different HT temperatures from 1050 °C to 1200 °C were carried out. The results showed that the uniformity of Fe element distribution within grain can be significantly improved by the homogenization HT. With increasing HT temperature, Fe atoms migration ability increases, and the uniformity of Fe element distribution improves. Homogenization HT at 1150 °C and 1200 °C for 12 h can effectively reduce the degree of Fe element segregation.
Sampling Theory for Mineral Process Flows
Authors: Lyman Geoffrey
Published: July 2023

Current literature dealing with the theory of sampling process flows is limited in scope, a situation addressed by papers presented at conferences by the author. This paper provides a summary of methods to quantify process sampling variance in a sound statistical manner. Two methods of calculation of the process sampling variance are presented here with models for robust estimation of the process covariance/variogram. The strategies for process sampling to acquire the data for process characterisation are described. The method for process characterisation can be based on special sampling campaigns, on the analysis of on-line measurement data, or on the analysis of historical data, which may be based on composite samples, such as shift samples. These scenarios are all dealt with as well as methods based on analysis of process dynamics. The latter analysis demonstrates that use of covariance functions drawn from geostatistical practice can be inappropriate for process analysis. The work is supported with plant data examples and quantitative analyses of process conditions.
The Relationship between the Source of Dietary Animal Fats and Proteins and the Gut Microbiota Condition and Obesity in Humans
Authors: Kazura Wojciech , Michalczyk Katarzyna , Stygar Dominika
Published: July 2023

The relationship between gut microbiota and obesity is well documented in humans and animal models. Dietary factors can change the intestinal microbiota composition and influence obesity development. However, knowledge of how diet, metabolism, and intestinal microbiota interact and modulate energy metabolism and obesity development is still limited. Epidemiological studies show a link between consuming dietary proteins and fats from specific sources and obesity. Animal studies confirm that proteins and fats of different origins differ in their ability to prevent or induce obesity. Protein sources, such as meat, dairy products, vegetables, pulses, and seafood, vary in their amino acid composition. In addition, the type and level of other factors, such as fatty acids or persistent organic pollutants, vary depending on the source of dietary protein. All these factors can modulate the intestinal microbiota composition and, thus, may influence obesity development. This review summarizes selected evidence of how proteins and fats of different origins affect energy efficiency, obesity development, and intestinal microbiota, linking protein and fat-dependent changes in the intestinal microbiota with obesity.
Eating Causes Clinically Significant Distress: Food Addiction as a Disordered Belief in Anorexia Nervosa?
Authors: de Oliveira Jônatas
Published: July 2023

Anorexia nervosa (AN) is characterized by an intense fear of weight gain, dietary restriction resulting in a significant weight loss compared with what is expected, and a disturbance in body image on a psychological basis. Recently, cases of AN associated with food addiction (FA) were described in almost all patients (69%), bringing a controversial aspect to the restrictive subtype (AN-r) that, in theory, even in the absence of binge eating, would present difficulties regarding control. Objectives: To report a case of an adolescent with AN-r associated with FA. Methods: Clinical history, current status, psychiatric diagnosis, and scores on scales to assess FA, food craving, and binge eating were analyzed. Results: This case report emphasizes the importance of new diagnostic tools to identify FA and whether it exists in people with AN-r beyond distress regarding eating behavior, cravings, and guilt. Eating behavior also presents a negative value that delays the elaboration process and the emergence of food cravings. In addition, an analysis of the association between the diagnostic criteria for substance use disorder, binge eating disorder, anorexia nervosa, and bulimia nervosa with the Yale Food Addiction Scale statements and criteria was discovered. Conclusions: Based on the characteristics of AN, emotional dysregulation and eating difficulties seem to overlap with FA symptoms.