bluuebunny/crossref_metadata_2025 huggingface dataset:
PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer
Authors: Khan Sajid , Cao Lin , Wiegand Janet , Zhang Peiyi , Zajac-Kaye Maria , Kaye Frederic J. , Zheng Guangrong , Zhou Daohong
Published: March 2024

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.
Approaching Thrombospondin-1 as a Potential Target for Mesenchymal Stromal Cells to Support Liver Regeneration after Partial Hepatectomy in Mouse and Humans
Authors: Tietze Lysann , Christ Madlen , Yu Jiyeon , Stock Peggy , Nickel Sandra , Schulze Annelie , Bartels Michael , Tautenhahn Hans-Michael , Christ Bruno
Published: March 2024

Extended liver resection carries the risk of post-surgery liver failure involving thrombospondin-1-mediated aggravation of hepatic epithelial plasticity and function. Mesenchymal stromal cells (MSCs), by interfering with thrombospondin-1 (THBS1), counteract hepatic dysfunction, though the mechanisms involved remain unknown. Herein, two-thirds partial hepatectomy in mice increased hepatic THBS1, downstream transforming growth factor-β3, and perturbation of liver tissue homeostasis. All these events were ameliorated by hepatic transfusion of human bone marrow-derived MSCs. Treatment attenuated platelet and macrophage recruitment to the liver, both major sources of THBS1. By mitigating THBS1, MSCs muted surgery-induced tissue deterioration and dysfunction, and thus supported post-hepatectomy regeneration. After liver surgery, patients displayed increased tissue THBS1, which is associated with functional impairment and may indicate a higher risk of post-surgery complications. Since liver dysfunction involving THBS1 improves with MSC treatment in various animal models, it seems feasible to also modulate THBS1 in humans to impede post-surgery acute liver failure.
Autologous T-Cell-Free Antigen Presentation System Unveils hCMV-Specific NK Cell Response
Authors: Ustiuzhanina Maria O. , Streltsova Maria A. , Timofeev Nikita D. , Kryukov Maxim A. , Chudakov Dmitriy M. , Kovalenko Elena I.
Published: March 2024

NK cells play a decisive role in controlling hCMV infection by combining innate and adaptive-like immune reactions. The hCMV-derived VMAPRTLFL (LFL) peptide is a potent activator of NKG2C+ NK cells. Proposed here is an autologous system of LFL stimulation without T lymphocytes and exogenous cytokines that allows us to evaluate NK-cell hCMV-specific responses in more native settings. In this model, we evaluated LFL-induced IFNγ production, focusing on signaling pathways and the degranulation and proliferation of NK cells orchestrated by microenvironment cytokine production and analyzed the transcriptome of expanded NK cells. NK cells of individuals having high anti-hCMV-IgG levels, in contrast to NK cells of hCMV-seronegative and low-positive donors, displayed increased IFNγ production and degranulation and activation levels and enhanced proliferation upon LFL stimulation. Cytokine profiles of these LFL-stimulated cultures demonstrated a proinflammatory shift. LFL-induced NK-cell IFNγ production was dependent on the PI3K and Ras/Raf/Mek signaling pathways, independently of cytokines. In hCMV-seropositive individuals, this model allowed obtaining NK-cell antigen-specific populations proliferating in response to LFL. The transcriptomic profile of these expanded NK cells showed increased adaptive gene expression and metabolic activation. The results complement the existing knowledge about hCMV-specific NK-cell response. This model may be further exploited for the identification and characterization of antigen-specific NK cells.
Bitter Taste Receptor T2R14 and Autophagy Flux in Gingival Epithelial Cells
Authors: Singh Nisha , Ulmer Ben , Medapati Manoj Reddy , Zhang Christine , Schroth Robert J. , Ghavami Saeid , Chelikani Prashen
Published: March 2024

Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway that functions in nutrient recycling and as a mechanism of innate immunity. Previously, we reported a novel host–bacteria interaction between cariogenic S. mutans and bitter taste receptor (T2R14) in gingival epithelial cells (GECs), leading to an innate immune response. Further, S. mutans might be using the host immune system to inhibit other Gram-positive bacteria, such as S. aureus. To determine whether these bacteria exploit the autophagic machinery of GEC, it is first necessary to evaluate the role of T2R14 in modulating autophagic flux. So far, the role of T2R14 in the regulation of autophagy is not well characterized. Therefore, in this study, for the first time, we report that T2R14 downregulates autophagy flux in GECs, and T2R14 knockout increases acidic vacuoles. However, the treatments of GEC WT with a T2R14 agonist and antagonist did not lead to a significant change in acidic vacuole formation. Transmission electron microscopy morphometric results also suggested an increased number of autophagic vesicles in T2R14-knockout GEC. Further, our results suggest that S. mutans competence stimulating peptide CSP-1 showed robust intracellular calcium release and this effect is both T2R14- and autophagy protein 7-dependent. In this study, we provide the first evidence that T2R14 modulates autophagy flux in GEC. The results of the current study could help in identifying the impact of T2R in regulation of the immuno-microenvironment of GEC and subsequently oral health.
Granular Insights: Neutrophil Predominance and Elastase Release in Severe Asthma Exacerbations in a Pediatric Cohort
Authors: Henley Kirstin , Tresselt Erin , Hook Jessica S. , Patel Parth A. , Gill Michelle A. , Moreland Jessica G.
Published: March 2024

The chronic inflammatory component of asthma is propagated by granulocytes, including neutrophils and eosinophils, in the peripheral circulation and airway. Previous studies have suggested that these cells have an altered expression of adhesion-related molecules and a propensity for the release of granule contents that may contribute to tissue damage and enhance inflammatory complications in patients with status asthmaticus. The goal of this prospective cohort study at a tertiary care pediatric hospital with a large population of asthma patients was to assess the role of granulocyte-based inflammation in the development of asthma exacerbation. Subjects were enrolled from two patient populations: those with mild-to-moderate asthma exacerbations seen in the emergency department and those with severe asthma admitted to the intensive care unit (PICU). Clinical data were collected, and blood was drawn. Granulocytes were immediately purified, and the phenotype was assessed, including the expression of cell surface markers, elastase release, and cytokine production. Severe asthmatics admitted to the PICU displayed a significantly higher total neutrophil count when compared with healthy donors. Moreover, little to no eosinophils were found in granulocyte preparations from severe asthmatics. Circulating neutrophils from severe asthmatics admitted to the PICU displayed significantly increased elastase release ex vivo when compared with the PMN from healthy donors. These data suggest that the neutrophil-based activation and release of inflammatory products displayed by severe asthmatics may contribute to the propagation of asthma exacerbations.
Deep Learning Powered Identification of Differentiated Early Mesoderm Cells from Pluripotent Stem Cells
Authors: Mohammad Sakib , Roy Arpan , Karatzas Andreas , Sarver Sydney L. , Anagnostopoulos Iraklis , Chowdhury Farhan
Published: March 2024

Pluripotent stem cells can be differentiated into all three germ-layers including ecto-, endo-, and mesoderm in vitro. However, the early identification and rapid characterization of each germ-layer in response to chemical and physical induction of differentiation is limited. This is a long-standing issue for rapid and high-throughput screening to determine lineage specification efficiency. Here, we present deep learning (DL) methodologies for predicting and classifying early mesoderm cells differentiated from embryoid bodies (EBs) based on cellular and nuclear morphologies. Using a transgenic murine embryonic stem cell (mESC) line, namely OGTR1, we validated the upregulation of mesodermal genes (Brachyury (T): DsRed) in cells derived from EBs for the deep learning model training. Cells were classified into mesodermal and non-mesodermal (representing endo- and ectoderm) classes using a convolutional neural network (CNN) model called InceptionV3 which achieved a very high classification accuracy of 97% for phase images and 90% for nuclei images. In addition, we also performed image segmentation using an Attention U-Net CNN and obtained a mean intersection over union of 61% and 69% for phase-contrast and nuclear images, respectively. This work highlights the potential of integrating cell culture, imaging technologies, and deep learning methodologies in identifying lineage specification, thus contributing to the advancements in regenerative medicine. Collectively, our trained deep learning models can predict the mesoderm cells with high accuracy based on cellular and nuclear morphologies.
Disulfiram Inhibits Opsonin-Independent Phagocytosis and Migration of Human Long-Lived In Vitro Cultured Phagocytes from Multiple Inflammatory Diseases
Authors: Li Chen , Schneider Julian M. , Schneider E. Marion
Published: March 2024

Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through its copper chelating derivatives and induction of oxidative stress in mitochondria. Since chronic/persistent borreliosis is characterized by increased amounts of pro-inflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration, and surface marker expression of in vivo activated and in vitro cultured human monocyte-derived phagocytes (macrophages and dendritic cells) with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads® M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24 h, imaging every 3.5 min. To simultaneously monitor phagocyte function, results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads. DSF decreased the phagocytic capacities exhibited by in vitro enriched and long-lived phagocytes. Although no chemotactic gradient was applied to the test system, vigorous spontaneous migration was observed. We therefore set up an algorithm to monitor and quantify both phagocytosis and migration simultaneously. DSF not only reduced phagocytosis in a majority of these long-lived phagocytes but also impaired their migration. Despite these selective effects by DSF, we found that DSF reduced the expression densities of surface antigens CD45 and CD14 in all of our long-lived phagocytes. In cells with a high metabolic activity and high mitochondrial contents, DSF led to cell death corresponding to mitochondrial oxidative stress, whereas metabolically inactive phagocytes survived our DSF treatment protocol. In conclusion, DSF affects the viability of metabolically active phagocytes by inducing mitochondrial stress and secondly attenuates phagocytosis and migration in some long-lived phagocytes.
5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells
Authors: Di Crosta Michele , Arena Andrea , Benedetti Rossella , Gilardini Montani Maria Saveria , Cirone Mara
Published: March 2024

Epigenetic modifications, including aberrant DNA methylation occurring at the promoters of oncogenes and oncosuppressor genes and histone modifications, can contribute to carcinogenesis. Aberrant methylation mediated by histone methylatransferases, alongside histones, can affect methylation of proteins involved in the regulation of pro-survival pathways such as JAK/STAT and contribute to their activation. In this study, we used DNA or histone demethylating agents, 5-Azacytidine (5-AZA) or DS-3201 (valemetostat), respectively, to treat primary effusion lymphoma (PEL) cells, alone or in combination with AG490, a Signal transducer and activator of transcription 3 (STAT3) inhibitor. Cell viability was investigated by trypan blue assay and FACS analysis. The molecular changes induced by 5-AZA and/or AG490 treatments were investigated by Western blot analysis, while cytokine release by PEL cells treated by these drugs was evaluated by Luminex. Statistical analyses were performed with Graphpad Prism® software (version 9) and analyzed by Student’s t test or a nonparametric one-way ANOVA test. The results obtained in this study suggest that 5-AZA upregulated molecules that inhibit STAT3 tyrosine phosphorylation, namely Suppressor of Cytokine Signaling 3 (SOCS3) and tyrosine–protein phosphatase non-receptor type (PTPN) 6/Src homology region 2 domain-containing phosphatase-1 (SHP-1), reducing STAT3 activation and downregulating several STAT3 pro-survival targets in PEL cells. As this lymphoma is highly dependent on the constitutive activation of STAT3, 5-AZA impaired PEL cell survival, and when used in combination with AG490 JAK2/STAT3 inhibitor, it potentiated its cytotoxic effect. Differently from 5-AZA, the inhibition of the EZH1/2 histone methyltransferase by DS-3201, reported to contribute to STAT3 activation in other cancers, slightly affected STAT3 phosphorylation or survival in PEL cells, either alone or in combination with AG490. This study suggests that 5-AZA, by upregulating the expression level of SOCS3 and PTPN6/SHP1, reduced STAT3 activation and improved the outcome of treatment targeting this transcription factor in PEL cells.
Exploring the Genomic Landscape of Bacillus paranthracis PUMB_17 as a Proficient Phosphatidylcholine-Specific Phospholipase C Producer
Authors: Baev Vesselin , Iliev Ivan , Stefanov Yordan , Tsankova Marinela , Marhova Mariana , Apostolova Elena , Gozmanova Mariyana , Yahubyan Galina , Kostadinova Sonya
Published: March 2024

Phospholipases find versatile applications across industries, including detergent production, food modification, pharmaceuticals (especially in drug delivery systems), and cell signaling research. In this study, we present a strain of Bacillus paranthracis for the first time, demonstrating significant potential in the production of phosphatidylcholine-specific phospholipase C (PC-PLC). The investigation thoroughly examines the B. paranthracis PUMB_17 strain, focusing on the activity of PC-PLC and its purification process. Notably, the PUMB_17 strain displays extracellular PC-PLC production with high specific activity during the late exponential growth phase. To unravel the genetic makeup of PUMB_17, we employed nanopore-based whole-genome sequencing and subsequently conducted a detailed genome annotation. The genome comprises a solitary circular chromosome spanning 5,250,970 bp, featuring a guanine–cytosine ratio of 35.49. Additionally, two plasmids of sizes 64,250 bp and 5845 bp were identified. The annotation analysis reveals the presence of 5328 genes, encompassing 5186 protein-coding sequences, and 142 RNA genes, including 39 rRNAs, 103 tRNAs, and 5 ncRNAs. The aim of this study was to make a comprehensive genomic exploration that promises to enhance our understanding of the previously understudied and recently documented capabilities of Bacillus paranthracis and to shed light on a potential use of the strain in the industrial production of PC-PLC.
The NLRP3 Inflammasome Gene Is Overexpressed in Hidradenitis Suppurativa Lesions: A Preliminary Study on the Role of Pyroptosis in Disease Pathogenesis
Authors: Krajewski Piotr K. , Szukała Weronika , Szepietowski Jacek C.
Published: March 2024

Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disorder, and its pathogenesis remains incompletely understood. This study aimed to investigate the role of the P2X7 receptor (P2X7R) and NLRP3 inflammasome in HS pathogenesis. RNA sequencing and real-time PCR were performed to assess the gene expression levels of P2X7R and NLRP3 in the skin biopsies of HS patients and healthy controls (HC). The results of our study revealed a significantly increased expression of the NLRP3 gene in both the lesional and perilesional skin of HS patients compared to healthy controls. Moreover, the mRNA levels of NLRP3 were significantly higher in lesional skin compared to non-lesional skin in HS patients, indicating the spread of inflammation to adjacent tissues. In contrast, no significant differences in P2X7R gene expression were observed between the three groups. These findings suggest the involvement of NLRP3 inflammasomes in HS pathogenesis, while P2X7R may not play a significant role in the disease. This research sheds light on the complex inflammatory pathways in HS, highlighting the potential of NLRP3 as a therapeutic target. Understanding the molecular mechanisms underlying HS is crucial for the development of targeted treatment modalities for this debilitating condition.
Effects of rpl1001 Gene Deletion on Cell Division of Fission Yeast and Its Molecular Mechanism
Authors: Yu Wen , Yuan Rongmei , Liu Mengnan , Liu Ke , Ding Xiang , Hou Yiling
Published: March 2024

The rpl1001 gene encodes 60S ribosomal protein L10, which is involved in intracellular protein synthesis and cell growth. However, it is not yet known whether it is involved in the regulation of cell mitosis dynamics. This study focuses on the growth, spore production, cell morphology, the dynamics of microtubules, chromosomes, actin, myosin, and mitochondria of fission yeast (Schizosaccharomyces pombe) to investigate the impact of rpl1001 deletion on cell mitosis. RNA-Seq and bioinformatics analyses were also used to reveal key genes, such as hsp16, mfm1 and isp3, and proteasome pathways. The results showed that rpl1001 deletion resulted in slow cell growth, abnormal spore production, altered cell morphology, and abnormal microtubule number and length during interphase. The cell dynamics of the rpl1001Δ strain showed that the formation of a monopolar spindle leads to abnormal chromosome segregation with increased rate of spindle elongation in anaphase of mitosis, decreased total time of division, prolonged formation time of actin and myosin loops, and increased expression of mitochondrial proteins. Analysis of the RNA-Seq sequencing results showed that the proteasome pathway, up-regulation of isp3, and down-regulation of mfm1 and mfm2 in the rpl1001Δ strain were the main factors underpinning the increased number of spore production. Also, in the rpl1001Δ strain, down-regulation of dis1 caused the abnormal microtubule and chromosome dynamics, and down-regulation of hsp16 and pgk1 were the key genes affecting the delay of actin ring and myosin ring formation. This study reveals the effect and molecular mechanism of rpl1001 gene deletion on cell division, which provides the scientific basis for further clarifying the function of the Rpl1001 protein in cell division.
Distinctive Oxide Films Develop on the Surface of FeCrAl as the Environment Changes for Nuclear Fuel Cladding
Authors: Qu Haozheng , Yin Liang , Larsen Michael , Rebak Raul B.
Published: March 2024

The corrosion-resistant properties of IronChromium–Aluminum (FeCrAl) alloys have been known for nearly a century. Since the 1950s, they have been explored for application in the generation of nuclear power. In the last decade, the focus has been on the use of FeCrAl as cladding for uranium dioxide fuel in light water reactors (LWRs). The corrosion resistance of this alloy depends on the oxide that it can develop on the surface. In LWRs in the vicinity of 300 °C, the external surface oxide of the FeCrAl cladding could be rich in Fe under oxidizing conditions but rich in Cr under reducing conditions. If there is an accident and the cladding is exposed to superheated steam, the cladding will protect itself by developing an alpha aluminum film on the surface.
Influence of NaAlO2 Concentration on the Characteristics of Micro-Arc Oxidation Coating Fabricated on a ZK60 Magnesium Alloy
Authors: Zhou Shu-Fan , Lu Sheng , Lv Wei-Gang , Wang Ze-Xin , Oleksandr Dubovyy , Gu Jun-Jie , Zhang Jin-Wei , Chen Liang-Yu
Published: March 2024

This study investigated the impact of NaAlO2 concentration in electrolytic solutions on micro-arc oxidation (MAO) coatings, focusing on their surface quality enhancement and corrosion resistance improvement. The surface morphology and microstructure of these coatings were assessed using scanning electron microscopy. Mechanical properties, such as hardness and wear resistance of MAO coatings, were tested. The hardness of the 6 g/L group was 411.2 HV. X-ray photoelectron spectroscopy examinations showed that MgAl2O4, CaMgP2O7, and MgSiO4 were the phases in the MAO coating. Antibacterial assessments were performed to evaluate the influence of NaAlO2 concentration, and the antibacterial rate of the 6 g/L group reached 97.08%. The hydrophilicity of the coatings was determined using water contact angle measurements, wherein the water contact angle of the 6 g/L was the lowest, at 58.25°. Corrosion resistance was evaluated with an electrochemical workstation. The findings revealed that the MAO coatings prepared with a NaAlO2 concentration of 6 g/L exhibited superior uniformity with fewer defects, enhanced corrosion resistance, and increased adhesive strength compared to other concentration groups. The 6 g/L NaAlO2 concentration MAO coating demonstrated the highest fitting coating resistance R3 (8.14 × 104 Ω∙cm2), signifying better corrosion resistance.
On the Thermally Induced Interfacial Behavior of Thin Two-Dimensional Hexagonal Quasicrystal Films with an Adhesive Layer
Authors: Dang Huayang , Zhang Wenkai , Fan Cuiying , Lu Chunsheng , Zhao Minghao
Published: March 2024

The mechanical response of a quasicrystal thin film is strongly affected by an adhesive layer along the interface. In this paper, a theoretical model is proposed to study a thin two-dimensional hexagonal quasicrystal film attached to a half-plane substrate with an adhesive layer, which undergoes a thermally induced deformation. A perfect non-slipping contact condition is assumed at the interface by adopting the membrane assumption. An analytical solution to the problem is obtained by constructing governing integral–differential equations for both single and multiple films in terms of interfacial shear stresses that are reduced to a linear algebraic system via the series expansion of Chebyshev polynomials. The solution is compared to that without adhesive layers, and the effects of the aspect ratio of films, material mismatch, and the adhesive layer, as well as the interaction between films, are discussed in detail. It is found that the adhesive layer can soften the localized stress concentration. This study is instructive to the accurate safety assessment and functional design of a quasicrystal film system.
Long-Distance Freezing Design and Construction Based on Monitoring Analysis of Subway Connection Aisle
Authors: Xu Yin , Liu Qiang , Zhi Weiting , Shao Guangqiang , Liu Peng
Published: March 2024

In the context of a main road area with significant traffic flow, posing challenges to constructing the freezing station on the ground, an innovative proposal suggests situating the freezing station at the station. This approach aims to facilitate construction at the same time for the connection aisle, tunneling, and track laying, thereby reducing the construction period; however, this will lead to a corresponding increase in the freezing pipeline distance. The theoretical analysis, numerical analysis, and integration with engineering practices were employed to examine the essential aspects and key technologies in the long-distance freezing design and construction, including the freezing hole construction, thermal insulation method of brine pipelines and tunnel segments, and technique program to retain the brine pressure and flow discharge, as well as the method to reduce the interplay of cross-construction. The validity of the construction program for the long-distance frozen excavation was finally evaluated based on onsite monitoring and theoretical analysis. The results show that the temperature of the brine in both the delivery and return pipelines first decreases linearly and then stabilizes gradually with freezing time, and the temperature difference is between 1 °C and 1.5 °C at the later freezing period. The temperature variation of the frozen wall is similar to that of brine in the delivery and return pipelines, and there is a good correlation between them. After the frozen wall encloses, the internal pressure of the frozen wall increases quickly, which can be effectively reduced to prevent wall cracking and breakage by regulating the pressure relief holes. The above theoretical analysis result shows that the average temperature of the frozen wall should be less than −9.7 °C when the designed thickness of the frozen wall is 2.2 m. The monitoring data indicates that the average temperature of the frozen wall reaches −13.9 °C, which satisfies the design requirement. The design and construction technology of long-distance freezing enhance the construction of the subway connection aisle. The novel method deviates from the conventional practice of establishing freezing stations within tunnels and offers valuable insight and guidance for comparable projects.
Ferroelectric Thin Films and Composites Based on Polyvinylidene Fluoride and Graphene Layers: Molecular Dynamics Study
Authors: Bystrov Vladimir , Paramonova Ekaterina , Meng Xiangjian , Shen Hong , Wang Jianlu , Lin Tie , Fridkin Vladimir
Published: March 2024

This work is devoted to the study of nanosized polymer polyvinylidene fluoride (PVDF) thin ferroelectric films (two-dimensional ferroelectrics) and their composites with graphene layers, using molecular dynamics methods to (1) study and calculate the polarization switching time depending on the electric field and film thickness, (2) study and calculate the polarization switching time depending on changes of the PVDF in PVDF-TrFE film, and (3) study the polarization switching time in PVDF under the influence of graphene layers. All calculations at each MD run step were carried out using the semi-empirical quantum method PM3. A comparison and analysis of the results of these calculations and the kinetics of polarization switching within the framework of the Landau–Ginzburg–Devonshire theory for homogeneous switching in ferroelectric polymer films is carried out. The study of the composite heterostructures of the “graphene-PVDF” type, and calculations of their polarization switching times, are presented. It is shown that replacing PVDF with PVDF-TrFE significantly changes the polarization switching times in these thin polymer films, and that introducing various graphene layers into the PVDF layered structure leads to both an increase and a decrease in the polarization switching time. It is shown that everything here depends on the position and displacement of the coercive field depending on the damping parameters of the system. These phenomena are very important for various ferroelectric coatings.
Correction: Pang et al. Burning Rate Prediction of Solid Rocket Propellant (SRP) with High-Energy Materials Genome (HEMG). Crystals 2023, 13, 237
Authors: Pang Weiqiang , Abrukov Victor , Anufrieva Darya , Chen Dongping
Published: March 2024

There was an error in the original publication [...]
Crystallography and Interface Structures in As-Arc Melted and Laser Surface-Remelted Aluminum–Silicon Alloys with and without Strontium Addition
Authors: Sahu Bibhu P. , Andani Mohsen T. , Ghosh Arkajit , Wang Jian , Misra Amit
Published: March 2024

The crystallography of the eutectic Al-Si microstructure in both unmodified and Sr (0.2 wt.%)-modified hypereutectic Al-20 wt.% Si alloys, processed via arc-melting and laser surface remelting, has been comprehensively characterized using transmission electron microscopy and electron diffraction. Although, under as-cast conditions, specific orientations between different planes of Al and Si, satisfying defined orientation relationships (ORs), have been investigated within the flake morphology, the rapid solidification induced by laser surface remelting results in a notable transformation from a flake morphology to nanocrystalline Si fibers dispersed in an Al matrix. Consequently, this transformation results in a mis-orientation of the interface between the eutectic Al and Si phases, preventing the formation of orientation relationships, thus promoting the formation of faceted interfaces exhibiting substantial lattice disregistry.
Biomarker Turnaround Times and Impact on Treatment Decisions in Patients with Advanced Non-Small Cell Lung Carcinoma at a Large Canadian Community Hospital with an Affiliated Regional Cancer Centre
Authors: Fleming Katelyn E. , Hupel Ava , Mithoowani Hamid , Lulic-Kuryllo Tea , Valdes Mario
Published: March 2024

Background: Timely reporting of molecular biomarkers is critical in guiding optimal treatment decisions in patients with advanced non-small cell lung carcinoma (NSCLC). Any delays along the tissue or treatment pathway may be associated with suboptimal treatment/outcomes and a reduced quality of life. For many centres, biomarkers are tested off-site. Methods: A retrospective chart review of 123 patients with advanced NSCLC seen between 1 June 2021 and 30 June 2022 was conducted. With a focus on core biomarkers (PD L1, EGFR, and ALK), the outcome variables were as follows: total turnaround time (total TAT), divided into pre-laboratory, laboratory, and post-laboratory time intervals, as well as time to treatment decision (TOTD) and time to optimal systemic therapy decision (TOTSD). Results: At first consult, only 20.3% of patients had all core biomarker results available. The median total TAT was significantly longer for non-squamous (non-SCC) than squamous cell carcinoma (SCC) specimens (36.5 versus 22 days, p < 0.001). The median pre-laboratory time for the entire cohort was 5 calendar days. The median laboratory testing time was greater for non-SCC compared to the SCC specimens (23 versus 12 days, p < 0.001). The median time from consult to TOTD was 19 calendar days for the entire cohort. Conclusions: This study emphasizes the need for the expansion of regional resources to meet the clinical needs of advanced NSCLC patients treated at a regional cancer centre which uses an off-site molecular laboratory.
Wedge Resection versus Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer Tumors ≤8 mm
Authors: Mansur Arian , Saleem Zain , Beqari Jorind , Mathey-Andrews Camille , Potter Alexandra L. , Cranor James , Nees Alexandra T. , Srinivasan Deepti , Yang Margaret E. , Yang Chi-Fu Jeffrey , Auchincloss Hugh G.
Published: March 2024

The objective of this study was to evaluate the overall survival of patients with ≤8 mm non-small cell lung cancer (NSCLC) who undergo wedge resection versus stereotactic body radiation therapy (SBRT). Kaplan–Meier analysis, multivariable Cox proportional hazards modeling, and propensity score-matched analysis were performed to evaluate the overall survival of patients with ≤8 mm NSCLC in the National Cancer Database (NCDB) from 2004 to 2017 who underwent wedge resection versus patients who underwent SBRT. The above-mentioned matched analyses were repeated for patients with no comorbidities. Patients who were coded in the NCDB as having undergone radiation because surgery was contraindicated due to patient risk factors (e.g., comorbid conditions, advance age, etc.) and those with a history of prior malignancy were excluded from analysis. Of the 1505 patients who had NSCLC ≤8 mm during the study period, 1339 (89%) patients underwent wedge resection, and 166 (11%) patients underwent SBRT. In the unadjusted analysis, multivariable Cox modeling and propensity score-matched analysis, wedge resection was associated with improved survival when compared to SBRT. These results were consistent in a sensitivity analysis limited to patients with no comorbidities.
Ecology, Diversity, Conservation and Management of Ungulates
Authors: Reimoser Friedrich , Nopp-Mayr Ursula
Published: March 2024

Wild ungulates are important drivers of the dynamics of many terrestrial ecosystems and impact biodiversity at different system levels [...]
An Assessment of the Implementation of the Convention on International Trade in Endangered Species of Wild Fauna and Flora in Kenya
Authors: Kilonzo Nicholus , Heinen Joel T. , Byakagaba Patrick
Published: March 2024

International trade is hastening extinction for many species of plants and animals despite the fact that many countries have ratified CITES. The adoption of treaties is often symbolic as many countries, especially in the developing world where most biodiversity is found, experience a lack of fit between international agreements and national laws and institutions. Our main objective here is to assess the extent of jurisdictional and institutional fit in the implementation of CITES in Kenya, an important issue given the amount of international trade in wild products and the importance of wildlife tourism to the country. The specific objectives are to assess the following: the capacity and level of coordination among state actors and conservation mandates in national policy and law using a mixed methods approach involving a literature review and 38 key informant surveys representing professional expertise from various stakeholder groups. We found that over 60% of respondents indicated only moderate capacity for the implementation of CITES and coordination between local and central governments. Some participants indicated that judicial officers lack adequate conservation knowledge, thus hampering enforcement via low prosecution rates. A moderate (at best) structural fit involving inefficiencies such as conflicting processes, unequal enforcement, and suboptimal coordination implies a degree of failure in developing the implementation capacity of CITES within Kenya. Our results also show a mismatch between agency staffing and workload at several levels of government, and we make suggestions for improvement.
Phylogeography of Dolichophis Populations in the Aegean Region (Squamata: Colubridae) with Taxonomic Remarks
Authors: Javorčík Adam , Strachinis Ilias , Thanou Evanthia , Kornilios Panagiotis , Avcı Aziz , Üzüm Nazan , Olgun Kurtuluş , Ilgaz Çetin , Kumlutaş Yusuf , Lymberakis Petros , Nagy Zoltán T. , Jablonski Daniel
Published: March 2024

In this study, we investigate the phylogeographic patterns of Dolichophis species in the Aegean region, aiming to elucidate their genetic diversity and putative historical colonisation routes through mitochondrial and nuclear DNA data. Our findings revealed distinct phylogeographic patterns: D. caspius exhibited a higher level of haplotypes within two shallow mitochondrial lineages, contrasting with D. jugularis, which displayed lower genetic variability in the area. Additionally, we identified evidence showing possible human-mediated historical translocation of D. caspius populations to Karpathos from the Balkans mainland. The mitochondrial variability in D. jugularis remained relatively uniform across southwestern Anatolia and Dodecanese, except for Rhodes Island. The evidence from mitochondrial and nuclear data confirming the previously described morphological differentiation of the Rhodes snakes, and thus the name D. j. zinneri Cattaneo, 2012, described on the island, could be applied to this isolated population. This result addresses the first genetic view on the long-standing taxonomic uncertainties regarding the subspecies status of Rhodes D. jugularis. Our results also raise questions regarding possible historical hybridisations between D. caspius and D. jugularis in the Dodecanese islands, prompting the need for further investigation using extensive field studies and genomic approaches. Ultimately, the Aegean islands, particularly Kos and Rhodes, seem to be important sites for the evolution of these colubrid snakes and their historical dynamics.
Innovative Strategies for Early Autism Diagnosis: Active Learning and Domain Adaptation Optimization
Authors: Alam Mohammad Shafiul , Elsheikh Elfatih A. A. , Suliman F. M. , Rashid Muhammad Mahbubur , Faizabadi Ahmed Rimaz
Published: March 2024

The early diagnosis of autism spectrum disorder (ASD) encounters challenges stemming from domain variations in facial image datasets. This study investigates the potential of active learning, particularly uncertainty-based sampling, for domain adaptation in early ASD diagnosis. Our focus is on improving model performance across diverse data sources. Utilizing the Kaggle ASD and YTUIA datasets, we meticulously analyze domain variations and assess transfer learning and active learning methodologies. Two state-of-the-art convolutional neural networks, Xception and ResNet50V2, pretrained on distinct datasets, demonstrate noteworthy accuracies of 95% on Kaggle ASD and 96% on YTUIA, respectively. However, combining datasets results in a modest decline in average accuracy, underscoring the necessity for effective domain adaptation techniques. We employ uncertainty-based active learning to address this, which significantly mitigates the accuracy drop. Xception and ResNet50V2 achieve 80% and 79% accuracy when pretrained on Kaggle ASD and applying active learning on YTUIA, respectively. Our findings highlight the efficacy of uncertainty-based active learning for domain adaptation, showcasing its potential to enhance accuracy and reduce annotation needs in early ASD diagnosis. This study contributes to the growing body of literature on ASD diagnosis methodologies. Future research should delve deeper into refining active learning strategies, ultimately paving the way for more robust and efficient ASD detection tools across diverse datasets.
Optimization of Traction Magnetic Resonance Imaging to Improve Visibility of the Elbow Cartilage
Authors: Kohyama Sho , Ikeda Kazuhiro , Okamoto Yoshikazu , Ochiai Naoyuki , Yoshii Yuichi
Published: March 2024

We previously reported that elbow magnetic resonance imaging (MRI) with 7 kg traction increases the joint space width of the radiocapitellar joint and improves articular cartilage visibility without arthrography. However, the optimal traction weight remains unclear. We assessed the effects of different traction weights on elbow MRI in 30 healthy volunteers. Elbow MRI was performed without traction and with 3, 5, and 7 kg axial tractions. The joint space width, humeral articular cartilage outline visibility, and intraprocedural pain/discomfort were evaluated. The joint and cartilage parameters were measured at the radiocapitellar joint and the lateral and medial thirds of the ulnohumeral joint. At the radiocapitellar joint, the joint space width increased significantly with traction. The cartilage outline visibility significantly increased with traction, with no significant differences among the traction weights. No significant result was observed at the lateral and medial thirds of the ulnohumeral joint. Pain and discomfort significantly increased as we used heavier traction weights. Elbow MRI with 3 kg traction showed sufficient effects similar to those observed with 7 kg traction with minimal pain and discomfort. There was no difference in the effect of traction between male and female participants. This procedure may enable enhanced visualization of intra-articular elbow injuries.
Automatic Active Lesion Tracking in Multiple Sclerosis Using Unsupervised Machine Learning
Authors: Uwaeze Jason , Narayana Ponnada , Kamali Arash , Braverman Vladimir , Jacobs Michael , Akhbardeh Alireza
Published: March 2024

Background: Identifying active lesions in magnetic resonance imaging (MRI) is crucial for the diagnosis and treatment planning of multiple sclerosis (MS). Active lesions on MRI are identified following the administration of Gadolinium-based contrast agents (GBCAs). However, recent studies have reported that repeated administration of GBCA results in the accumulation of Gd in tissues. In addition, GBCA administration increases health care costs. Thus, reducing or eliminating GBCA administration for active lesion detection is important for improved patient safety and reduced healthcare costs. Current state-of-the-art methods for identifying active lesions in brain MRI without GBCA administration utilize data-intensive deep learning methods. Objective: To implement nonlinear dimensionality reduction (NLDR) methods, locally linear embedding (LLE) and isometric feature mapping (Isomap), which are less data-intensive, for automatically identifying active lesions on brain MRI in MS patients, without the administration of contrast agents. Materials and Methods: Fluid-attenuated inversion recovery (FLAIR), T2-weighted, proton density-weighted, and pre- and post-contrast T1-weighted images were included in the multiparametric MRI dataset used in this study. Subtracted pre- and post-contrast T1-weighted images were labeled by experts as active lesions (ground truth). Unsupervised methods, LLE and Isomap, were used to reconstruct multiparametric brain MR images into a single embedded image. Active lesions were identified on the embedded images and compared with ground truth lesions. The performance of NLDR methods was evaluated by calculating the Dice similarity (DS) index between the observed and identified active lesions in embedded images. Results: LLE and Isomap, were applied to 40 MS patients, achieving median DS scores of 0.74 ± 0.1 and 0.78 ± 0.09, respectively, outperforming current state-of-the-art methods. Conclusions: NLDR methods, Isomap and LLE, are viable options for the identification of active MS lesions on non-contrast images, and potentially could be used as a clinical decision tool.
Pan-Immune-Inflammation Value Could Be a New Marker to Predict Amyloidosis and Disease Severity in Familial Mediterranean Fever
Authors: Ocak Tuğba , Görünen Ahmet , Coşkun Belkıs Nihan , Yağız Burcu , Ozemri Sağ Sebnem , Ocakoğlu Gökhan , Dalkılıç Ediz , Pehlivan Yavuz
Published: March 2024

Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever and serositis. Blood-based biomarkers determined in FMF patients during attack-free periods could be used to predict the risk of amyloidosis and the severity of the disease. The recently defined pan-immune-inflammation value (PIV) comprises four distinct subsets of blood cells and serves as an easily accessible and cost-effective marker. The objective of this study was to assess the role of PIV in predicting amyloidosis and moderate-to-severe disease. Clinical characteristics and laboratory values during the attack-free period were retrospectively analyzed in 321 patients over 18 years of age diagnosed with familial Mediterranean fever (FMF). In our tertiary adult rheumatology outpatient clinic, disease severity and laboratory markers were evaluated during the first attack-free interval. At baseline, patients with amyloidosis were excluded. Patients were categorized based on the presence of amyloidosis and the severity of the disease. When focusing on amyloidosis in receiver operating characteristic (ROC) analysis, optimal cut-off values for pan-immune-inflammation value (PIV), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio were determined as ≥518.1, ≥2.3, and ≥127.2, respectively. In multivariate analysis, PIV, C-reactive protein (CRP), and the presence of the M694V homozygous mutation emerged as independent risk factors for both amyloidosis and moderate-to-severe disease. Additionally, NLR was identified as an independent risk factor for amyloidosis, while red blood cell distribution width was associated with moderate-to-severe disease. In patients with FMF, especially in the presence of the M694V homozygous mutation, CRP and PIV may be useful in predicting both amyloidosis and moderate-to-severe disease.
Exploring PGE2 and LXA4 Levels in Migraine Patients: The Potential of LXA4-Based Therapies
Authors: Kocaturk Idris , Gulten Sedat , Ece Bunyamin , Kukul Guven Fatma Mutlu
Published: March 2024

Neurogenic inflammation plays a significant role in the pathogenesis of migraines. This study aimed to investigate the serum levels of prostaglandin E2 (PGE2), lipoxin A4 (LXA4), and other inflammatory biomarkers (C-reactive protein, fibrinogen) in migraine patients. In total, 53 migraine patients and 53 healthy controls were evaluated. Blood serum samples were collected during both attack and interictal periods and compared with the control group. In both the attack and interictal periods, PGE2 and LXA4 values were significantly lower in migraine patients compared to the control group (p < 0.001). Additionally, PGE2 values during the attack period were significantly higher than those during the interictal period (p = 0.016). Patients experiencing migraine attacks lasting ≥ 12 h had significantly lower serum PGE2 and LXA4 levels compared to those with attacks lasting < 12 h (p = 0.028 and p = 0.009, respectively). In ROC analysis, cut-off values of 332.7 pg/mL for PGE2 and 27.2 ng/mL for LXA4 were determined with 70–80% sensitivity and specificity. In conclusion, PGE2 and LXA4 levels are significantly lower in migraine patients during both interictal and attack periods. Additionally, the levels of LXA4 and PGE2 decrease more with the prolongation of migraine attack duration. Our findings provide a basis for future treatment planning.