bluuebunny/crossref_metadata_2025 huggingface dataset:
Building Test Batteries Based on Analyzing Random Number Generator Tests within the Framework of Algorithmic Information Theory
Authors: Ryabko Boris
Published: June 2024

The problem of testing random number generators is considered and a new method for comparing the power of different statistical tests is proposed. It is based on the definitions of random sequence developed in the framework of algorithmic information theory and allows comparing the power of different tests in some cases when the available methods of mathematical statistics do not distinguish between tests. In particular, it is shown that tests based on data compression methods using dictionaries should be included in test batteries.
Underwater Wavelength Attack on Discrete Modulated Continuous-Variable Quantum Key Distribution
Authors: Feng Kangyi , Wang Yijun , Li Yin , Wang Yuang , Zuo Zhiyue , Guo Ying
Published: June 2024

The wavelength attack utilizes the dependence of beam splitters (BSs) on wavelength to cause legitimate users Alice and Bob to underestimate their excess noise so that Eve can steal more secret keys without being detected. Recently, the wavelength attack on Gaussian-modulated continuous-variable quantum key distribution (CV-QKD) has been researched in both fiber and atmospheric channels. However, the wavelength attack may also pose a threat to the case of ocean turbulent channels, which are vital for the secure communication of both ocean sensor networks and submarines. In this work, we propose two wavelength attack schemes on underwater discrete modulated (DM) CV-QKD protocol, which is effective for the case with and without local oscillator (LO) intensity monitor, respectively. In terms of the transmittance properties of the fused biconical taper (FBT) BS, two sets of wavelengths are determined for Eve’s pulse manipulation, which are all located in the so-called blue–green band. The derived successful criterion shows that both attack schemes can control the estimated excess noise of Alice and Bob close to zero by selecting the corresponding condition parameters based on channel transmittance. Additionally, our numerical analysis shows that Eve can steal more bits when the wavelength attack controls the value of the estimated excess noise closer to zero.
A Review Analysis of Electricity Generation Studies with Social Life Cycle Assessment
Authors: Tsalidis Georgios Archimidis , Batsioula Maria , Banias George F. , Katsou Evina
Published: June 2024

This review explores the social impacts of electricity production by applying the framework of Social Life Cycle Assessment (S-LCA). The authors adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to select studies that were published post-2010 and used S-LCA in the context of various electricity sources, including bioelectricity, solar, wind, and hydropower. The search yielded 13 eligible studies that employed both generic and site-specific assessment strategies, primarily relying on the Social Hotspot Database and Product Social Impact Life Cycle Assessment database for generic evaluations. The findings emphasize the Workers stakeholder as the most frequently examined, with significant attention also given to the Local Community, Society, Value Chain Actors, and Consumer stakeholders when social databases are employed. The studies primarily assessed socioeconomic impact subcategories related to labor practices, health and safety, and economic contributions, as well as a tailored set of self-developed social impacts and indicators specific to the energy sources and geographical contexts examined. This review demonstrates the crucial role of S-LCA in revealing the socio-economic impacts of electricity generation and the need to consider the impacts on Local Community and Society stakeholders through site-specific assessments. Such insights are crucial for guiding policy reforms and industry practices towards more socially responsible energy production.
Hydrogen Production from Enzymatic Pretreated Organic Waste with Thermotoga neapolitana
Authors: Tix Julian , Moll Fabian , Krafft Simone , Betsch Matthias , Tippkötter Nils
Published: June 2024

Biomass from various types of organic waste was tested for possible use in hydrogen production. The composition consisted of lignified samples, green waste, and kitchen scraps such as fruit and vegetable peels and leftover food. For this purpose, the enzymatic pretreatment of organic waste with a combination of five different hydrolytic enzymes (cellulase, amylase, glucoamylase, pectinase and xylase) was investigated to determine its ability to produce hydrogen (H2) with the hydrolyzate produced here. In course, the anaerobic rod-shaped bacterium T. neapolitana was used for H2 production. First, the enzymes were investigated using different substrates in preliminary experiments. Subsequently, hydrolyses were carried out using different types of organic waste. In the hydrolysis carried out here for 48 h, an increase in glucose concentration of 481% was measured for waste loads containing starch, corresponding to a glucose concentration at the end of hydrolysis of 7.5 g·L−1. In the subsequent set fermentation in serum bottles, a H2 yield of 1.26 mmol H2 was obtained in the overhead space when Terrific Broth Medium with glucose and yeast extract (TBGY medium) was used. When hydrolyzed organic waste was used, even a H2 yield of 1.37 mmol could be achieved in the overhead space. In addition, a dedicated reactor system for the anaerobic fermentation of T. neapolitana to produce H2 was developed. The bioreactor developed here can ferment anaerobically with a very low loss of produced gas. Here, after 24 h, a hydrogen concentration of 83% could be measured in the overhead space.
Innovative, Three-Dimensional Model for Time-Dependent, Mechanical Battery Module Behaviour Due to Cell Volume Change
Authors: Bozalp Tolga , Kulkarni Shraddha Suhas , Opfer Holger , Vietor Thomas
Published: June 2024

Battery cells experience volume changes due to intercalation and ageing processes, which may pose a challenge when integrating cells into a battery module. This study presents an innovative, numerical model, which spatially resolved predicts the time-dependent, overall mechanical behaviour of battery modules caused by volume changes in built-in cells. An already self-developed battery module model, which statically describes the three-dimensional (3D), mechanical behaviour in a 0D simulation environment, is extended by the time dimension for dynamic modelling. The existing model abilities and features are maintained, such as the inclusion of multiple size scales from the cell to module level as well as the automatized model building process for the investigation of different module designs in regard to the number and arrangement of foam pads and multiple other design parameters. The validation of the predication abilities against those of complex, commercial software solutions, which use Finite Element Analysis (FEA) in a 3D model environment, have shown good agreement regarding sensitivity, robustness and numerical stability, revealing the impact and interdependencies of model parameters as well as the numerical limits of the model. In this study, the potential of the novel model regarding computational time and resources is underlined, making it a useful and effective tool for fast optimization studies.
Energy Efficiency of Lignocellulosic Biomass Pyrolysis in Two Types of Reactors: Electrical and with Primary Forest Biomass Fuel
Authors: Cobos-Torres Juan-Carlos , Izquierdo Juan , Alvarez-Vera Manuel
Published: June 2024

In this industrialized world, in which the daily consumption of fossil fuels occurs, companies seek to prioritize energy generation through renewable energy sources with minimal environmental impact to improve their energy efficiency. The research objective was to calculate CO2 emissions for the pyrolysis process (conventional low-temperature pyrolysis) in two types of reactors, electric and traditional, where solar panels power the electric reactor. In addition, the amount of polluting gases and the energy consumption necessary to convert biomass into biochar were compared. Residual lignocellulosic biomass (RLB) from various species present in the southern region of Ecuador (eucalyptus, capuli, and acacia) was used, with three replicates per reactor. The electrical reactor (ER) consumed 82.60% less energy than the primary forest biomass fuel “traditional reactor (TR)” and distributed heat better in each pyrolytic process. The TR generated more pollution than the ER; it generated 40.48% more CO, 50% more NO2, 66.67% more SO2, and 79.63% more CH4. Undoubtedly, the pyrolysis process in an ER reduces environmental pollution and creates new bioproducts that could replace fossil fuels. This study provides relevant information on the residual biomass pyrolysis of plant species. These species are traditionally grown in the southern Ecuadorian region. In addition, an analysis of polluting gases for the TR and ER is presented.
WMO Global Energy Resilience Atlas—Climate Risk Indices for Hydropower
Authors: Bastani Hamid , Contreras Beatriz , Boorman Penny , Wu Richaihu , Troccoli Alberto , Boscolo Roberta
Published: June 2024

The importance of energy transition was underlined at COP28 in Dubai, where governments committed to tripling renewables capacities and doubling the rate of energy efficiency by 2030. However, the power generated by climate-dependent energy sources exhibits greater vulnerability to potential climate changes in the long term. Therefore, climate models play a pivotal role in estimating the effects of climate change on renewables in the context of strategic planning for the development and operation of new renewable power plants. In this context, the World Meteorological Organization (WMO) developed a Global Energy Resilience Atlas aimed at providing insights into the climate change risks for the hydropower sector, the largest renewable electricity source for most countries, generating over 4300 TWh globally. This study focuses on defining four Hydro Climate Risk indices (HCRIs) using historical and climate projection precipitation data for three climate scenarios. The final product is a freely available and interactive tool. The developed methodology and tool address how climate changes have historically affected hydropower generation and how they will impact the future at national scales. The final product also addresses the needs of policymakers at national, regional, and global levels in crafting long-term planning for a more secure energy sector, accelerating the energy transition to more sustainable and reliable energies.
Disordered Eating Attitudes and Their Association with Age, BMI, Stress, and Diet in College Students
Authors: Sifre Niliarys , Deringer Rianna , Prapkree Lukkamol , Palacios Cristina
Published: June 2024

Objective: College students are at risk of disordered eating, particularly students with overweight/obesity and with higher stress, but little is known about how disordered eating may be related to diet. This study evaluated the associations between the Disordered Eating Attitudes Scale (DEAS) and age, BMI, stress, and diet. Methods: This is a secondary analysis of the baseline data in participants from the Snackability Trial. Participants completed a questionnaire on socio-demographics, DEAS, and snacking, self-reported their weight and height (to calculate BMI), and completed two 24 h non-consecutive dietary recalls (to calculate diet quality using HEI-2015 and snack quality score using an algorithm developed by our group). Associations between variables were assessed with Spearman correlations. Results: A total of 140 participants completed all assessments. The median age was 21.0 and the median BMI was 28.5 kg/m2 (43.7% had overweight and 41.5% had obesity). A total of 86.4% were females, 41.4% were white, 51.4% were low-income, and 30.7% were Hispanic/Latino. The total DEAS and the subscale ‘Relationship with food’ were positively correlated with stress and BMI (p < 0.05) but inversely correlated with HEI-2015 (p < 0.05). The subscales ‘Restrictive and compensatory behaviors’ and ‘Concern about food and weight gain’ were also positively correlated with stress (p < 0.001). Conclusion: College students with higher disordered eating attitudes also had higher stress and BMI but poorer diet quality. Interventions may be needed for this group to manage stress and improve weight and diet quality, as well as promote awareness about disordered eating attitudes.
Feeling Supported as a Remote Worker: The Role of Support from Leaders and Colleagues and Job Satisfaction in Promoting Employees’ Work–Life Balance
Authors: Buonomo Ilaria , De Vincenzi Clara , Pansini Martina , D’Anna Francesco , Benevene Paula
Published: June 2024

Due to the increasing use of remote work, understanding the dynamics of employee support and its implications for job satisfaction and work–life balance is crucial. Utilizing the Conservation of Resources (COR) theory as a theoretical framework, this research investigated how feeling supported by leaders and colleagues at work fosters work–life balance and job satisfaction among remote employees. The study involved 635 remote workers (females = 61%, mean age, 46.7, SD = 11) from various service-based industries and public administration in Italy. Results from the structural equation model showed a total mediating effect of job satisfaction in the link between colleague support and work–life balance (χ2(22) = 68.923, p = 0.00, CFI = 0.973, TLI = 0.955, RMSEA = 0.059 (90% CI = 0.044–0.075, p = 0.158), SRMR = 0.030), emphasizing the role of interpersonal relationships within the workplace in enhancing remote workers’ job satisfaction and, consequently, their work–life balance. Contrary to expectations, the study found no significant direct or indirect link between leader support and work–life balance. This research highlights the significance of fostering strong social connections and ensuring employee satisfaction to promote well-being and work–life balance in remote work arrangements.
Perceptions of Adulthood and Mental Health
Authors: Tavakkoli Mediss , Valarezo Erick , García Luis F.
Published: June 2024

Background: In contrast to conventional definitions, the contemporary conceptualization of adulthood emphasizes psychological characteristics over sociodemographic milestones. At the same time, an increasing number of theorists propose that the way individuals view adulthood may have a significant impact on the mental health of both adolescents and adults. However, empirical examination of this hypothesis has been notably limited to date. The aim of this study is to explore the association between individuals’ perceptions of adulthood and multiple dimensions of mental health. Method: This study applied some adulthood markers and multiple mental health indexes (including well-being, optimism, Alexithymia, satisfaction with life, Goldberg’s index of mental health, the dark triad, and dimensional personality disorders) to a community sample comprising 1772 individuals in Spain, spanning ages from 16 to 93 years. Results: The findings support the overarching hypothesis, as perceptions of adulthood display strong correlations with nearly every assessed index of mental health, particularly those that comprise a dimension of negative emotions. These associations persist even after accounting for age and socio-economic status, and in alignment with the psychological paradigm of adulthood, they show a notable consistency across various age groups. Conclusions: This study establishes that such perceptions of adulthood represent a modifiable factor contributing to positive mental health. The implications of these findings for the formulation of public policies aimed at promoting mental health in the context of adulthood, as well as a number of future studies, are deliberated.
Advances in Applications of Polysaccharides and Polysaccharide-Based Materials
Authors: Bhuniya Sankarprasad , Demina Tatiana S. , Akopova Tatiana A.
Published: June 2024

Polysaccharides, complex carbohydrates composed of long chains of residues of sugar molecules, have garnered significant attention in recent years due to their diverse applications across various industries [...]
Disarib, a Specific BCL2 Inhibitor, Induces Apoptosis in Triple-Negative Breast Cancer Cells and Impedes Tumour Progression in Xenografts by Altering Mitochondria-Associated Processes
Authors: Manjunath Meghana , Ravindran Febina , Sharma Shivangi , Siddiqua Humaira , Raghavan Sathees C. , Choudhary Bibha
Published: June 2024

Targeted cancer therapy aims to disrupt the functions of proteins that regulate cancer progression, mainly by using small molecule inhibitors (SMIs). SMIs exert their effect by modulating signalling pathways, organelle integrity, chromatin components, and several biosynthetic processes essential for cell division and survival. Antiapoptotic protein BCL2 is highly upregulated in many cancers compared with normal cells, making it an ideal target for cancer therapy. Around 75% of primary breast cancers overexpress BCL2, providing an opportunity to explore BCL2 inhibitors as a therapeutic option. Disarib is an SMI that has been developed as a selective BCL2 inhibitor. Disarib works by disrupting BCL2-BAK interaction and activating intrinsic apoptotic pathways in leukemic cells while sparing normal cells. We investigated the effects of Disarib, a BCL2 specific inhibitor, on breast cancer cells and xenografts. Cytotoxicity and fluorometric assays revealed that Disarib induced cell death by increasing reactive oxygen species and activating intrinsic apoptotic pathways in Triple-Negative Breast Cancer cells (MDA-MB-231 and MDA-MB-468). Disarib also affected the colony-forming properties of these cells. MDA-MB-231- and MDA-MB-468-derived xenografts showed a significant reduction in tumours upon Disarib treatment. Through the transcriptomics approach, we also explored the influence of BCL2 inhibitors on energy metabolism, mitochondrial dynamics, and epithelial-to-mesenchymal transition (EMT). Mitochondrial dynamics and glucose metabolism mainly regulate energy metabolism. The change in energetics regulates tumour growth through epithelial–mesenchymal transition, and angiogenesis. RNA sequencing (RNAseq) analysis revealed that BCL2 inhibitors ABT-199 and Disarib maintain Oxphos levels in MDA-MB-231. However, key glycolytic genes were significantly downregulated. Mitochondrial fission genes were seen to be downregulated both in RNAseq data and semi quantitative real time polymerase chain reaction (qRTPCR) in Disarib-treated TNBC cells and xenografts. Lastly, Disarib inhibited wound healing and epithelial-to-mesenchymal transition. This study showed that Disarib disrupts mitochondrial function, activates the intrinsic apoptotic pathway in breast cancer, and inhibits epithelial-to-mesenchymal transition both in vitro and in vivo. These findings highlight Disarib’s potential as a multifaceted therapeutic strategy for patients with Triple-Negative Breast Cancer.
Therapeutic Potential and Challenges of Mesenchymal Stem Cell-Derived Exosomes for Peripheral Nerve Regeneration: A Systematic Review
Authors: Dogny Clelia , André-Lévigne Dominik , Kalbermatten Daniel F. , Madduri Srinivas
Published: June 2024

Gap injuries to the peripheral nervous system result in pain and loss of function, without any particularly effective therapeutic options. Within this context, mesenchymal stem cell (MSC)-derived exosomes have emerged as a potential therapeutic option. Thus, the focus of this study was to review currently available data on MSC-derived exosome-mounted scaffolds in peripheral nerve regeneration in order to identify the most promising scaffolds and exosome sources currently in the field of peripheral nerve regeneration. We conducted a systematic review following PRISMA 2020 guidelines. Exosome origins varied (adipose-derived MSCs, bone marrow MSCs, gingival MSC, induced pluripotent stem cells and a purified exosome product) similarly to the materials (Matrigel, alginate and silicone, acellular nerve graft [ANG], chitosan, chitin, hydrogel and fibrin glue). The compound muscle action potential (CMAP), sciatic functional index (SFI), gastrocnemius wet weight and histological analyses were used as main outcome measures. Overall, exosome-mounted scaffolds showed better regeneration than scaffolds alone. Functionally, both exosome-enriched chitin and ANG showed a significant improvement over time in the sciatica functional index, CMAP and wet weight. The best histological outcomes were found in the exosome-enriched ANG scaffold with a high increase in the axonal diameter and muscle cross-section area. Further studies are needed to confirm the efficacy of exosome-mounted scaffolds in peripheral nerve regeneration.
Lysophosphatidic Acid Receptor 3 (LPA3): Signaling and Phosphorylation Sites
Authors: Solís K. Helivier , Romero-Ávila M. Teresa , Rincón-Heredia Ruth , García-Sáinz J. Adolfo
Published: June 2024

LPA3 receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA3-mediated calcium signaling, the agonists, and the phorbol ester-induced LPA3 internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin–LPA3 receptor association. The agonist and the phorbol ester-induced marked LPA3 receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute β-arrestin binding sites. These data provide insight into LPA3 receptor signaling and regulation.
Integrative Analysis of Metabolome and Transcriptome of Carotenoid Biosynthesis Reveals the Mechanism of Fruit Color Change in Tomato (Solanum lycopersicum)
Authors: Hu Jiahui , Wang Juan , Muhammad Tayeb , Yang Tao , Li Ning , Yang Haitao , Yu Qinghui , Wang Baike
Published: June 2024

Tomato fruit ripening is accompanied by carotenoid accumulation and color changes. To elucidate the regulatory mechanisms underlying carotenoid synthesis during fruit ripening, a combined transcriptomic and metabolomic analysis was conducted on red-fruited tomato (WP190) and orange-fruited tomato (ZH108). A total of twenty-nine (29) different carotenoid compounds were identified in tomato fruits at six different stages. The abundance of the majority of the carotenoids was enhanced significantly with fruit ripening, with higher levels of lycopene; (E/Z)-lycopene; and α-, β- and γ-carotenoids detected in the fruits of WP190 at 50 and 60 days post anthesis (DPA). Transcriptome analysis revealed that the fruits of two varieties exhibited the highest number of differentially expressed genes (DEGs) at 50 DPA, and a module of co-expressed genes related to the fruit carotenoid content was established by WGCNA. qRT-PCR analysis validated the transcriptome result with a significantly elevated transcript level of lycopene biosynthesis genes (including SlPSY2, SlZCIS, SlPDS, SlZDS and SlCRTSO2) observed in WP190 at 50 DPA in comparison to ZH108. In addition, during the ripening process, the expression of ethylene biosynthesis (SlACSs and SlACOs) and signaling (SlEIN3 and SlERF1) genes was also increased, and these mechanisms may regulate carotenoid accumulation and fruit ripening in tomato. Differential expression of several key genes in the fruit of two tomato varieties at different stages regulates the accumulation of carotenoids and leads to differences in color between the two varieties of tomato. The results of this study provide a comprehensive understanding of carotenoid accumulation and ethylene biosynthesis and signal transduction pathway regulatory mechanisms during tomato fruit development.
Detailed Profiling of the Tumor Microenvironment in Ethnic Breast Cancer, Using Tissue Microarrays and Multiplex Immunofluorescence
Authors: Zaakouk Mohamed , Longworth Aisling , Hunter Kelly , Jiman Suhaib , Kearns Daniel , El-Deftar Mervat , Shaaban Abeer M
Published: June 2024

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.
HEMA-Lysine-Based Cryogels for Highly Selective Heparin Neutralization
Authors: Mecca Tommaso , Spitaleri Fabiola , La Spina Rita , Gioria Sabrina , Giglio Valentina , Cunsolo Francesca
Published: June 2024

Unfractionated heparin (UFH) and its low-molecular-weight fragments (LMWH) are widely used as anticoagulants for surgical procedures and extracorporeal blood purification therapies such as cardiovascular surgery and dialysis. The anticoagulant effect of heparin is essential for the optimal execution of extracorporeal blood circulation. However, at the end of these procedures, to avoid the risk of bleeding, it is necessary to neutralize it. Currently, the only antidote for heparin neutralization is protamine sulphate, a highly basic protein which constitutes a further source of serious side events and is ineffective in neutralizing LMWH. Furthermore, dialysis patients, due to the routine administration of heparin, often experience serious adverse effects, among which HIT (heparin-induced thrombocytopenia) is one of the most severe. For this reason, the finding of new heparin antagonists or alternative methods for heparin removal from blood is of great interest. Here, we describe the synthesis and characterization of a set of biocompatible macroporous cryogels based on poly(2-hydroxyethyl methacrylate) (pHEMA) and L-lysine with strong filtering capability and remarkable neutralization performance with regard to UFH and LMWH. These properties could enable the design and creation of a filtering device to rapidly reverse heparin, protecting patients from the harmful consequences of the anticoagulant.
Streamlined Full-Length Total RNA Sequencing of Paraformaldehyde-Fixed Brain Tissues
Authors: Ji Bingqing , Chen Jiale , Gong Hui , Li Xiangning
Published: June 2024

Paraformaldehyde (PFA) fixation is the preferred method for preserving tissue architecture for anatomical and pathological observations. Meanwhile, PFA reacts with the amine groups of biomolecules to form chemical cross-linking, which preserves RNA within the tissue. This has great prospects for RNA sequencing to characterize the molecular underpinnings after anatomical and pathological observations. However, RNA is inaccessible due to cross-linked adducts forming between RNA and other biomolecules in prolonged PFA-fixed tissue. It is also difficult to perform reverse transcription and PCR, resulting in low sequencing sensitivity and reduced reproducibility. Here, we developed a method to perform RNA sequencing in PFA-fixed tissue, which is easy to use, cost-effective, and allows efficient sample multiplexing. We employ cross-link reversal to recover RNA and library construction using random primers without artificial fragmentation. The yield and quality of recovered RNA significantly increased through our method, and sequencing quality metrics and detected genes did not show any major differences compared with matched fresh samples. Moreover, we applied our method for gene expression analysis in different regions of the mouse brain and identified unique gene expression profiles with varied functional implications. We also find significant dysregulation of genes involved in Alzheimer’s disease (AD) pathogenesis within the medial septum (MS)/vertical diagonal band of Broca (VDB) of the 5×FAD mouse brain. Our method can thus increase the performance of high-throughput RNA sequencing with PFA-fixed samples and allows longitudinal studies of small tissue regions isolated by their in situ context.
Disease-Modifying Effects of Lenvatinib, a Multiple Receptor Tyrosine Kinase Inhibitor, on Posttraumatic Osteoarthritis of the Knee
Authors: Sogo Yasuyuki , Toyoda Eriko , Nagai Toshihiro , Takahashi Takumi , Takizawa Daichi , Watanabe Masahiko , Sato Masato
Published: June 2024

Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control (n = 12), L0.3: 0.3 mg/kg/day (n = 15), L1.0: 1.0 mg/kg/day (n = 14), and L3.0: 3.0 mg/kg/day (n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral–tibial (FT), femoral–patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn’s grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA.
Pseudolaric Acid B Targets CD147 to Selectively Kill Acute Myeloid Leukemia Cells
Authors: Zou Sheng , Parfenova Ekaterina , Vrdoljak Nikolina , Minden Mark D. , Spagnuolo Paul A.
Published: June 2024

Acute myeloid leukemia (AML) is an aggressive blood cancer. With low survival rates, new drug targets are needed to improve treatment regimens and patient outcomes. Pseudolaric acid B (PAB) is a plant-derived bioactive compound predicted to interact with cluster of differentiation 147 (CD147/BSG). CD147 is a transmembrane glycoprotein overexpressed in various malignancies with suggested roles in regulating cancer cell survival, proliferation, invasion, and apoptosis. However, the detailed function of PAB in AML remains unknown. In this study, AML cell lines and patient-derived cells were used to show that PAB selectively targeted AML (IC50: 1.59 ± 0.47 µM). Moreover, proliferation assays, flow cytometry, and immunoblotting confirmed that PAB targeting of CD147 resulted in AML cell apoptosis. Indeed, the genetic silencing of CD147 significantly suppressed AML cell growth and attenuated PAB activity. Overall, PAB imparts anti-AML activity through transmembrane glycoprotein CD147.
Methylation-Based Characterization of a New IDH2 Mutation in Sinonasal Undifferentiated Carcinoma
Authors: Burgermeister Simon , Stoykova Simona , Krebs Fanny S. , Zoete Vincent , Mbefo Martial , Egervari Kristof , Reinhard Antoine , Bisig Bettina , Hewer Ekkehard
Published: June 2024

Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.
Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells
Authors: Inukai Ryuta , Mori Kanako , Maki Masatoshi , Takahara Terunao , Shibata Hideki
Published: June 2024

Cell death-inducing p53-target protein 1 (CDIP1) is a proapoptotic protein that is normally expressed at low levels and is upregulated by genotoxic and endoplasmic reticulum stresses. CDIP1 has been reported to be localized to endosomes and to interact with several proteins, including B-cell receptor-associated protein 31 (BAP31) and apoptosis-linked gene 2 (ALG-2). However, the cellular and molecular mechanisms underlying CDIP1 expression-induced apoptosis remain unclear. In this study, we first demonstrated that CDIP1 was upregulated after treatment with the anticancer drug adriamycin in human breast cancer MCF-7 cells but was degraded rapidly in the lysosomal pathway. We also demonstrated that treatment with the cyclin-dependent kinase 5 (CDK5) inhibitor roscovitine led to an increase in the electrophoretic mobility of CDIP1. In addition, a phosphomimetic mutation at Ser-32 in CDIP1 resulted in an increase in CDIP1 expression-induced apoptosis. We also found that CDIP1 expression led to the induction of autophagy prior to apoptosis. Treatment of cells expressing CDIP1 with SAR405, an inhibitor of the class III phosphatidylinositol 3-kinase VPS34, caused a reduction in autophagy and promoted apoptosis. Therefore, autophagy is thought to be a defense mechanism against CDIP1 expression-induced apoptosis.
Ibogaine Induces Cardiotoxic Necrosis in Rats—The Role of Redox Processes
Authors: Vidonja Uzelac Teodora , Tatalović Nikola , Mijović Milica , Miler Marko , Grahovac Tanja , Oreščanin Dušić Zorana , Nikolić-Kokić Aleksandra , Blagojević Duško
Published: June 2024

Ibogaine is an organic indole alkaloid that is used in alternative medicine to combat addiction. Numerous cases of life-threatening complications and sudden deaths associated with ibogaine use have been reported, and it has been hypothesized that the adverse effects are related to ibogaine’s tendency to induce cardiac arrhythmias. Considering that the bioavailability of ibogaine and its primary metabolite noribogaine is two to three times higher in female rats than in male rats, we here investigated the effect of a single oral dose (1 or 20 mg/kg) of ibogaine on cardiac histopathology and oxidative/antioxidant balance. Our results show that ibogaine induced dose-dependent cardiotoxic necrosis 6 and 24 h after treatment and that this necrosis was not a consequence of inflammation. In addition, no consistent dose- and time-dependent changes in antioxidant defense or indicators of oxidative damage were observed. The results of this study may contribute to a better understanding of ibogaine-induced cardiotoxicity, which is one of the main side effects of ibogaine use in humans and is often fatal. Nevertheless, based on this experiment, it is not possible to draw a definitive conclusion regarding the role of redox processes or oxidative stress in the occurrence of cardiotoxic necrosis after ibogaine administration.
Valorization of Olive Pomace Using Ultrasound-Assisted Extraction for Application in Active Packaging Films
Authors: Fotiadou Renia , Fragkaki Ioanna , Pettas Kyriakos , Stamatis Haralambos
Published: June 2024

Bioactive compounds that can be recovered by the solid wastes of the olive oil sector, such as polyphenols, are known for their significant antioxidant and antimicrobial activities with potential application in nutraceutical, cosmetic, and food industries. Given that industrial demands are growing, and the polyphenol market value is ever increasing, a systematic study on the recovery of natural antioxidant compounds from olive pomace using ultrasound-assisted extraction (UAE) was conducted. Single-factor parameters, i.e., the extraction solvent, time, and solid-to-liquid ratio, were investigated evaluating the total phenolic content (TPC) recovery and the antioxidant activity of the final extract. The acetone–water system (50% v/v, 20 min, 1:20 g mL−1) exhibited the highest total phenolic content recovery (168.8 ± 5.5 mg GAE per g of dry extract). The olive pomace extract (OPE) was further assessed for its antioxidant and antibacterial activities. In DPPH, ABTS, and CUPRAC, OPE exhibited an antioxidant capacity of 413.6 ± 1.9, 162.72 ± 3.36 and 384.9 ± 7.86 mg TE per g of dry extract, respectively. The antibacterial study showed that OPE attained a minimum inhibitory activity (MIC) of 2.5 mg mL−1 against E. coli and 10 mg mL−1 against B. subtilis. Hydroxytyrosol and tyrosol were identified as the major phenolic compounds of OPE. Furthermore, active chitosan–polyvinyl alcohol (CHT/PVA) films were prepared using different OPE loadings (0.01–0.1%, w/v). OPE-enriched films showed a dose-dependent antiradical scavenging activity reaching 85.7 ± 4.6% (ABTS) and inhibition growth up to 81% against B. subtilis compared to the control film. Increased UV light barrier ability was also observed for the films containing OPE. These results indicate that OPE is a valuable source of phenolic compounds with promising biological activities that can be exploited for developing multifunctional food packaging materials.
Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer’s Disease: Systematic Review
Authors: Bougea Anastasia , Angelopoulou Efthalia , Vasilopoulos Efthimios , Gourzis Philippos , Papageorgiou Sokratis
Published: June 2024

Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer’s disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its anti-degenerative mechanisms of action and clinical implications. According to PRISMA, we searched MEDLINE, up to 1 April 2024, for animal and human studies examining the efficacy of fluoxetine with regard to the recovery of cognitive function in AD. Methodological quality was evaluated using the ARRIVE tool for animal AD studies and the Cochrane tool for clinical trials. In total, 22 studies were analyzed (19 animal AD studies and 3 clinical studies). Fluoxetine promoted neurogenesis and enhanced synaptic plasticity in preclinical models of AD, through a decrease in Aβ pathology and increase in BDNF, by activating diverse pathways (such as the DAF-16-mediated, TGF-beta1, ILK-AKT-GSK3beta, and CREB/p-CREB/BDNF). In addition, fluoxetine has anti-inflammatory properties/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome. Only three clinical studies showed that fluoxetine ameliorated the cognitive performance of people with AD; however, several methodological issues limited the generalizability of these results. Overall, the high-quality preclinical evidence suggests that fluoxetine may have neuroprotective, antioxidant, and anti-inflammatory effects in AD animal models. While more high-quality clinical research is needed to fully understand the mechanisms underlying these effects, fluoxetine is a promising potential treatment for AD patients. If future clinical trials confirm its anti-degenerative and neuroprotective effects, fluoxetine could offer a new therapeutic approach for slowing down the progression of AD.
Targeted Metabolomics of Tissue and Plasma Identifies Biomarkers in Mice with NOTCH1-Dependent T-Cell Acute Lymphoblastic Leukemia
Authors: Tosello Valeria , Di Martino Ludovica , Piovan Erich
Published: June 2024

While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute lymphoblastic leukemia (ALL), metabolic studies are still lagging, especially regarding how the metabolism differs between healthy and diseased individuals. T-cell ALL (T-ALL) is an aggressive hematological neoplasm deriving from the malignant transformation of T-cell progenitors characterized by frequent NOTCH1 pathway activation. The aim of our study was to characterize tumor and plasma metabolomes during T-ALL development using a NOTCH1-induced murine T-ALL model (ΔE-NOTCH1). In tissue, we found a significant metabolic shift with leukemia development, as metabolites linked to glycolysis (lactic acid) and Tricarboxylic acid cycle replenishment (succinic and malic acids) were elevated in NOTCH1 tumors, while metabolites associated with lipid oxidation (e.g., carnitine) as well as purine and pyrimidine metabolism were elevated in normal thymic tissue. Glycine, serine, and threonine metabolism, glutathione metabolism, as well as valine, leucine, and isoleucine biosynthesis were enriched pathways in tumor tissue. Phenylalanine and tyrosine metabolism was highly enriched in plasma from leukemia-bearing mice compared to healthy mice. Further, we identified a metabolic signature consisting of glycine, alanine, proline, 3-hydroxybutyrate, and glutamic acid as potential biomarkers for leukemia progression in plasma. Hopefully, the metabolic differences detected in our leukemia model will apply to humans and contribute to the development of metabolism-oriented therapeutic approaches.
Expression Profiles of Dopamine-Related Genes and miRNAs Regulating Their Expression in Breast Cancer
Authors: Sirek Tomasz , Sirek Agata , Borawski Przemysław , Ryguła Izabella , Król-Jatręga Katarzyna , Opławski Marcin , Boroń Dariusz , Chalcarz Michał , Ossowski Piotr , Dziobek Konrad , Zmarzły Nikola , Boroń Kacper , Mickiewicz Patrycja , Grabarek Beniamin Oskar
Published: June 2024

This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A (n = 130), luminal B (n = 196, including HER2−, n = 100; HER2+, n = 96), HER2+ (n = 36), and TNBC (n = 43); they underwent surgery, during which tumor tissue was removed along with a margin of healthy tissue (control material). The molecular analysis included a microarray profile of mRNAs and miRNAs associated with the dopaminergic system, a real-time polymerase chain reaction preceded by reverse transcription for selected genes, and determinations of their concentration using enzyme-linked immunosorbent assay (ELISA). The conducted statistical analysis showed that five mRNAs statistically significantly differentiated breast cancer sections regardless of subtype compared to control samples; these were dopamine receptor 2 (DRD2), dopamine receptor 3 (DRD3), dopamine receptor 25 (DRD5), transforming growth factor beta 2 (TGF-β-2), and caveolin 2 (CAV2). The predicted analysis showed that hsa-miR-141-3p can regulate the expression of DRD2 and TGF-β-2, whereas hsa-miR-4441 is potentially engaged in the expression regulation of DRD3 and DRD5. In addition, the expression pattern of DRD5 mRNA can also be regulated by has-miR-16-5p. The overexpression of DRD2 and DRD3, with concomitant silencing of DRD5 expression, confirms the presence of dopaminergic abnormalities in breast cancer patients. Moreover, these abnormalities may be the result of miR-141-3P, miR-16-5p, and miR-4441 activity, regulating proliferation or metastasis.
NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues
Authors: Kim Bae-Hoon , Chung Yeon-Ho , Woo Tae-Gyun , Kang So-mi , Park Soyoung , Kim Minju , Park Bum-Joon
Published: June 2024

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein–protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.