bluuebunny/crossref_metadata_2025 huggingface dataset:
E-LEARNING: EXPLORING THE FACTORS INFLUENCING FACULTY READINESS DURING COVID -19 PANDEMIC FOR ONLINE TEACHING
Authors: Wali Aisha , Sethi Ahsan , Alam Shams Nadeem , Haq Muhammad Ain ul , Hashmi Ruqayyah
Published: December 2024

Objectives: The study aimed to assess the e- learning readiness amongst faculty members in the discipline of Medicine, Dentistry & Allied.Materials and Methods: The present descriptive cross-sectional study was carried out to analyze faculty readiness for online teaching of the University from May 2020- July 2021. The ethical approval was obtained from the ethical committee of the University. Faculty members from Dental College, Medical University and Allied Departments were selected with the census sampling method and sample obtained was 222. An online survey method was selected for data collection and pre structured validated questionnaire “Students’ E-learning Readiness Scale” developed by Watkins et al was used. Subject expert validated the questionnaire.Results: The overall mean score ranged from 2.11 – 3.12, indicated that experience of online readiness for the faculty members was found to be low. The highest mean score of 3.12 was reported from the faculty members of the Dental College followed by Faculty of Medical College (mean score= 2.94) and Allied (mean score=2.72) regarding readiness for online discussions.Conclusion: The overall readiness is found to be low and this is common for all faculties of all levels. The faculty from Dental College was found to be ready for conducting online lectures as compared to the faculty from Medical and Allied Departments of the University. It should be mandatory that Medical Education Department of the university to conduct more series of workshops for the faculty so that they feel motivated to conduct online teaching.
Педагогічні умови реалізації міждисциплінарних зв’язків у професійній підготовці студентів фахових коледжів із застосуванням ІКТ
Authors: Боско Наталя
Published: December 2024

Процес професійної підготовки конкурентоспроможних фахівців у мінливому глобалізованому світі потребує застосування інтегрованих підходів та реалізації міждисциплінарних зв’язків. Для цього необхідно виокремити педагогічні умови, що забезпечать успішність впровадження міждисциплінарності у освітній процес закладів фахової передвищої освіти із застосуванням ІКТ.
Вивчення сутності поняття «педагогічна умова» дозволило з’ясувати, що у контексті реалізації міждисциплінарних зв’язків, педагогічні умови – це агенти позитивного впливу на процес реалізації міждисциплінарних зв’язків під час професійної підготовки здобувачів. Педагогічні умови є системою науково обґрунтованих заходів, запровадження яких сприятиме підвищенню рівня та якості професійної підготовки студентів фахових коледжів. До таких умов належать: 1) готовність здобувачів та викладачів до реалізації міждисциплінарних зв’язків за допомогою ІКТ; 2) використання технологічного підходу, зокрема актуальних його елементів, таких як доступ до інформації, інтерактивне навчання та індивідуалізоване, онлайн навчання і дистанційна освіта, імерсивні технології, штучний інтелект, мобільні технології та інше; 3) застосування STEM-підходу до процесу освіти, орієнтованого на забезпечення єдності природничих та професійних дисциплін.
Для перевірки зазначених педагогічних умов та ефективності методики реалізації міждисциплінарних зв’язків під час професійної підготовки здобувачів було створено та апробовано професійно орієнтований елективний дистанційний курс «STEM для майбутніх фахівців», доповнений сучасними можливостями ІКТ, зокрема симуляціями, датчиками смартфонів, сервісами для спільної роботи, засобами оцінювання та чат-ботами. Результати дослідження його ефективності (із використанням коефіцієнта рангової кореляції Спірмена), дозволили підтвердити гіпотезу про те, що проходження елективного курсу сприяє підвищенню рівня професійної компетентності, яка буде продемонстрована під час вивчення пропедевтичної фахової дисципліни «Технології». Водночас, було зафіксовано неоднорідність результатів експериментальних груп різних спеціальностей, що розкриває перспективи для подальших досліджень та свідчить про необхідність розробки додаткових універсальних підходів до реалізації міждисциплінарних зв’язків у професійній підготовці студентів.
Tax Evasion Attitudes among Category A and B Business Income Taxpayers in Ethiopia
Authors: Daba Chali Birhanu , Lakatos Vilmos
Published: December 2024

This study investigates the activities of tax evasion attitude in Ethiopia using a mixed-methods approach. The target populations are category A and B taxpayers and tax officials of revenue offices. Data is collected through surveys and structured interviews with taxpayers, focusing on variables such as reported income, tax compliance rates, and demographic factors. Statistical techniques, regression analysis, and in-depth interviews with key stakeholders are employed for nuanced insights. Thematic analysis is employed for qualitative data analysis, with ethical considerations prioritized. Data was collected from 566 taxpayers and selected officials, using a mixed research approach with both descriptive and explanatory research design. The dependent variable is tax evasion attitude, measured by questionnaires that show taxpayers' compliance indirectly. The study found that variables such as the complexity of the tax system, tax rate, weak tax administration, compliant peers, and the role of tax advisors have a positive relationship with tax evasion attitudes. Government legitimacy had a weak and negative correlation with tax evasion attitude, while peer influence, corruption, Tax rate and tax system had a weak and positive correlation with tax evasion attitude. The study recommends that revenue authority should train taxpayers to prepare and present their tax returns, encourage large taxpayers to establish their own accounting information systems and collaborate with certified accountants.
Morocco's Strategic Use of Soft Power, Primarily with the United Nations in the Western Sahara Occupation
Authors: Trinh Evan , Trinh Kevin
Published: December 2024

Morocco strategically uses soft power to reinforce its sovereignty claim over Western Sahara, focusing on engagement with the United Nations and the broader international community. Through Morocco’s economic soft power in its phosphate industry, overpowering hegemony, and continuous autonomy proposals to gain sovereignty and international favor, Morocco has sought to legitimize its position globally while countering opposing beliefs. Western Sahara has experienced this control of soft power, emphasized through liberalism in UN external assistance, restricted development, and its pursuit of self-determination within the bounds of the United Nations. Through institutional frameworks, Security Council dynamics, and postcolonial control, the analysis draws on case studies of UN negotiations, international diplomacy, and Morocco’s outreach efforts. This paper highlights Morocco's soft power usage to influence international perspectives on Western Sahara and garner political and economic support, mirroring other conflicts worldwide.
Berberine alleviates AGEs-induced ferroptosis by activating NRF2 in the skin of diabetic mice
Authors: Jiang Chunjie , Lao Guojuan , Ran Jianmin , Zhu Ping
Published: December 2024

Advanced glycation end products (AGEs) have adverse effects on the development of diabetic complications. Berberine (BBR), a natural alkaloid, has demonstrated its ability to promote the delayed healing of skin wounds. However, the impact of BBR on AGEs-induced ferroptosis in skin cells and the underlying molecular mechanisms remains unexplored. This study investigated the involvement of ferroptosis in AGEs-induced keratinocyte death, and the impact of BBR on ferroptosis in a db/db mouse model with long-term hyperglycemia was elucidated. A remarkable reduction in cell viability was observed along with increased malondialdehyde (MDA) production in AGEs-induced HaCaT cells. Intracellular reactive oxygen species (ROS) and iron levels were elevated in cells exposed to AGEs. Meanwhile, the protein expression of glutathione peroxidase 4 (GPX4) and ferritin light chain (FTL) was significantly decreased in AGEs-treated cells. However, pretreatment with BBR markedly protected cell viability and inhibited MDA levels, attenuating the intracellular ROS and iron levels and increased expression of GPX4 and FTL in vitro. Significantly diminished antiferroptotic effects of BBR on AGEs-treated keratinocytes were observed upon the knockdown of the nuclear factor E2–related factor 2 (NRF2) gene. In vivo, GPX4, FTL, and FTH expression in the epidermis of diabetic mice was significantly reduced, accompanied by enhanced lipid peroxidation. Treatment with BBR effectively rescued lipid peroxidation accumulation and upregulated GPX4, FTL, FTH, and NRF2 levels in diabetic skin. Collectively, the findings indicate that ferroptosis may play a significant role in AGEs-induced keratinocyte death. BBR protects diabetic keratinocytes against ferroptosis, partly by activating NRF2.
Growth-promoting effects of self-selected microbial community on wheat seedlings in saline-alkali soil environments
Authors: Li Min , Li Wenjie , Wang Chunxue , Ji Lei , Han Kun , Gong Jiahui , Dong Siyuan , Wang Hailong , Zhu Xueming , Du Binghai , Liu Kai , Jiang Juquan , Wang Chengqiang
Published: December 2024

Saline-alkali land is a type of soil environment that causes poor crop growth and low yields. Its management and utilization are, therefore of great significance for increasing arable land resources, ensuring food security, and enhancing agricultural production capacity. The application of plant growth-promoting rhizobacteria (PGPR) is an effective way to promote the establishment of symbiotic relationships between plants and the rhizosphere microenvironment, plant growth and development, and plant resistance to saline-alkali stress. In this study, multiple saline-alkali-resistant bacteria were screened from a saline-alkali land environment and some of them were found to have significantly promotive effects on the growth of wheat seedlings under saline-alkali stress. Using these PGPR, a compound microbial community was selectively obtained from the root-zone soil environment of wheat seedlings, and the metagenomic sequencing analysis of wheat root-zone soil microbiomes was performed. As a result, a compound microbial agent with a Kocuria dechangensis 5–33:Rossellomorea aquimaris S-3:Bacillus subtilis BJYX:Bacillus velezensis G51-1 ratio of 275:63:5:1 was obtained through the self-selection of wheat seedlings. The synthetic compound microbial agent significantly improved the growth of wheat seedlings in saline-alkali soil, as the physiological plant height, aboveground and underground fresh weights, and aboveground and underground dry weights of 21-day-old wheat seedlings were increased by 27.39% (p < 0.01), 147.33% (p < 0.01), 282.98% (p < 0.01), 194.86% (p < 0.01), and 218.60% (p < 0.01), respectively. The promoting effect of this compound microbial agent was also greater than that of each strain on the growth of wheat seedlings. This microbial agent could also regulate some enzyme activities of wheat seedlings and the saline-alkali soil, thereby, promoting the growth of these seedlings. In this study, we analyze an efficient microbial agent and the theoretical basis for promoting the growth of wheat seedlings under saline-alkali stress, thereby, suggesting an important solution for the management and utilization of saline-alkali land.
Simulation study on crack extension law of asphalt pavement under temperature effect
Authors: Xie Jing , Xu Hui , Huang Tuo
Published: December 2024

In modern highway construction, asphalt pavement is a widely used structural form, which is easily affected by various external conditions, among which the temperature effect is the most significant. In this paper, the cohesion model is used to simulate the structural cracks of asphalt pavement, the finite element method is used to simulate the asphalt concrete pavement model, and the temperature field simulation model of the pavement is established by using ABAQUS software, with the help of which the spatial distribution of stresses under different temperature conditions is deeply explored, and then the crack extension law during the process of temperature change is systematically investigated, and the effect of the temperature load on the degree of damage to the asphalt pavement is also studied. With the temperature change, the pavement surface layer is affected the most, and the soil base layer is affected the least. The higher the external temperature, the larger the crack expansion width inside the pavement structure, and the faster the corresponding expansion rate. The fatigue damage rate of the pavement structure is accelerated along with the increase of temperature. The research results can provide a theoretical basis for improving the high temperature performance of asphalt pavement.
Novel transition metal-free synthetic protocols toward the construction of 2,3-dihydrobenzofurans: a recent update
Authors: Mushtaq Aqsa , Irfan Muhammad , Haq Atta ul , Mansha Asim , Khan Samreen Gul , Zahoor Ameer Fawad , Parveen Bushra , Irfan Ali , Kotwica-Mojzych Katarzyna , Glowacka Mariola , Mojzych Mariusz
Published: December 2024

2,3-Dihydrobenzofurans are noteworthy scaffolds in organic and medicinal chemistry, constituting the structural framework of many of the varied medicinally active organic compounds. Moreover, a diverse variety of biologically potent natural products also contain this heterocyclic nucleus. Reflecting on the wide biological substantiality of dihydrobenzofurans, several innovative and facile synthetic developments are evolving to achieve these heterocycles. This review summarizes the transition-metal-free, efficient, and novel synthetic pathways toward constructing the dihydrobenzofuran nucleus established after 2020.
Lotus seed (Nelumbinis semen) extract: anticancer potential and chemoprofiling by in vitro, in silico and GC-MS studies
Authors: Mallela Vijaya Jyothi , Rudrapal Mithun , Prasanth D. S. N. B. K. , Pasala Praveen Kumar , Bendale Atul R. , Bhattacharya Soumya , Aldosari Sahar M. , Khan Johra
Published: December 2024

Lotus seeds, also known as Nelumbinis semen, has been utilized for over 7,000 years as vegetable, functional food and medicine. In this study, we primarily investigated the anticancer effects of lotus seed extracts, particularly of the methanolic extract (MELS) on cell proliferation inhibition, apoptosis induction and cell cycle arrest in ovarian cancer cell lines. Further, we studied the phytochemical composition of the MELS by gas chromatography-mass spectrometry (GC-MS) analysis. Additionally, molecular docking was performed in order to substantiate the in vitro anticancer effect by in silico inhibitory study of human survivin protein. Our in vitro study demonstrated significant inhibition of SKOV3 (IC50: 79.73 ± 0.91), A2780 (IC50: 100.18 ± 2.42), SKOV3-CisR (IC50: 115.87 ± 2.2) and A2780-CisR (IC50: 138.86 ± 2.46) cells by MELS, compared to acetone, petroleum ether, n-hexane extracts, and the standard drug, cisplatin. Furthermore, MELS resulted in a substantial increase in apoptosis cell count to 78% in A2780-CisR cells and 82% in SKOV3-CisR cells, whereas a significant reduction in the G1 and G2/M phases of cells treated with MELS when compared to the control group. To identify the potential phytocompounds present in the MELS, we conducted GC-MS analysis, which led to the identification of 14 compounds. Molecular docking analysis revealed that oleic acid, stigmast-5-en-3-ol, phytol and glyceryl linolenate exhibited remarkable binding affinities of −6.1, −5.9, −5.8 and −5.6 kcal/mol, respectively against survivin. Our findings suggest that certain phytochemicals presented above found in MELS may have therapeutic potential for management of ovarian cancer.
Connecting dots of long COVID-19 pathogenesis: a vagus nerve- hypothalamic-pituitary- adrenal-mitochondrial axis dysfunction
Authors: Camici Marta , Del Duca Giulia , Brita Anna Clelia , Antinori Andrea
Published: December 2024

The pathogenesis of long COVID (LC) still presents many areas of uncertainty. This leads to difficulties in finding an effective specific therapy. We hypothesize that the key to LC pathogenesis lies in the presence of chronic functional damage to the main anti-inflammatory mechanisms of our body: the three reflexes mediated by the vagus nerve, the hypothalamic-pituitary-adrenal (HPA) hormonal axis, and the mitochondrial redox status. We will illustrate that this neuro-endocrine-metabolic axis is closely interconnected and how the SARS-CoV-2 can damage it at all stages through direct, immune-inflammatory, epigenetic damage mechanisms, as well as through the reactivation of neurotropic viruses. According to our theory, the direct mitochondrial damage carried out by the virus, which replicates within these organelles, and the cellular oxidative imbalance, cannot be countered in patients who develop LC. This is because their anti-inflammatory mechanisms are inconsistent due to reduced vagal tone and direct damage to the endocrine glands of the HPA axis. We will illustrate how acetylcholine (ACh) and cortisol, with its cytoplasmatic and cellular receptors respectively, are fundamental players in the LC process. Both Ach and cortisol play multifaceted and synergistic roles in reducing inflammation. They achieve this by modulating the activity of innate and cell-mediated immunity, attenuating endothelial and platelet activation, and modulating mitochondrial function, which is crucial for cellular energy production and anti-inflammatory mechanisms. In our opinion, it is essential to study the sensitivity of the glucocorticoids receptor in people who develop LC and whether SARS-CoV-2 can cause long-term epigenetic variations in its expression and function.
Evolving perspectives of medial temporal memory function: hippocampal processes in visual and auditory forms of episodic and working memory
Authors: Hawkins Chris , Yonelinas Andrew P.
Published: December 2024

A cornerstone of memory science is the finding that the medial temporal lobe plays a critical role in supporting episodic long-term memory. However, the role that this brain region plays in supporting other forms of memory such as working memory is controversial. In this selective review, we describe some of the key studies that have informed our current understanding of the role that the medial temporal lobe plays in working memory. We first describe the early studies that supported the idea that the medial temporal lobe is selectively important for long-term episodic memory function, then discuss the subsequent research that indicated that the hippocampus also plays a critical role in visual perception and visual working memory. We then review more recent work suggesting that the medial temporal lobe, and particularly the hippocampus, is critical in supporting a familiarity-based memory signal in working memory, and we propose that this function may not be limited to the visual domain, but rather may support familiarity for auditory working memory as well.
Case Report: Loeffler endocarditis as a cause of left ventricular thrombosis in young women: a case study and literature review
Authors: Cui Yue , Shi Yugen , Wang Xiaojun
Published: December 2024

It is unusual for young patients without any underlying diseases to experience sudden cerebral infarction and heart failure. Here, we report a rare case of a 28-year-old female patient who presented with chest tightness and dizziness. Left ventricular thrombus formation and cardiac insufficiency were evident on echocardiogram, while multiple acute or subacute cerebral infarctions were visible on brain magnetic resonance imaging. We preliminarily determined that this was a different manifestation of the same disease. After investigating the cause, we diagnosed the patient with Loeffler endocarditis caused by idiopathic eosinophilia syndrome involving the heart. Although no endocardial biopsy was performed, this diagnosis was confirmed through cardiac magnetic resonance imaging (CMR). After drug treatment consisting of corticosteroids and anticoagulants, the eosinophil count decreased significantly; however, the thrombus did not completely disappear, as assessed in multiple follow-up echocardiogram sessions. Further exploration of the tissue composition of the patient's left ventricular mass suggested that the mass was a mixture of thrombus and eosinophilic granulation tissue. The addition of imatinib to the treatment plan had a good therapeutic effect, and the patient's left ventricular mass completely disappeared. Loeffler endocarditis progresses rapidly and requires early identification and intervention by clinicians. This case emphasizes that, despite the lack of an endocardial biopsy, the early diagnosis of Loeffler endocarditis can be made through CMR, while avoiding the occurrence of irreversible endocardial fibrosis. We also explored the nature of the patient's cardiac mass and proposed different insights. The nature of cardiac mass varies in different stages of Loeffler endocarditis, and individualized treatment strategies are needed.
A two-sample Mendelian randomization study reveals the causal effects of statin medication on gut microbiota abundance in the European population
Authors: Zhou Peng , Qiu Chen , Zhuang Zequn , Shi Kaihang , Yang Zhihui , Ding Yuyan , Qu Huiheng , Xia Jiazeng
Published: December 2024

Background

Observational studies have reported changes in gut microbiota abundance caused by long-term statin medication therapy. However, the causal relation between statin medication and gut microbiota subsets based on genetic variants remains unclear.

Methods

We used genome-wide association study (GWAS) data on statin medication from the FinnGen database and gut microbiota abundance GWAS data from the IEU OpenGWAS project. A Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of statin medication on gut microbiota abundance using the inverse variance weighting (IVW) method, MR-Egger regression, and weighted median approach. Meanwhile, heterogeneity and pleiotropy analyses were also undertaken in this study.

Results

Statin medication was negatively correlated with five species of gut microbiota abundance: Parabacteroides (BetaIVW = −0.2745, 95% CI = (−0.4422, −0.1068), and PIVW = 0.0013), Ruminococcaceae UCG-009 (BetaIVW = −0.1904, 95% CI = (−0.3255, −0.0553), and PIVW = 0.0057), Coprococcus 1 (BetaIVW = −0.1212, 95% CI = (−0.2194, −0.0231), and PIVW = 0.0154), Ruminococcaceae UCG-010 (BetaIVW = −0.1149, 95% CI = (−0.2238, −0.0060), and PIVW = 0.0385), and Veillonellaceae (BetaIVW = −0.0970, 95% CI = (−0.2238, 0.0060), and PIVW = 0.0400) and positively correlated with one species of gut microbiota: Desulfovibrio (BetaIVW = 0.2452, 95% CI = (0.0299, 0.4606), and PIVW = 0.0255). In addition, no significant heterogeneity or pleiotropy was detected in the abovementioned gut microbiota.

Conclusion

This Mendelian randomization analysis indicates a causal relationship between statin medication and six gut microbiota species. These findings may provide new strategies for health monitoring in populations taking long-term statin medications.
Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma
Authors: Xiang Huihui , Kasajima Rika , Azuma Koichi , Tagami Tomoyuki , Hagiwara Asami , Nakahara Yoshiro , Saito Haruhiro , Igarashi Yuka , Wei Feifei , Ban Tatsuma , Yoshihara Mitsuyo , Nakamura Yoshiyasu , Sato Shinya , Koizume Shiro , Tamura Tomohiko , Sasada Tetsuro , Miyagi Yohei
Published: December 2024

Background

Studies have shown that tumor cell amino acid metabolism is closely associated with lung adenocarcinoma (LUAD) development and progression. However, the comprehensive multi-omics features and clinical impact of the expression of genes associated with amino acid metabolism in the LUAD tumor microenvironment (TME) are yet to be fully understood.

Methods

LUAD patients from The Cancer Genome Atlas (TCGA) database were enrolled in the training cohort. Using least absolute shrinkage and selection operator Cox regression analysis, we developed PTAAMG-Sig, a signature based on the expression of tumor-specific amino acid metabolism genes associated with overall survival (OS) prognosis. We evaluated its predictive performance for OS and thoroughly explored the effects of the PTAAMG-Sig risk score on the TME. The risk score was validated in two Gene Expression Omnibus (GEO) cohorts and further investigated against an original cohort of chemotherapy combined with immune checkpoint inhibitors (ICIs). Somatic mutation, chemotherapy response, immunotherapy response, gene set variation, gene set enrichment, immune infiltration, and plasma-free amino acids (PFAAs) profile analyses were performed to identify the underlying multi-omics features.

Results

TCGA datasets based PTAAMG-Sig model consisting of nine genes, KYNU, PSPH, PPAT, MIF, GCLC, ACAD8, TYRP1, ALDH2, and HDC, could effectively stratify the OS in LUAD patients. The two other GEO-independent datasets validated the robust predictive power of PTAAMG-Sig. Our differential analysis of somatic mutations in the high- and low-risk groups in TCGA cohort showed that the TP53 mutation rate was significantly higher in the high-risk group and negatively correlated with OS. Prediction from transcriptome data raised the possibility that PTAAMG-Sig could predict the response to chemotherapy and ICIs therapy. Our immunotherapy cohort confirmed the predictive ability of PTAAMG-Sig in the clinical response to ICIs therapy, which correlated with the infiltration of immune cells (e.g., T lymphocytes and nature killer cells). Corresponding to the concentrations of PFAAs, we discovered that the high PTAAMG-Sig risk score patients showed a significantly lower concentration of plasma-free α-aminobutyric acid.

Conclusion

In patients with LUAD, the PTAAMG-Sig effectively predicted OS, drug sensitivity, and immunotherapy outcomes. These findings are expected to provide new targets and strategies for personalized treatment of LUAD patients.
NECTIN-4-redirected T cell Antigen Coupler T cells bearing CD28 show superior antitumor responses against solid tumors
Authors: Wei Cheng , Huang Xin , Xu Tianlong , Fang Yinan , Wang Fabao , He Qiaolin , Zhang Peiyuan , Yu Qianjin , Zhang Ying , Zheng Binjiao , Gao Yue , Chen Yongping , Zhuge Qichuan , Zhao Ai , Gao Jimin , Jiang Jinhong
Published: December 2024

Introduction

T cell Antigen Coupler (TAC) T cells harness all signaling subunits of endogenous T cell receptor (TCR) to trigger T-cell activation and tumor cell lysis, with minimal release of cytokines. Some of the major obstacles to cellular immunotherapy in solid tumors include inefficient cell infiltration into tumors, lack of prolonged cellular persistence, and therapy-associated toxicity.

Methods

To boost the cytotoxic potential of TAC-T cells against solid tumors, we generated a novel NECTIN-4-targeted TAC-T variant, NECTIN-4 TAC28-T, which integrated the co-stimulatory CD28 cytoplasmic region, and compared the anti-tumor activities between NECTIN-4 TAC-T cells and NECTIN-4 TAC28-T cells in vitro and vivo.

Results

We demonstrated NECTIN-4 TAC28-Tcells could be effectively activated by NECTIN-4 protein-coated magnetic beads (NECTIN-4-beads), and further revealed that the incorporated CD28 co-stimulatory domain enhanced their activation and proliferation capabilities. Notably, NECTIN-4 TAC28-T cells exhibited better anti-tumor effects both in vitro and in vivo than the original NECTIN-4 TAC-T cells.

Discussion

Our data highlighted that NECTIN-4 TAC28-T cells may represent a promising, safe and effective cell therapy for NECTIN-4-overexpressing solid tumors.
Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in preeclampsia
Authors: Ramos Alex , Youssef Lina , Molina Patricia , Torramadé-Moix Sergi , Martinez-Sanchez Julia , Moreno-Castaño Ana Belen , Blasco Miquel , Guillén-Olmos Elena , De Moner Blanca , Pino Marc , Tortajada Marta , Camacho Marta , Borrell Maria , Crovetto Francesca , Ramirez-Bajo Maria Jose , Ventura-Aguiar Pedro , Banon-Maneus Elisenda , Rovira Jordi , Escolar Gines , Carreras Enric , Gratacos Eduard , Diaz-Ricart Maribel , Crispi Fatima , Palomo Marta
Published: December 2024

Background

Preeclampsia (PE) is a pregnancy complication characterized by hypertension, proteinuria, endothelial dysfunction, and complement dysregulation. Placenta-derived extracellular vesicles (EVs), necessary in maternal–fetal communication, might contribute to PE pathogenesis. Moreover, neutrophil extracellular traps (NETs) play a pathogenic role in other complement-mediated pathologies, and their contribution in PE remains unexplored.

Materials and methods

EVs were isolated from PE (peEVs) and normotensive pregnant women sera. NETs were obtained incubating donor-pre-activated neutrophils with PE or control sera. Microvascular (HMEC) endothelial cells (ECs) were incubated with PE or control sera with or without (depleted sera) EVs or NETs, to assess changes in VCAM-1, ICAM-1, VE-cadherin, eNOS, VWF, ROS, and C5b-9 deposits. Results were expressed as fold increase vs. control.

Results

VWF, VCAM-1, and ROS expression was significantly higher in cells exposed to PE sera vs. control (12.3 ± 8.1, 3.6 ± 2.3, and 1.8 ± 0.2, respectively, p < 0.05), though significantly lower in cells exposed to depleted PE (dPE) sera (6.1 ± 2.7, 0.7 ± 0.6, and 1.2 ± 0.1, respectively, vs. control, p < 0.05). EC exposure to depleted control sera supplemented with peEVs (dC+peEVs) significantly increased VWF, VCAM-1, and ROS compared to non-supplemented sera (4.5 ± 0.3, 2.8 ± 2.0, and 1.4 ± 0.2, respectively, p < 0.05). ICAM-1, VE-cadherin, and C5b-9 did not differ among groups. ECs incubated with PE-NETs increased VWF and VCAM-1 and decreased VE-cadherin expression vs. control (4 ± 1.6, 5.9 ± 1.2, and 0.5 ± 0.1, respectively, p < 0.05), and notably increased C5b-9 deposit (7.5 ± 2.9, p < 0.05). ICAM-1 and ROS did not differ.

Conclusions

Both circulating EVs and NETs from PE pregnant women exhibit a deleterious effect on ECs. Whereas EVs trigger a pro-oxidant and proinflammatory state, NETs potentiate the activation of the complement system, as already described in PE.
IL-27 as a novel biomarker for pruritus in nodular prurigo and bullous pemphigoid
Authors: Wang Yifei , Zhang Xin , Teng Yun Te , Shen Chen
Published: December 2024

Introduction

Bullous pemphigoid (BP) and prurigo nodularis (PN) are chronic pruritic skin diseases that severely impact patients’ quality of life. Despite the widespread attention these two diseases have garnered within the dermatological field, the specific pathogenesis, particularly the molecular mechanisms underlying the pruritus, remains largely unclear. Limited clinical sequencing studies focusing on BP and PN have hindered the identification of pathological mechanisms and the exploration of effective treatment strategies.

Methods

To address this gap, we collected a total of 23 peripheral blood mononuclear cell samples from BP and PN patients, as well as healthy controls, and performed RNA sequencing analysis. By integrating bioinformatics and machine learning techniques, we aimed to uncover the shared immune regulatory networks and pruritus-related mechanisms between BP and PN.

Results

Our study identified 161 differentially expressed genes shared between BP and PN, which were primarily enriched in immune activation and neural pathways, providing crucial molecular insights into the pruritus-related mechanisms of both diseases. Furthermore, using the machine learning algorithms of support vector machines and random forest, we pinpoint 7 crucial genes shared between the BP and PN databases. Among these, IL-27 emerged as a potential pivotal gene, as its mRNA expression levels strongly correlated with clinical parameters including pruritus scores, immunoglobulin E levels, and eosinophil counts. Validation experiments conducted on clinical samples from an additional 22 participants confirmed the upregulation of IL-27 expression in both BP and PN lesions.

Discussion

This study is the first to unveil the shared inflammatory and immune pathways common to BP and PN, highlighting the critical role of IL-27 in the pathogenesis of these conditions. Our findings not only enhance the understanding of the intricate relationship between BP and PN, but also provide a foundation for the development of novel therapeutic strategies targeting these two dermatological conditions.
In vivo programmed myeloid cells expressing novel chimeric antigen receptors show potent anti-tumor activity in preclinical solid tumor models
Authors: Argueta Shannon , Wang Yuxiao , Zhao Hongyun , Diwanji Neha , Gorgievski Michael , Cochran Edward , Grudzien-Nogalska Ewa , D’Alessandro Josephine , McCreedy Bruce , Prod’homme Thomas , Hofmeister Robert , Ding Jian , Getts Daniel
Published: December 2024

Introduction

The approval of chimeric antigen receptor (CAR) T cell therapies for the treatment of B cell malignancies has fueled the development of numerous ex vivo cell therapies. However, these cell therapies are complex and costly, and unlike in hematological malignancies, outcomes with most T cell therapies in solid tumors have been disappointing. Here, we present a novel approach to directly program myeloid cells in vivo by administering novel TROP2 CAR mRNA encapsulated in lipid nanoparticles (LNPs).

Methods

The CAR comprises a TROP2 specific single-chain variable fragment (scFv) fused to a truncated CD89 which requires association with the FcRγ signal adapter to trigger myeloid-specific cell activation. The mRNA encoding the TROP2 CAR was encapsulated in LNPs. Co-immunoprecipitation, flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to measure CAR expression and functional activity in vitro. Anti-tumor efficacy of the TROP2 CAR mRNA/LNP was evaluated after intravenous administration in various murine tumor models.

Results

In vitro, transient expression of the TROP2 CAR on monocytes triggers antigen-dependent cytotoxicity and cytokine release. In tumor bearing mice and cynomolgus monkeys, the TROP2 CAR mRNA/LNP are primarily expressed by myeloid cells. In a mouse xenograft model, intravenous administration of TROP2 CAR mRNA/LNP results in tumor growth inhibition and in a B16/F10-OVA immunocompetent melanoma mouse model, anti-tumor efficacy of a gp75-specific CAR correlates with increased number of activated T cells, activation of dendritic cells and a humoral response against B16/F10-OVA melanoma tumors.

Discussions

These findings demonstrate that myeloid cells can be directly engineered in vivo to kill tumor cells and orchestrate an adaptive immune response and guide clinical studies for the treatment of solid tumors.
Functional MRGPRX2 expression on peripheral blood-derived human mast cells increases at low seeding density and is suppressed by interleukin-9 and fetal bovine serum
Authors: Ieven Toon , Goossens Janne , Roosens Willem , Jonckheere Anne-Charlotte , Cremer Jonathan , Dilissen Ellen , Persoons Rune , Dupont Lieven , Schrijvers Rik , Vandenberghe Peter , Breynaert Christine , Bullens Dominique M. A.
Published: December 2024

Primary human mast cells (MC) obtained through culturing of blood-derived MC progenitors are the preferred model for the ex vivo study of MRGPRX2- vs. IgE-mediated MC activation. In order to assess the impact of culture conditions on functional MRGPRX2 expression, we cultured CD34+-enriched PBMC from peripheral whole blood (PB) and buffy coat (BC) samples in MethoCult medium containing stem cell factor (SCF) and interleukin (IL)-3, modified through variations in seeding density and adding or withholding IL-6, IL-9 and fetal bovine serum (FBS). Functional expression of MRGPRX2 was assessed after 4 weeks via flow cytometry. We found similar proportions of CD34+ MC-committed progenitors in BC and PB. Higher seeding densities (≥ 1x105 cells/mL) and exposure to IL-9 and FBS suppressed functional MRGPRX2 expression at 4 weeks, while leaving MC yield largely unaffected. IL-6 had no impact on MRGPRX2 expression. MRGPRX2-expressing MC upregulated CD63 upon stimulation with polyclonal anti-IgE, substance P and compound 48/80 at 4 weeks. Ketotifen and dasatinib but not cromolyn sodium inhibited both IgE- and MRGPRX2-dependent pathways. Our results confirm the feasibility of functional MC activation studies on PB-derived MC after a short 4-week culture and highlight the impact of culture conditions on functional MRGPRX2 expression.
From formalism to intuition: probing the role of the trochee in German nominal plural forms in L1 and L2 German speakers
Authors: Schuhmann Katharina S. , Smith Laura Catharine
Published: December 2024

Accounting for plural formation in Standard German (SG) nominals has proven to be a challenging endeavor. Numerous formalisms and models have been proposed and intensely debated over the past decades. The fundamental difficulty lies in the fact that German has a large number of suffix allomorphs, some of which can be used with or without stem-vowel fronting/raising (umlaut). Current research suggests that, at the segmental level, it is impossible to fully predict how plurality will be marked for a given singular form. At the suprasegmental level, however, the vast majority of German plurals, except plurals ending in <-s> /-s/, exhibit a specific prosodic shape word-finally: a strong-weak pattern, i.e., a sequence of a stressed syllable followed by an unstressed syllable. In other words, German plurals tend to end in a disyllabic trochee. Previous experimental investigations have sought to provide empirical evidence in favor of various formal models. To date, these experimental studies have focused primarily on the segmental composition of plural suffixes. It remains untested—and thus largely unknown—whether the prosodic pattern at the interface between morphology and phonology is an active, productive part of the grammar of first language (L1) and second language (L2) users of German across proficiency levels. We therefore set out to test whether users actively apply the trochaic principle in the production and comprehension of German plural nouns. To this end, we tested L1 German and L1 English-L2 German users across four proficiency levels on a non-word plural elicitation task, in which they produced plural forms for non-words, akin to a wug-test; L2 users additionally completed a plural elicitation task with existing German nouns. All users then participated in a grammatical acceptability judgment task, in which they rated German nouns with various incorrect and correct (i.e., SG) plural forms on a Likert scale. L2 learners produced more trochaic plural forms as proficiency increased, and more advanced users showed a stronger correlation between their ratings and plural forms depending on the forms' correctness and prosody. We further analyzed how prosodic patterns varied with morphological context across proficiency levels, before discussing how the data can be accounted for within various models of German plurals.
A study on microscopic damage characteristics of freeze-thaw sandstone cyclic loading and unloading based on DEM
Authors: Sun Lichen , Lou Peijie , Pan Cheng , Ji Penghui
Published: December 2024

With the goal of examining the micromechanics damage characteristics of freeze-thaw red sandstone under the influence of cyclic loads, a model of freeze-thaw cyclic rock particles is developed based on Discrete Element Method numerical simulation in order to investigate and study the micromechanics response mechanism of rocks under the coupling effect of freeze-thaw and cyclic loads. The findings demonstrate that lower rock elastic modulus and higher irreversible strain are driven by longer loading/unloading durations and more frequent freeze-thaw cycles. Its bearing capacity and resistance to deformation are diminished by the damage brought on by freeze-thaw; Rock anisotropy and the spatial organisation of microcracks are significantly altered by different loading techniques; In freeze-thaw rocks, the frequency and intensity of acoustic emission breaking follow the law of normal distribution. Under cyclic stress, samples exposed to several freeze-thaw cycles exhibit an escalation in large-scale fractures, accompanied by a concentrated spatial distribution of acoustic emission events. Three phases may be distinguished in the energy evolution of red sandstone: the initial, accumulation, and release phases. The energy storage capacity is compromised by freeze-thaw degradation, resulting in an elevated conversion rate of dissipative energy and rendering the energy conversion mechanism more unstable. The previously described study results possess considerable relevance for rock engineering construction and catastrophe mitigation in cold climates.
Research hotspots and trends on NF-κB in cognitive impairment: a bibliometric analysis
Authors: Bai Lin , Xu Fangyuan , Hu Peijia , Shen Zhiqiang , Xingxing Su , Wang Qingqing , Cheng Hongliang
Published: December 2024

Background

Cognitive impairment (CI) endangers the physical and mental health of patients in a significant manner, and it is expected that the number of people with CI in China will rise to 45.33 million by 2050. Therefore, CI has become a popular research topic. Inflammatory damage plays a key role in the pathogenesis of CI, and NF-κB is an important inflammatory signaling pathway. However, no bibliometric analysis regarding the relationship between CI and NF-κB has been reported.

Methods

A bibliometric analysis regarding NF-κB and CI from 1 January 2008 to 12 December 2023 was conducted in the Science Citation Index-Expanded of the Web of Science Core Collection. The frontiers, hotspots, and trends of research regarding the role of NF-κB in CI were identified. VOSviewer and CiteSpace were used to analyze the retrieved articles and identify the author, country, institution, and keywords, as well as co-cited authors, co-cited journals, and co-cited references.

Results

We analyzed 1,468 original articles and reviews. Publications on NF-κB in CI began in 2010 and increased sharply in 2018. Hong Hao was the most represented author, having published 19 articles, and Chinese authors published more studies than those from other countries. China Pharmaceutical University published the most papers; however, the United States has a strong influence and demonstrates international cooperation. The keywords “apolipoprotein e” and “therapeutic target” demonstrated strong citation bursts, and this tendency may persist in the upcoming years. Neuroinflammation demonstrated a strong influence in research regarding NF-κB in CI. Gut microbiota and ketogenic diet also play an important role in NF-κB in CI.

Conclusion

This bibliometric analysis and visualization using VOSviewer and CiteSpace revealed that the role of NF-κB in CI has become a research hotspot. The results of this study indicated that “neuroinflammation,” “microglial,” and “pathway” remain hotspots for future research. However, studies regarding NF-κB in CI have predominantly focussed on basic research; future research should include therapeutic targets, microbiota, and ketogenic diet.
The value of endocervical curettage for diagnosis of cervical precancers or worse at colposcopy of women with atypical glandular cells cytology
Authors: Chen Yusha , Wen Fanghong , Chen Jiancui , Xue Huifeng , Zheng Xiangqin , Pan Diling
Published: December 2024

Objective

This study evaluates the effectiveness of endocervical curettage (ECC) in identifying additional cervical cancer and its precursors in women with atypical glandular cells (AGC) cytology.

Methods

We conducted a retrospective analysis of medical records for women referred to colposcopy with AGC cytology between January 2019 and December 2023. The study included 433 women with AGC cytology who underwent both biopsy and ECC. Clinical characteristics such as demographics, clinical history, cytology, HPV status, colposcopic findings, and pathology were analyzed. Chi-square and Fisher's exact tests were applied to compare the characteristics of ECC-diagnosed cervical precancers or worse (HSIL+) and normal/low-grade squamous intraepithelial lesions (LSIL).

Results

The overall detection rate of HSIL+ in this population was 19.4% (86/443), with ECC alone identifying HSIL+ in 1.3% (6/443) of cases. However, ECC showed greater utility in certain subgroups. The highest additional HSIL+ detection from ECC was observed in women with HPV 16/18 infection (7.2%) and those with AGC-FN cytology (4.4%). ECC's additional yield of HSIL+ was higher in those with normal or LSIL colposcopic impressions compared to those with HSIL+ impressions. Conversely, no additional HSIL+ cases were identified by ECC alone in women under 30 years old, those with negative high-risk HPV results, or those with type 1/2 transformation zones.

Conclusion

For women with AGC cytology, ECC should be performed in patients with AGC-FN cytology, HPV 16/18 infections, type 3 transformation zones, and normal or low-grade colposcopic impressions. This approach enhances the identification of HSIL+ cases by reducing false negatives. However, for women younger than 30 years old and those with type 1/2 transformation zones, ECC offers limited benefit.
Changes in retinal nerve fiber layer and vessel densities after scleral buckling in patients with rhegmatogenous retinal detachment observed by OCTA
Authors: Zhang Cuiwen , Liu Linlin , Jiang Yiping
Published: December 2024

Purpose

To observe the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and peripapillary vessel densities (VD) in patients with rhegmatogenous retinal detachment (RRD) after scleral buckling (SB) by OCTA.

Methods

A total of 40 patients (40 eyes) with monocular RRD who underwent SB were included in the study, with the operated eyes (40 eyes) as the study group and the contralateral healthy eyes (40 eyes) as the control to analyse the changes in peripapillary RNFL thickness and VD before and after surgery. Data were analysed by paired samples t-test or Wilcoxon signed rank sum test.

Results

Comparison of the peripapillary RNFL thickness in the 8 areas between the two groups during the 6-month follow-up period: All 8 peripapillary areas of the optic disc were statistically different before surgery, except for the tempo superior and tempo inferior, which were statistically different at each postoperative follow-up point, and the remaining 6 areas in the operated eyes group were progressively closer to those in the healthy eyes group, and there was no significant difference between the two groups. Comparison of peripapillary VD in the 8 areas between the two groups during the 6-month follow-up: Peripapillary VD in the 8 areas in the two groups were all statistically different before surgery, and except for superior tempo, which was statistically different at each postoperative follow-up time point, the remaining seven areas in the operated eyes group became progressively closer to that in the healthy eyes group and there was no significant difference.

Conclusion

RRD negatively affects the peripapillary RNFL, but both peripapillary RNFL thickness and VD gradually improved in the operated eyes close to the contralateral eyes after SB.