bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Nitazoxanide Dry Suspensions After Single Oral Doses in Healthy Subjects: Food Effects Evaluation and Bioequivalence Study
Authors: Zhang Chenning , Liang Rui , Liu Dejie , Wang Xianghua , Yang Shuhua , Hu Qingwen , Wen Qing , Zhao Hengli 
Published: April 2024

AbstractNitazoxanide (NTZ) is an effective antiparasitic drug with potent antiviral and antimicrobial activity. This randomized, open‐label, 2‐sequence, 2‐period crossover trial was designed to evaluate the bioequivalence (BE) of the NTZ dry suspension in healthy subjects and investigated the effect of food intake on the pharmacokinetic (PK) properties of tizoxanide (an active metabolite of NTZ, TIZ). Sixty healthy Chinese subjects were enrolled and received a single dose of 500 mg/25 mL of preparations on days 1 and 4 under overnight fasting or fed conditions, respectively. The plasma concentration of TIZ was determined using high‐performance liquid chromatography/tandem mass spectrometry. PK parameters were calculated using WinNonlin 8.2 and BE was evaluated using SAS 9.4. The 90% confidence intervals for the geometric mean ratio (test/reference) of maximum concentration (Cmax), the area under the curve from time 0 to the time of the last quantifiable concentration (AUC0‐t), and the area under the curve from time 0 to extrapolation to infinity (AUC0‐∞) were all within the equivalent interval of 80%‐125%, compliant with BE requirements. In comparison with fasting, on taking the reference and test preparations of the NTZ dry suspension after a meal, the AUC0‐t increased by 48.9% and 47.3%, respectively, the AUC0‐∞ increased by 48.4% and 48.3%, respectively, and the post‐meal Tmax was prolonged by 1.8‐2 hours. Our results demonstrate that the test and reference preparations were bioequivalent. High‐fat meals significantly improve the degree of drug absorption and delay the rate of drug absorption.
EPIDL: Towards efficient and privacy‐preserving inference in deep learning
Authors: Nie Chenfei , Zhou Zhipeng , Dong Mianxiong , Ota Kaoru , Li Qiang 
Published: April 2024

SummaryDeep learning has shown its great potential in real‐world applications. However, users(clients) who want to use deep learning applications need to send their data to the deep learning service provider (server), which can make the client's data leak to the server, resulting in serious privacy concerns. To address this issue, we propose a protocol named EPIDL to perform efficient and secure inference tasks on neural networks. This protocol enables the client and server to complete inference tasks by performing secure multi‐party computation (MPC) and the client's private data is kept secret from the server. The work in EPIDL can be summarized as follows: First, we optimized the convolution operation and matrix multiplication, such that the total communication can be reduced; Second, we proposed a new method for truncation following secure multiplication based on oblivious transfer and garbled circuits, which will not fail and can be executed together with the ReLU activation function; Finally, we replace complex activation function with MPC‐friendly approximation function. We implement our work in C++ and accelerate the local matrix computation with CUDA support. We evaluate the efficiency of EPIDL in privacy‐preserving deep learning inference tasks, such as the time to execute a secure inference on the MNIST dataset in the LeNet model is about 0.14 s. Compared with the state‐ofthe‐art work, our work is 1.8–98 faster over LAN and WAN, respectively. The experimental results show that our EPIDL is efficient and privacy‐preserving.
m6A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia
Authors: Zhao Yanchun , Zhou Yutong , Qian Yu , Wei Wenwen , Lin Xiangjie , Mao Shihui , Sun Jie , Jin Jie 
Published: April 2024

AbstractBackgroundAcute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6‐methyladenosine (m6A) RNA methylation and super‐enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated.MethodsChromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE‐related genes. The mechanisms of m6 A‐binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co‐immunoprecipitation (Co‐IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21.ResultsWe identified two SE‐associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A‐dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells.ConclusionsDysregulation of SE‐IGF2BP2/IGF2BP3‐DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.
RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy
Authors: Chen Huanxiang , Liu Hongyang , Zhang Chenxing , Xiao Nan , Li Yang , Zhao Xiangzhuan , Zhang Ruike , Gu Huihui , Kang Qiaozhen , Wan Junhu 
Published: April 2024

AbstractRNA methylation is widespread in nature. Abnormal expression of proteins associated with RNA methylation is strongly associated with a number of human diseases including cancer. Increasing evidence suggests that targeting RNA methylation holds promise for cancer treatment. This review specifically describes several common RNA modifications, such as the relatively well‐studied N6‐methyladenosine, as well as 5‐methylcytosine and pseudouridine (Ψ). The regulatory factors involved in these modifications and their roles in RNA are also comprehensively discussed. We summarise the diverse regulatory functions of these modifications across different types of RNAs. Furthermore, we elucidate the structural characteristics of these modifications along with the development of specific inhibitors targeting them. Additionally, recent advancements in small molecule inhibitors targeting RNA modifications are presented to underscore their immense potential and clinical significance in enhancing therapeutic efficacy against cancer.Key Points
In this paper, several important types of RNA modifications and their related regulatory factors are systematically summarised.
Several regulatory factors related to RNA modification types were associated with cancer progression, and their relationships with cancer cell migration, invasion, drug resistance and immune environment were summarised.
In this paper, the inhibitors targeting different regulators that have been proposed in recent studies are summarised in detail, which is of great significance for the development of RNA modification regulators and cancer treatment in the future.
Mechanistic Insights Into the [3+1] Cycloadditions of Me3SiN3 on Bis‐Silylene and the Formation of Pseudo‐Silaazatriene
Authors: Muhammed Shahila , Parameswaran Pattiyil 
Published: April 2024

AbstractThe reaction mechanism for the formation of the pseudo‐silaazatriene 1 (LN(SiMe3)2−Si−N−Si(L)NSiMe3; L=PhC−(NtBu)2) by the reaction of 1 equivalent of bis‐silylene (LSi−SiL; L=PhC(NtBu)2) with 3 equivalents of azide Me3SiN3 has been explored at M06/def2‐TZVPP//BP86‐D3(BJ)/def2‐TZVPP level of theory. The reaction mechanism is guided by the high Lewis basicity of the silicon lone pair and the high Lewis acidic character of Si−N bonds, as well as by the high tendency to eliminate N2 from Me3SiN3. The first step of the reaction is the formation of [3+1] cycloaddition product (I1) by the synergetic interactions of the lone pair on the silylene silicon with the π* molecular orbital of Me3SiN3 which is majorly localized on the terminal nitrogen atom, and the donation of the σ‐type lone pair on the nitrogen atom connected to the SiMe3 group with the Si−N σ* orbital on silylene. The elimination of N2 from I1 results in the formation of pseudo‐silaimine intermediate I2 having a dicoordinated, monovalent nitrogen atom. The most favourable pathway involves the second addition of Me3SiN3 followed by N2 elimination resulting bis‐silaimine intermediate I4‐P2. The highly reactive lone pair on the dicoordinated, monovalent nitrogen atom can be coordinated to the Si−N σ* MO of the second silylene moiety resulting in Si−N bond formation and Si−Si bond cleavage. This step is similar to the SN2′ reaction where the incoming nucleophile and the leaving group are on the same side resulting in the formation of silaimine I5. Further, the [3+1] cycloaddition of one more molecule of Me3SiN3 followed by N2 elimination results in the formation of silaimine intermediate I7. I7 undergoes 1,3‐silyl migration leading to the final product 1. The lone pairs on di‐ and tricoordinated nitrogen centres of all the intermediates are stabilized by hyperconjugative interactions. The delocalized hyperconjugative interaction stabilizes the lone pairs in 1.
Women's representation in managerial hierarchies: An examination of trickle‐down and pipeline effects
Authors: Stainback Kevin , Roberts Helen , Biswas Pallab Kumar 
Published: April 2024

AbstractThe trickle‐down effect has been proposed as one means to address women's continued underrepresentation in leadership positions globally. While earlier research supported the trickle‐down effect's prediction that increasing women's representation at higher managerial levels will positively impact women's careers at lower managerial levels, recent studies provide inconsistent evidence, leading to claims that it may be spurious. Due to data limitation, most prior trickle‐down research has explored just two managerial levels—board and executives—making it difficult to separate a trickle‐down effect from external pressures (e.g., shareholders, law) or internal factors (e.g., organizational culture) that may cause it. Furthermore, prior research does not adequately account for women's representation in managerial pipelines, a crucial source of potential managerial talent. To address these concerns, we analyze Australian workplace panel data (2014–2020) that allow for a more robust test of the trickle‐down effect than previously examined. Our results support the trickle‐down effect across multiple managerial levels below the board level, independent of managerial pipeline effects. The trickle‐down and pipeline effects were only observed for positions immediately above and below each managerial level. This highlights the proximity of positions within management hierarchies where the in‐group preference and women's direct advocacy for other women are most likely to occur. Our study suggests that simply appointing more women to top positions, such as boards, while beneficial, is not enough to address gender inequality in management meaningfully. We recommend that rather than focusing on gender representation at the top, organizations should set gender diversity goals and monitor progress at all managerial levels. We conclude with implications for theory, practice, and future research.
Teaching Model Based System Engineering – A Banking Benchmark Problem
Authors: Jeppu Aditya Y , Nasreen Azra , Mittal Mudit 
Published: April 2024

AbstractMBSE has been widely used for industry processes and safety critical avionic and space systems. The use of MBSE process with STPA for safety analysis, mutation testing for verification, model checking and simulations for formal validation, has shown a better alternative to normal development methods. The growth of online financial transactions due to ease of internal payment methods, has resulted in a number of payment applications. System Engineering is not widely popular in academia and undergraduate levels. Benchmark problems are required for the students to get their hands “dirty” and for the instructors to provide hands on examples, matched to theory in textbooks. This paper looks into performing STPA and Model based analysis of such an application, with the goal to teach MBSE methods through industry example.
A slight degree of osteoarthritis appears to be present after anterior cruciate ligament reconstruction compared with contralateral healthy knees at a minimum of 20 years: A systematic review of the literature
Authors: D'Ambrosi Riccardo , Carrozzo Alessandro , Meena Amit , Corona Katia , Yadav Amit Kumar , Annibaldi Alessandro , Kambhampati Srinivas B. S. , Abermann Elisabeth , Fink Christian 
Published: April 2024

AbstractPurposeThe aim of the present systematic review was to quantitatively synthesize the best literature evidence regarding osteoarthritis developing after anterior cruciate ligament reconstruction (ACLR), including only studies with a follow‐up duration of at least 20 years.Material and MethodsA systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines on four electronic databases (PubMed, Scopus, EMBASE and Cochrane Library). The outcome measures extracted from the studies were failure rate, subsequent knee surgery on the same knee, radiographic development of osteoarthritis measured with Kellgren–Lawrence, International Knee Documentation Committee (IKDC) radiographic score and Ahlbäck classification. The health of both the ACLR knee and the contralateral knee was compared.ResultsA total of 1552 patients were included in the study, of which 1290 (83.11%) were operated on using a patellar tendon graft, 190 (12.24%) with hamstrings, 27 (1.73%) with an iliotibial band and 45 (2.89%) with patellar tendon plus a ligament augmentation device (LAD). The mean age at the time of surgery was 25.18 ± 1.91 years, and the mean follow‐up time was 23.34 ± 2.56 years. Analysing IDKC Score at final follow‐up, ACLR Group showed a higher degree of OA compared with contralateral healthy knee (p < 0.01), but only 33.2% (324/976) of the patients showed a moderate to severe degree (Grade C or D) of osteoarthritis, while for Kellgren–Lawrence, ACLR Group showed a higher degree of OA compared with contralateral healthy knee (p < 0.01), but only 28.9% (196/678) of the patients showed a moderate to severe degree (Grade III or IV) of osteoarthritis. In total, 1552 patients were registered, 155 reruptures (9.98%) and a total of 300 (19.3%) new surgeries, of which 228 meniscectomy (14.69%), 21 (1.35%) knee arthroplasty and 17 (1.09%) hardware removal were recorded.ConclusionsACL reconstruction appears to result in mild osteoarthritis in the long term in most of the patients and only less than 33.2% develop a moderate to severe degree of knee OA according to IKDC radiographic score. A slight degree of osteoarthritis appears to be present in ACLR knees compared with contralateral healthy knees.Level of EvidenceLevel IV.
NLRC4‐mediated pyroptosis was involved in coagulation disorders of acute pancreatitis
Authors: Hu Sunkuan , Lin Tiesu , Chen Yufeng , Guo Yimo , Sun Xuecheng , Shi Lingyan , Pan Jingye 
Published: April 2024

AbstractBackgroundAcute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP.MethodsRNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation‐related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme‐linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs).ResultsCoagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes—DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC—may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation‐related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL‐1β, IL‐18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs.ConclusionsNLRC4‐mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.
Gut microbiota: the indispensable player in neurodegenerative diseases
Authors: Li Sen , Cai Yuwei , Wang Shuo , Luo Lei , Zhang Yu , Huang Kai , Guan Xiao 
Published: April 2024

AbstractAs one of the most urgent social and health problems in the world, neurodegenerative diseases have always been of interest to researchers. However, the pathological mechanisms and therapeutic approaches are not achieved. In addition to the established roles of oxidative stress, inflammation and immune response, changes of gut microbiota are also closely related to the pathogenesis of neurodegenerative diseases. Gut microbiota is the central player of the gut–brain axis, the dynamic bidirectional communication pathway between gut microbiota and central nervous system, and emerging insights have confirmed its indispensability in the development of neurodegenerative diseases. In this review, we discuss the complex relationship between gut microbiota and the central nervous system from the perspective of the gut–brain axis; review the mechanism of microbiota for the modulation different neurodegenerative diseases and discuss how different dietary patterns affect neurodegenerative diseases via gut microbiota; and prospect the employment of gut microbiota in the therapeutic approach to those diseases. © 2024 Society of Chemical Industry.
Genetic and the Environmental Influences on the Concentrations Iron and Zinc in Small Seeded Common Bean (Phaseolus vulgaris L.) Varieties and Advanced Lines From Ethiopia
Authors: Ejigu Girum K. , Glahn Raymond P. , Mukankusi Clare M. , Fenta Berhanu A. , Wiesinger Jason A. 
Published: April 2024

ABSTRACTCommon bean (Phaseolus vulgaris L.) is a grain legume rich in proteins and micronutrients, particularly iron and zinc. In this study, 30 small‐seeded genotypes were planted in five locations in Ethiopia, following an alpha lattice design with three replications, to determine environmental and genotypic influence on the Fe and Zn concentration. Based on their Fe and Zn contents, bean cultivars were evaluated for adaptability and stability using AMMI analysis. The Fe concentrations of raw bean seed varied from 44.4 to 84.4 μg/g within the panel of small‐seeded genotypes, with an average range of variance of 18 μg/g across environments, and its seed Zn concentrations varied from 19.7 to 32.3 μg/g, with an average range of variance of 12.6 μg/g across environments. The averages bean Fe concentration among the small‐seeded genotypes across sites in Ethiopia was 62.2 and 26.1 μg/g for Zn concentrations. Results from the analysis of variance using the AMMI model indicated that genotypes accounted for 20.53% and 9.49% of the total variance in seed Fe and Zn concentrations, respectively. The environment had a greater impact, affecting 60.92% and 81.52% of total sum of squares for Fe and Zn concentrations, respectively. According to the broad‐sense heritability, there appears to be some genetic control over Fe and Zn concentrations. However, the substantial effects of the environment and genotype‐by‐environment interaction on Fe and Zn concentrations in small‐seeded genotypes indicates breeding for higher amounts of trace minerals in new bean varieties could be a challenging task. This means the notion that beans can be biofortified to have higher concentrations of Fe and Zn might not be achievable in Ethiopia. A shift in breeding strategies that focuses on traits to enhance the bioavailability of Fe and Zn from bean is warranted and could be a solution to enhance the delivery of iron from small‐seeded beans produced in Ethiopia.
Antiferroptosis therapy alleviated the development of atherosclerosis
Authors: Yang Zhou , He Yue , Wu Dejun , Shi Weihao , Liu Ping , Tan Jinyun , Wang Rui , Yu Bo 
Published: April 2024

AbstractFerroptosis has been confirmed to be associated with various diseases, but the relationship between ferroptosis and atherosclerosis (AS) remains unclear. Our research detailly clarified the roles of ferroptosis in three continuous and main pathological stages of AS respectively (injury of endothelial cells [ECs], adhesion of monocytes, and formation of foam cells). We confirmed that oxidized low‐density lipoprotein (ox‐LDL), the key factor in the pathogenesis of AS, strongly induced ferroptosis in ECs. Inhibition of ferroptosis repressed the adhesion of monocytes to ECs by inhibiting inflammation of ECs. Ferroptosis also participated in the formation of foam cells and lipids by regulating the cholesterol efflux of macrophages. Further research confirmed that ox‐LDL repressedthe activity of glutathione peroxidase 4 (GPX4), the classic lipid peroxide scavenger. Treatment of a high‐fat diet significantly induced ferroptosis in murine aortas and aortic sinuses, which was accompanied by AS lesions and hyperlipidemia. Treatment with ferroptosis inhibitors significantly reduced ferroptosis, hyperlipidemia, and AS lesion development. In conclusion, our research determined that ox‐LDL induced ferroptosis by repressing the activity of GPX4. Antiferroptosis treatment showed promising treatment effects in vivo. Ferroptosis‐associated indexes also showed promising diagnostic potential in AS patients.