bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic modulation through BET bromodomain inhibitors as a novel therapeutic strategy for progranulin-deficient frontotemporal dementia
Authors: Rosenthal Zachary C. , Fass Daniel M. , Payne N. Connor , She Angela , Patnaik Debasis , Hennig Krista M. , Tesla Rachel , Werthmann Gordon C. , Guhl Charlotte , Reis Surya A. , Wang Xiaoyu , Chen Yueting , Placzek Michael , Williams Noelle S. , Hooker Jacob , Herz Joachim , Mazitschek Ralph , Haggarty Stephen J. 
Published: April 2024

AbstractFrontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.
Detection and genomic characterization of Klebsiella pneumoniae and Escherichia coli harboring tet(X4) in black kites (Milvus migrans) in Pakistan
Authors: Mansoor Muhammad Hassan , Lu Xiaoyu , Woksepp Hanna , Sattar Amna , Humak Farwa , Ali Jabir , Li Ruichao , Bonnedahl Jonas , Mohsin Mashkoor 
Published: April 2024

AbstractThe emergence of plasmid-mediated tigecycline resistance gene tet(X4) among clinically relevant bacteria has promoted significant concerns, as tigecycline is considered a last-resort drug against serious infections caused by multidrug-resistant bacteria. We herein focused on the isolation and molecular characterization of tet(X4)-positive Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) in wild bird populations with anthropogenic interaction in Faisalabad, Pakistan. A total of 150 birds including black kites (Milvus migrans) and house crows (Corvus splendens) were screened for the presence of tigecycline resistance K. pneumoniae and E. coli. We found two K. pneumoniae and one E. coli isolate carrying tet(X4) originating from black kites. A combination of short- and long-read sequencing strategies showed that tet(X4) was located on a broad host range IncFII plasmid family in K. pneumoniae isolates whereas on an IncFII-IncFIB hybrid plasmid in E. coli. We also found an integrative and conjugative element ICEKp2 in K. pneumoniae isolate KP8336. We demonstrate the first description of tet(X4) gene in the WHO critical-priority pathogen K. pneumoniae among wild birds. The convergence of tet(X4) and virulence associated ICEKp2 in a wild bird with known anthropogenic contact should be further investigated to evaluate the potential epidemiological implications. The potential risk of global transmission of tet(X4)-positive K. pneumoniae and E. coli warrant comprehensive evaluation and emphasizes the need for effective mitigation strategies to reduce anthropogenic-driven dissemination of AMR in the environment.
Integrative analysis in head and neck cancer reveals distinct role of miRNome and methylome as tumour epigenetic drivers
Authors: Mandić Katarina , Milutin Gašperov Nina , Božinović Ksenija , Dediol Emil , Krasić Jure , Sinčić Nino , Grce Magdalena , Sabol Ivan , Barešić Anja 
Published: April 2024

AbstractHead and neck cancer is the sixth most common malignancy worldwide, with the relatively low 5-year survival rate, mainly because it is diagnosed at a late stage. Infection with HPV is a well known aetiology, which affects the nature of these cancers and patients’ survival. Besides, it is considered that the main driving force for this type of cancer could be epigenetics. In this study we aimed to find potential epigenetic biomarkers, by integrating miRNome, methylome, and transcriptome analyses. From the fresh head and neck cancer tissue samples, we chose a group for miRNome, methylome and transcriptome profiling, in comparison to adequate control samples. Bioinformatics analyses are performed in R v4.2.2. Count normalisation and group differential expression for mRNA and the previously obtained miRNA count data was performed with DESeq2 v1.36. Gene set enrichment analysis was performed and visualised using gProfiler2 v0.2.1 Identification of miRNA targets was performed by querying in miRTarBase using multiMiR v1.18.0. Annotation of CpG sites merging into islands was obtained from RnBeads.hg19 v1.28.0. package. For the integrative analysis we performed kmeans clustering using stats v4.2.2 package, using 8–12 clusters and nstart 100. We found that transcriptome analysis divides samples into cancers and controls clusters, with no relation to HPV status or cancer anatomical location. Differentially expressed genes (n = 2781) were predominantly associated with signalling pathways of tumour progression. We identified a cluster of genes under the control of the transcription factor E2F that are significantly underexpressed in cancer tissue, as well as T cell immunity genes and genes related to regulation of transcription. Among overexpressed genes in tumours we found those that belong to cell cycle regulation and vasculature. A small number of genes were found significantly differentially expressed in HPV-positive versus HPV-negative tumours (for example NEFH, ZFR2, TAF7L, ZNF541, and TYMS). In this comprehensive study on an overlapping set of samples where the integration of miRNome, methylome and transcriptome analysis were performed for head and neck cancer, we demonstrated that the majority of genes were associated exclusively with miRNome or methylome and, to a lesser extent, under the control of both epigenetic mechanisms.
Apigetrin ameliorates doxorubicin prompted testicular damage: biochemical, spermatological and histological based study
Authors: Ijaz Muhammad Umar , Yaqoob Saba , Hamza Ali , David Mehwish , Afsar Tayyaba , Husain Fohad Mabood , Amor Houda , Razak Suhail 
Published: April 2024

AbstractDoxorubicin (DOX) is a highly effective, commonly prescribed, potent anti-neoplastic drug that damages the testicular tissues and leads to infertility. Apigetrin (APG) is an important flavonoid that shows diverse biological activities. The present research was designed to evaluate the alleviative role of APG against DOX-induced testicular damages in rats. Forty-eight adult male albino rats were randomly distributed into 4 groups, control, DOX administered (3 mgkg−1), DOX + APG co-administered (3 mgkg−1 of DOX; 15 mgkg−1 of APG), and APG administered group (15 mgkg−1). Results of the current study indicated that DOX treatment significantly reduced the activities of superoxide dismutase (SOD), glutathione reductase (GSR), catalase (CAT) and glutathione peroxidase (GPx), while increasing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). DOX treatment also reduced the sperm count, viability, and motility. Moreover, DOX significantly increased the sperm morphological anomalies and reduced the levels of plasma testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The administration of DOX significantly increased the expressions of Bax and Caspase-3, as well as the levels of inflammatory markers. Additionally, DOX treatment significantly downregulated the expressions of steroidogenic enzymes (StAR, 3β-HSD and 17β-HSD) and Bcl-2. Furthermore, DOX administration provoked significant histopathological abnormalities in the testicular tissues. However, APG supplementation significantly reversed all the testicular damages due to its androgenic, anti-apoptotic, anti-oxidant and anti-inflammatory nature. Therefore, it is concluded that APG may prove a promising therapeutic agent to treat DOX-induced testicular damages.
Reliability-based design optimization for a vertical-type breakwater with multiple limit-state equations under Korean marine environments varying from sea to sea
Authors: Cho Yong Jun 
Published: April 2024

AbstractIn this study, as part of basic research aimed at enhancing the accuracy of load and resistance coefficients to ensure their suitability for practical design and promoting the application of underutilized reliability-based design in Korea, the author conducts optimal design based on the reliability analysis of a vertical-type breakwater in the seas off of Haeundae, Yeosu, Mokpo, Gunsan, and Incheon—representative ports in Korea. In doing so, the author utilized the double-loop approach, which simultaneously addresses a reliability problem nested within an optimization process, employing the Polak–He optimization algorithm. To mitigate the substantial numerical effort required by the double-loop approach based on the Polak–He optimization algorithm, which necessitates the gradients of both cost and constraint functions, the subset simulation method was employed. In this process, the author deliberately refrained from using design waves of a specific return period and linear probabilistic models such as the Gaussian distribution, especially concerning wave and lift forces, often viewed as barriers to the widespread application of reliability-based design in Korea. Instead, the author focused on characterizing the uncertainties associated with the wave force, lift force, and overturning moment—variables that significantly impact the integrity of vertical-type breakwaters—by developing probabilistic models for these random variables directly from long-term in situ wave data. These models capture the varied characteristics of the Korean marine environment from sea to sea. In this way, the need for additional assumptions concerning the interrelationship between significant wave and maximum wave heights, along with the wave period, can be eliminated. Following Occam's razor principle, which suggests that explanations constructed with the smallest possible set of assumptions are superior, the reliability-based design optimization of a vertical-type breakwater presented in this study demonstrates promise in terms of simplicity and practicality. The limit state of the vertical-type breakwater was defined to encompass sliding, overturning, and collapse failures, and the strong interrelations between the wave force, lift force, and overturning moment were described using the Nataf joint distribution. As anticipated, simulation results show that solely considering sliding failure, as in the current reliability-based design platform in Korea, leads to an underestimated failure probability. Furthermore, ensuring a consistent failure probability for vertical-type breakwaters using design waves with a specific return period, as in past studies, is not feasible. In contrast, this study demonstrated that breakwaters optimally designed to meet the reliability index requirement of β = 3.5–4 consistently maintain a target failure probability in all sea areas.
Associations between life’s essential 8 and sarcopenia in US adults: a cross-sectional analysis
Authors: Long Feng , Zou Su , Dong Youhai 
Published: April 2024

AbstractCardiovascular disease (CVD) is closely associated with sarcopenia. We aimed to examine the relationship between Life’s Essential 8 (LE8) and the incidence of sarcopenia among adults in the United States. In this study, a cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey from 2013 to 2018 and included 5999 adult participants. LE8 score was categorized into low (< 49), moderate (49–79), and high CVH (≥ 79) groups and consisted of health behavior score and health factor score based on American Heart Association definitions. Sarcopenia was defined according to The Foundation for the National Institutes of Health Sarcopenia Project. Multivariate logistic regressions, restricted cubic spline regressions, and subgroup analyses were used to assess the association between LE8 and sarcopenia. LE8 and its subscales score were negatively associated with the incidence of sarcopenia in US adults.
Beliefs and behaviors associated with the first named heat wave in Seville Spain 2022
Authors: Metzger Aaron , Baharav Yuval , Nichols Lilly , Finke Megan , Saunders Breahnna , Mitchell Peter , Wellenius Gregory A. , Baughman McLeod Kathy , Shickman Kurt 
Published: April 2024

AbstractHeat waves pose a substantial and increasing risk to public health. Heat health early warning systems (HHEWSs) and response plans are increasingly being adopted to alert people to the health risks posed by days of extreme heat and recommend protective behaviors. However, evidence regarding the effectiveness of HHEWSs remains limited. We examined the impact of heat wave naming on heat-related beliefs and behaviors to ascertain the potential effectiveness of heat wave naming as a heat health risk communication and management tool. Specifically, we surveyed members of the public exposed to the proMETEO Sevilla HHEWS messaging campaign which in the summer of 2022 applied a name to heat waves considered to pose the greatest risk to public health. During the heat season we evaluated, the proMETEO Sevilla HHEWS campaign applied a name to one heat wave, heat wave “Zoe”. Our analysis of the post-survey of 2022 adults indicated that the 6% of participants who recalled the name Zoe unaided reported greater engagement in heat wave safety behaviors and more positive beliefs about naming heat waves and their local governments’ heat wave response. These results provide initial evidence for potential utility in naming heat waves as part of HHEWSs and HAPs.
Construction of power network security risk assessment model based on LSA-SVM algorithm in the background of smart grid
Authors: Qi Haojin , Zhu Wan , Ye Mingda , Hu Yichen , Wang Yong 
Published: April 2024

AbstractDue to theintricate and interdependent nature of the smart grid, it has encountered an increasing number of security threats in recent years. Currently, conventional security measures such as firewalls, intrusion detection, and malicious detection technologies offer specific protection based on their unique perspectives. However, as the types and concealment of attacksincrease, these measures struggle to detect them promptly and respond accordingly. In order to meet the social demand for the accuracy and computation speed of the power network security risk evaluation model, the study develops a fusion power network security risk evaluation algorithm by fusing the flash search algorithm with the support vector machine. This algorithm is then used as the foundation for building an improved power network security risk evaluation model based on the fusion algorithm.The study's improved algorithm's accuracy is 96.2%, which is higher than the accuracy of the other comparative algorithms; its error rate is 3.8%, which is lower than the error rate of the other comparative algorithms; and its loss function curve convergence is quicker than that of the other algorithms.The risk evaluation model's accuracy is 97.8%, which is higher than the accuracy of other comparative models; the error rate is 1.9%, which is lower than the error rate of other comparative models; the computing time of the improved power network security risk evaluation model is 4.4 s, which is lower than the computing time of other comparative models; and its expert score is high. These findings are supported by empirical analysis of the improved power network security risk evaluation model proposed in the study. According to the study's findings, the fusion algorithm and the upgraded power network security risk evaluation model outperform other approaches in terms of accuracy and processing speed. This allows the study's maintenance staff to better meet the needs of the community by assisting them in identifying potential security hazards early on and taking the necessary preventative and remedial action to ensure the power system's continued safe operation.
Detection of pit and fissure sealant microleakage using quantitative light-induced fluorescence technology: an in vitro study
Authors: Nam Sang-Mi , Ku Hye-Min , Lee Eun-Song , Kim Baek-Il 
Published: April 2024

AbstractThis in vitro study aimed to evaluate the feasibility of quantitative light-induced fluorescence (QLF) technology for detecting the presence and severity of microleakage of pit and fissure sealants. The areas of interest (AOIs) were 160 pits and fissures of 40 extracted permanent teeth. Fluorescent images were acquired using a QLF device, and the maximum fluorescence loss ΔFmax of each AOI was analyzed. After staining and cross-sectioning of the teeth, histological dye penetration was scored on a scale of 0 to 3. The relationship between ΔFmax and microleakage depth was analyzed, and the areas under the curve (AUCs) were calculated. The │ΔFmax│ increased as microleakage depth increased. The ΔFmax values of microleakage areas showed a strong significant correlation with the histological scores of dye penetration (r = − 0.72, P = 0.001). AUC analysis showed a high diagnostic accuracy for microleakage depth (AUC = 0.83–0.91). The highest AUC of 0.91 was found when differentiating the outer half microleakage of the sealant (histological score 0 vs. 1–3). QLF technology is effective in assessing the presence and severity of microleakage, suggesting its potential for noninvasive detection and monitoring of sealant microleakage in clinical settings.
The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience
Authors: Singh Jagdev , Hunt Sharon , Simonds Sharon , Boyton Christie , Middleton Anna , Elias Matthew , Towns Susan , Pandit Chetan , Robinson Paul , Fitzgerald Dominic A. , Selvadurai Hiran 
Published: April 2024

AbstractThe impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [− 3.86% (95% CI − 5.28–2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [− 3.46% (95% CI − 4.95–1.96)] and Pseudomonas aeruginosa [− 2.80%95% CI (− 4.26–1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (− 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.
Experimental test and mechanism analysis of soil crust erosion resistance of rammed earth Great Wall in rainy season
Authors: Liu Liang , Zhang Yun , Guo Lianjun , Cao Haiying , Dai Zhenwei , Zhao Zhiyong , Guo Ying , Li Dongdong , Zheng Lingling , Li Tianli 
Published: April 2024

AbstractRammed earth is a kind of cleaning material, widely used in all kinds of buildings in the world. The Great Wall of ancient China is a typical world cultural site built from rammed earth. The rammed earth Great Wall of Shanhaiguan is close to Bohai Bay, which has suffered from long-term erosion by rain, causing a series of problems such as soil loss, collapse and gully flushing. The protection materials of the rammed earth site have always puzzled scholars. However, during the rainy season, it was found that some of the walls at Xiaowan Gouge and Nantuzhuang Gouge in the Shanhaiguan Great Wall had unwashed traces, the soil surface of the walls was intact, and the anti-erosion ability of the walls was significantly higher than that of other places. In order to explore the reasons for its strong anti-erosion ability in the natural state of rammed earth wall, guide the protection of rammed earth Great Wall, and carry out different experimental tests to explore its anti-erosion reasons and internal mechanisms. Firstly, the characteristics of rammed soil were understood through the composition test of rammed soil, and the indoor and outdoor erosion test was carried out to determine that the anti-erosion reason was the protection of gray-green soil crust. The property and composition of soil crust were determined through the immersion test and genome sequencing. Finally, the protection mechanism of soil crust was analyzed by scanning electron microscopy.
Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure
Authors: Stević Ivana , Janković Slobodan M. , Georgiev Andrijana Milošević , Marinković Valentina , Lakić Dragana 
Published: April 2024

AbstractSerious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients.