bluuebunny/crossref_metadata_2025_split huggingface dataset:
Azilsartan inhibits inflammation-triggered bone resorption and osteoclastogenesis in vivo via suppression of TNF-α expression in macrophages
Authors: Fan Ziqiu , Kitaura Hideki , Ren Jiayi , Ohori Fumitoshi , Noguchi Takahiro , Marahleh Aseel , Ma Jinghan , Kanou Kayoko , Miura Mariko , Narita Kohei , Lin Angyi , Mizoguchi Itaru 
Published: September 2023

IntroductionHypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo.MethodsIn vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted.ResultsAzilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group.ConclusionThese findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo.
Research status, development trends, and the prospects of cultivated land risk
Authors: Zhao Zhenting , Lei Ming , Wen Liangyou , Xie Enyi , Kong Xiangbin 
Published: September 2023

Cultivated land risk poses a critical threat to food security, and managing it is crucial for sustainable land use. To effectively manage this risk, it is essential to identify different types of cultivated land risk, understand their development trends, and research hotspots. This review constructs a comprehensive search strategy for subject terms in CiteSpace to analyze 12,581 literature sources related to cultivated land risk. Through tracking hot spots in cultivated land risk research, we have identified two main phases over the past 20 years. The first phase (2002–2015) focused on exploring various types of cultivated land risk, including soil, nitrogen, sewage sludge, organic matter, and carbon sequestration. Three keywords:soil, nitrogen, and sewage sludge were studied extensively during this period, with research on agricultural intensification, transport conservation, all aimed at enhancing the theoretical framework concerning cultivated land risk. The second phase (2015–2022) emphasized in-depth research into the mechanisms behind the generation of cultivated land risk. Key topics included methods and models for cultivated land risk research, source analysis, and source apportionment, as well as potentially toxic element and random forest analyses. This phase saw a shift towards a more comprehensive understanding of cultivated land risk, with a focus on uncovering underlying causes and developing effective mitigation strategies. Our research has identified three pivotal steps aimed at reducing cultivated land risk: 1) Rigorous Land Use Management: Implement stringent land use regulations to safeguard high-quality land resources. 2) Sustainable Agricultural Practices: Curtail the utilization of chemical fertilizers and pesticides, fostering improved soil fertility and minimizing environmental repercussions. 3) Robust Environmental Oversight: Establish a robust monitoring network to consistently track environmental concerns, concurrently encouraging the adoption of eco-friendly farming techniques. This comprehensive review holds substantial theoretical significance in advancing the agenda of sustainable cultivated land management and effectively alleviating the perils linked with land use alterations.
Mitochondrial DNA heteroplasmy analysis in keratoconus patients from China
Authors: Xu Liyan , Yang Kaili , Fan Qi , Gu Yuwei , Ren Shengwei 
Published: September 2023

Background: Mitochondrial DNA (mtDNA) variants have been implicated in keratoconus (KC). The present study aimed to characterize the mtDNA heteroplasmy profile in KC and explore the association of mitochondrial heteroplasmic levels with KC.Methods: Mitochondrial sequencing of peripheral blood samples and corneal tomography were conducted in 300 KC cases and 300 matched controls. The number of heteroplasmic and homoplasmic variants was calculated across the mitochondrial genome. Spearman’s correlation was used to analyze the correlation between the number of heteroplasmic variants and age. The association of mtDNA heteroplasmic level with KC was analyzed by logistic regression analysis. Moreover, the relationship between mitochondrial heteroplasmic levels and clinical parameters was determined by linear regression analysis.Results: The distribution of mtDNA heteroplasmic variants showed the highest number of heteroplasmic variants in the non-coding region, while the COX3 gene exhibited the highest number in protein-coding genes. Comparisons of the number of heteroplasmic and homoplasmic non-synonymous variants in protein-coding genes revealed no significant differences between KC cases and controls (all p &gt; 0.05). In addition, the number of heteroplasmic variants was positively associated with age in all subjects (r = 0.085, p = 0.037). The logistic regression analyses indicated that the heteroplasmic levels of m.16180_16181delAA was associated with KC (p &lt; 0.005). Linear regression analyses demonstrated that the heteroplasmic levels of m.16180_16181delAA and m.302A&gt;C were not correlated with thinnest corneal thickness (TCT), steep keratometry (Ks), and flat keratometry (Kf) (all p &gt; 0.05) in KC cases and controls separately.Conclusion: The current study characterized the mtDNA heteroplasmy profile in KC, and revealed that the heteroplasmic levels of m.16180_16181delAA were associated with KC.
The history and evolution of HLA typing external proficiency testing schemes in UK NEQAS for H&I
Authors: De’Ath A. , Rees M. T. , Pritchard D. 
Published: September 2023

The UK National External Quality Assessment Service (NEQAS) provide an external proficiency testing (EPT) service for clinical laboratories. UK NEQAS for Histocompatibility and Immunogenetics (H&amp;I) has been providing EPT schemes for over 45 years and has grown during this time to provide 19 EPT schemes. Accurate human leucocyte antigen (HLA) typing is critical to support safe clinical services, including transplantation, therefore high quality, relevant EPT schemes are required as part of a laboratory’s quality assurance. This article reviews the development of the HLA typing EPT schemes, from the first HLA phenotyping scheme in 1975, via the first HLA genotyping scheme in 1992, through to the introduction in 2017 of HLA third field assessment results from next-generation sequencing technology. In addition, the introduction of EPT schemes to cover HLA associated diseases and pharmacogenetic reactions, including HLA-B27, HLA*B*57:01 and HLA-DQ for coeliac disease are discussed. The accuracy of laboratory EPT results for HLA phenotyping are &gt;96% (2018–2022), HLA genotyping &gt;99% (2020–2022), HLA-B27 testing &gt;99% (2018–2022) and B*57:01 testing &gt;99% (2017–2022). However, for HLA genotyping for coeliac disease 22%–46% of laboratories made errors in 2020–2022. On investigation, the high rate of unsatisfactory performance was attributed to laboratories lacking specific knowledge to interpret HLA genotyping results and accurately report HLA types for coeliac disease. A misleading commercial kit insert was also identified. The assessment of scheme results has uncovered several issues which have been addressed with the intention of educating participants and improving clinical services. The UK NEQAS for H&amp;I EPT schemes have evolved over the past four decades to reflect changes in HLA typing technology, laboratory clinical practice and to cover post-analytical interpretative elements of HLA typing.
Safety and immunogenicity of a modified Omicron-adapted inactivated vaccine in healthy adults: a randomized, double-blind, active-controlled Phase III clinical trial
Authors: Hu Jialei , Liu Yueyue , Liu Shuo , Shu Qun , Yang Xuenan , Chu Kai , Qiao Yaping , Hu Yaling , Wang Kaiqin , Pan Hongxing 
Published: September 2023

BackgroundUpdated vaccine strategies are needed to protect against new SARS-CoV-2 variants with increased immune escape. Here, information on the safety and immunogenicity of an inactivated Omicron-adapted vaccine is presented, as compared with CoronaVac.MethodsA randomized, double-blind, active-controlled, phase III clinical trial was conducted to compare a modified Omicron-adapted vaccine (Omicron vaccine) with the authorized prototype vaccine (CoronaVac®) as a booster dose. Healthy adults aged ≥18 years, who have previously received 2 or 3 doses of CoronaVac (2C or 3C cohort) at least 6 months before, were enrolled to get a booster dose of Omicron vaccine or CoronaVac in a ratio of 2:1 (2C/3C+1O/1C). Back-up serums after two initial doses of CoronaVac (2C+0) for adults aged 26-45 years were collected from a previous study. Immunogenicity and safety data at 28 days after vaccination were collected and analyzed. One of the primary objectives was to evaluate the superiority of immunogenicity of Omicron vaccine booster against Omicron BA.1, compared with CoronaVac booster against BA.1. Another objective was to evaluate the non-inferiority of immunogenicity of Omicron vaccine booster against BA.1, compared with two initial doses of CoronaVac against ancestral strain.ResultsBetween June 1st and July 21st, 2022, a total of 1,500 healthy adults were enrolled. Results show that all pre-specified superiority criteria for BA.1 neutralizing antibody were met. Specifically, within the 3C cohort (3C+1O vs. 3C+1C), the geometric mean titers’ (GMT) ratio and 95% confidence interval (CI) was 1.64 (1.42, 1.89), with the lower 95%CI ≥1; a GMT ratio of 1.84 (1.57, 2.16) was observed for 2C+1O versus 3C+1C. For seroconversion rate, the lower 95%CIs of differences between immuno-comparative groups (2/3C+1O vs. 3C+1C) were all above the superiority criterion 0%. However, the non-inferiority criterion of the lower 95%CI of GMT ratio ≥2/3 was unfulfilled for 2C/3C+1O against BA.1 versus 2C+0 against ancestral strain. Safety profiles were similar between groups, with no safety concerns identified.ConclusionThe Omicron-adapted vaccine was well-tolerated and could elicit superior immune responses as compared with CoronaVac against Omicron, while it appeared inferior to CoronaVac against ancestral strain.Clinical trial registrationhttps://classic.clinicaltrials.gov/ct2/show/NCT05381350?term=NCT05381350&amp;draw=2&amp;rank=1, identifier NCT05381350.
Deciphering the immunological and prognostic features of bladder cancer through platinum-resistance-related genes analysis and identifying potential therapeutic target P4HB
Authors: Xiong Situ , Li Sheng , Zeng Jin , Nie Jianqiang , Liu Taobin , Liu Xiaoqiang , Chen Luyao , Fu Bin , Deng Jun , Xu Songhui 
Published: September 2023

ObjectivesTo identify the molecular subtypes and develop a scoring system for the tumor immune microenvironment (TIME) and prognostic features of bladder cancer (BLCA) based on the platinum-resistance-related (PRR) genes analysis while identifying P4HB as a potential therapeutic target.MethodsIn this study, we analyzed gene expression data and clinical information of 594 BLCA samples. We used unsupervised clustering to identify molecular subtypes based on the expression levels of PRR genes. Functional and pathway enrichment analyses were performed to understand the biological activities of these subtypes. We also assessed the TIME and developed a prognostic signature and scoring system. Moreover, we analyzed the efficacy of immune checkpoint inhibitors. Then we conducted real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) experiments to detect the expression level of prolyl 4-hydroxylase subunit beta (P4HB) in BLCA cell lines. Transfection of small interference ribonucleic acid (siRNA) was performed in 5637 and EJ cells to knock down P4HB, and the impact of P4HB on cellular functions was evaluated through wound-healing and transwell assays. Finally, siRNA transfection of P4HB was performed in the cisplatin-resistant T24 cell to assess its impact on the sensitivity of BLCA to platinum-based chemotherapy drugs.ResultsIn a cohort of 594 BLCA samples (TCGA-BLCA, n=406; GSE13507, n=188), 846 PRR-associated genes were identified by intersecting BLCA expression data from TCGA and GEO databases with the PRR genes from the HGSOC-Platinum database. Univariate Cox regression analysis revealed 264 PRR genes linked to BLCA prognosis. We identified three molecular subtypes (Cluster A-C) and the PRR scoring system based on PRR genes. Cluster C exhibited a better prognosis and lower immune cell infiltration compared to the other Clusters A and B. The high PRR score group was significantly associated with an immunosuppressive tumor microenvironment, poor clinical-pathological features, and a poor prognosis. Furthermore, the high PRR group showed higher expression of immune checkpoint molecules and a poorer response to immune checkpoint inhibitors than the low PRR group. The key PRR gene P4HB was highly expressed in BLCA cell lines, and cellular functional experiments in vitro indicate that P4HB may be an important factor influencing BLCA migration and invasion.ConclusionOur study demonstrates that the PRR signatures are significantly associated with clinical-pathological features, the TIME, and prognostic features. The key PRR gene, P4HB, s a biomarker for the individualized treatment of BLCA patients.
Predicting potential microbe-disease associations with graph attention autoencoder, positive-unlabeled learning, and deep neural network
Authors: Peng Lihong , Huang Liangliang , Tian Geng , Wu Yan , Li Guang , Cao Jianying , Wang Peng , Li Zejun , Duan Lian 
Published: September 2023

BackgroundMicrobes have dense linkages with human diseases. Balanced microorganisms protect human body against physiological disorders while unbalanced ones may cause diseases. Thus, identification of potential associations between microbes and diseases can contribute to the diagnosis and therapy of various complex diseases. Biological experiments for microbe–disease association (MDA) prediction are expensive, time-consuming, and labor-intensive.MethodsWe developed a computational MDA prediction method called GPUDMDA by combining graph attention autoencoder, positive-unlabeled learning, and deep neural network. First, GPUDMDA computes disease similarity and microbe similarity matrices by integrating their functional similarity and Gaussian association profile kernel similarity, respectively. Next, it learns the feature representation of each microbe–disease pair using graph attention autoencoder based on the obtained disease similarity and microbe similarity matrices. Third, it selects a few reliable negative MDAs based on positive-unlabeled learning. Finally, it takes the learned MDA features and the selected negative MDAs as inputs and designed a deep neural network to predict potential MDAs.ResultsGPUDMDA was compared with four state-of-the-art MDA identification models (i.e., MNNMDA, GATMDA, LRLSHMDA, and NTSHMDA) on the HMDAD and Disbiome databases under five-fold cross validations on microbes, diseases, and microbe-disease pairs. Under the three five-fold cross validations, GPUDMDA computed the best AUCs of 0.7121, 0.9454, and 0.9501 on the HMDAD database and 0.8372, 0.8908, and 0.8948 on the Disbiome database, respectively, outperforming the other four MDA prediction methods. Asthma is the most common chronic respiratory condition and affects ~339 million people worldwide. Inflammatory bowel disease is a class of globally chronic intestinal disease widely existed in the gut and gastrointestinal tract and extraintestinal organs of patients. Particularly, inflammatory bowel disease severely affects the growth and development of children. We used the proposed GPUDMDA method and found that Enterobacter hormaechei had potential associations with both asthma and inflammatory bowel disease and need further biological experimental validation.ConclusionThe proposed GPUDMDA demonstrated the powerful MDA prediction ability. We anticipate that GPUDMDA helps screen the therapeutic clues for microbe-related diseases.
Leveraging natural cognitive systems in conjunction with ResNet50-BiGRU model and attention mechanism for enhanced medical image analysis and sports injury prediction
Authors: Xiao Duo , Zhu Fei , Jiang Jian , Niu Xiaoqiang 
Published: September 2023

IntroductionIn this study, we explore the potential benefits of integrating natural cognitive systems (medical professionals' expertise) and artificial cognitive systems (deep learning models) in the realms of medical image analysis and sports injury prediction. We focus on analyzing medical images of athletes to gain valuable insights into their health status.MethodsTo synergize the strengths of both natural and artificial cognitive systems, we employ the ResNet50-BiGRU model and introduce an attention mechanism. Our goal is to enhance the performance of medical image feature extraction and motion injury prediction. This integrated approach aims to achieve precise identification of anomalies in medical images, particularly related to muscle or bone damage.ResultsWe evaluate the effectiveness of our method on four medical image datasets, specifically pertaining to skeletal and muscle injuries. We use performance indicators such as Peak Signal-to-Noise Ratio and Structural Similarity Index, confirming the robustness of our approach in sports injury analysis.DiscussionOur research contributes significantly by providing an effective deep learning-driven method that harnesses both natural and artificial cognitive systems. By combining human expertise with advanced machine learning techniques, we offer a comprehensive understanding of athletes' health status. This approach holds potential implications for enhancing sports injury prevention, improving diagnostic accuracy, and tailoring personalized treatment plans for athletes, ultimately promoting better overall health and performance outcomes. Despite advancements in medical image analysis and sports injury prediction, existing systems often struggle to identify subtle anomalies and provide precise injury risk assessments, underscoring the necessity of a more integrated and comprehensive approach.
Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus
Authors: Renkhold Lina , Wiegmann Henning , Pfleiderer Bettina , Süer Aysenur , Zeidler Claudia , Pereira Manuel P. , Schmelz Martin , Ständer Sonja , Agelopoulos Konstantin 
Published: September 2023

BackgroundChronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch–scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification.AimThe aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli.MethodsAnalyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch.ResultsAnalysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification.ConclusionOur results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch.