bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual oxidase 1 is dispensable during Mycobacterium tuberculosis infection in mice
Authors: Gupta Tuhina , Sarr Demba , Fantone Kayla , Ashtiwi Nuha Milad , Sakamoto Kaori , Quinn Frederick D. , Rada Balázs 
Published: March 2023

IntroductionMycobacterium tuberculosis (Mtb) is the primary cause of human tuberculosis (TB) and is currently the second most common cause of death due to a singleinfectious agent. The first line of defense against airborne pathogens, including Mtb, is the respiratory epithelium. One of the innate defenses used by respiratory epithelial cells to prevent microbial infection is an oxidative antimicrobial system consisting of the proteins, lactoperoxidase (LPO) and Dual oxidase 1 (Duox1), the thiocyanate anion (SCN-) and hydrogen peroxide (H2O2), which together lead to the generation of antimicrobial hypothiocyanite (OSCN-) in the airway lumen. OSCN- kills bacteria and viruses in vitro, but the role of this Duox1-based system in bacterial infections in vivo remains largely unknown. The goal of this study was to assess whether Duox1 contributes to the immune response against the unique respiratory pathogen, Mtb.MethodsDuox1-deficient (Duox1 KO) and wild-type (WT) mice were infected with Mtb aerosols and bacterial titers, lung pathology, cytokines and immune cell recruitment were assessed.Results and discussionMtb titers in the lung, spleen and liver were not different 30 days after infection between WT and Duox1 KO mice. Duox1 did not affect lung histology assessed at days 0, 30, and 90 post-Mtb infection. Mtb-infected Duox1 KO animals exhibited enhanced production of certain cytokines and chemokines in the airway; however, this response was not associated with significantly higher numbers of macrophages or neutrophils in the lung. B cell numbers were lower, while apoptosis was higher in the pulmonary lesions of Mtb-infected Duox1 KO mice compared to infected WT animals. Taken together, these data demonstrate that while Duox1 might influence leukocyte recruitment to inflammatory cell aggregates, Duox1 is dispensable for the overall clinical course of Mtb lung infection in a mouse model.
Characteristics of humoral and cellular responses to coronavirus disease 2019 (COVID-19) inactivated vaccine in central China: A prospective, multicenter, longitudinal study
Authors: Yuan Youhua , Xu Junhong , Ma Bing , Chen Guohua , Wang Zhibin , Wang Shanmei , Jing Nan , Zhang Jiangfeng , Wang Baoya , Yan Wenjuan , Zhang Qi , Zhao Qiongrui , Li Yi 
Published: March 2023

IntroductionIn China, the long-term immunogenicity and adverse effects of inactivated vaccines produced by different or the same manufacturer remain unclear. Therefore, the objective of this study was to evaluate the cellular immune responses and neutralizing antibody kinetics of homologous and heterologous administrations of an inactivated coronavirus disease 2019 (COVID-19) vaccine 240 days after the second vaccination.MethodsThis prospective, multicenter, observational, longitudinal study involved 595 participants with a negative SARS-CoV-2 polymerase chain reaction result who were serologically tested and followed for 8 months after vaccination. Neutralizing antibodies, interferon-gamma (IFN-γ), interleukin (IL)-6, CD4+ T-lymphocyte, and B-lymphocyte counts were evaluated in serum samples after stimulation with 2 μg/mL SARS-CoV-2 spike protein for 16 h at follow-up intervals of 2 months.ResultsMost participants [582/595; 146 male participants, 449 female participants; mean age 35 (26–50 years)] rapidly developed neutralizing antibodies after two doses of the vaccine administered 3-weeks apart. The positive rate of neutralizing antibodies peaked at 97.7% at 60–90 days, decreased, and stabilized at 82.9% at 181–240 days post-vaccination. Lower antibody concentrations were correlated with older age, longer duration after vaccination, non-health care workers, mixed-manufacturer vaccinations, and intervals of less than 40 days between two doses of vaccination, whereas lower IFN-γ levels and B-lymphocyte counts were associated with older age, blood type A, and non-health care workers. A higher IL-6 level was associated with older age, mixed-manufacturer vaccinations, intervals of less than 40 days between two doses of vaccination, and medical staff. Adverse reactions were mild or moderate and self-limited, with no serious events reported.DiscussionTwo doses of the Chinese inactivated vaccine induced robust and rapid antibody expression and cellular immune responses. Boosting vaccination is considered important, as antibodies and cellular immune responses were reduced in susceptible populations.
Intra-articular delivery of AAV vectors encoding PD-L1 attenuates joint inflammation and tissue damage in a mouse model of rheumatoid arthritis
Authors: Li Wenjun , Sun Junjiang , Feng Susi Liu , Wang Feng , Miao Michael Z. , Wu Eveline Y. , Wallet Shannon , Loeser Richard , Li Chengwen 
Published: March 2023

ObjectiveRheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model.MethodsMice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21.ResultsAfter administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (P&lt;0.05). The levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-17 and TNFα, were lower in AAV5/PD-L1 treated than untreated joints (P&lt;0.05). Furthermore, the administration of AAV5/PD-L1 vectors into the joints of CIA mice did not impact serum cytokine levels and the antibody titers to type II collagen. Biodistribution of AAV vectors after intra-articular injection showed undetectable AAV genomes in other tissues except for a low level in the liver. Similar to the results of AAV5/PD-L1 vector administration on day 0, decreased joint swelling and lower histopathological damage were observed in joints treated with AAV5/PD-L1 vectors on day 21.ConclusionThe results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways.
Deciphering comprehensive features of tumor microenvironment controlled by chromatin regulators to predict prognosis and guide therapies in uterine corpus endometrial carcinoma
Authors: Wu Qihui , Tian Ruotong , Liu Jiaxin , Ou Chunlin , Li Yimin , Fu Xiaodan 
Published: March 2023

BackgroundDysregulation of chromatin regulators (CRs) can perturb the tumor immune microenvironment, but the underlying mechanism remains unclear. We focused on uterine corpus endometrial carcinoma (UCEC) and used gene expression data from TCGA-UCEC to investigate this mechanism.MethodsWe used weighted gene co-expression network analysis (WGCNA) and consensus clustering algorithm to classify UCEC patients into Cluster_L and Cluster_H. TME-associated CRs were identified using WGCNA and differential gene expression analysis. A CR risk score (CRRS) was constructed using univariate Cox and LASSO-Cox regression analyses. A nomogram was developed based on CRRS and clinicopathologic factors to predict patients' prognosis.ResultsLower CRRS was associated with lower grade, more benign molecular subtypes, and improved survival. Patients with low CRRS showed abundant immune infiltration, a higher mutation burden, fewer CNVs, and better response to immunotherapy. Moreover, low CRRS patients were more sensitive to 24 chemotherapeutic agents.ConclusionA comprehensive assessment of CRRS could identify immune activation and improve the efficacy of UCEC treatments.
Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer
Authors: Yang Hao , Zou Xiaoming , Yang Shifeng , Zhang Ange , Li Nana , Ma Zhen 
Published: March 2023

BackgroundThe epigenetic regulatory chemical lactate is a product of glycolysis. It can regulate gene expression through histone lactylation, thereby promoting tumor proliferation, metastasis, and immunosuppression.MethodsIn this study, a lactylation-related model for gastric cancer (GC) was constructed, and its relationships to prognosis, immune cell infiltration, and immunotherapy were investigated. By contrasting normal tissues and tumor tissues, four lactylation-related pathways that were substantially expressed in GC tissues were found in the GSEA database. Six lactylation-related genes were screened for bioinformatic analysis. The GC data sets from the TCGA and GEO databases were downloaded and integrated to perform cluster analysis, and the lactylation related model was constructed by secondary clustering.ResultsThe fingding demonstrated that the lactylation score has a strong correlation with the overall survival rate from GC and the progression of GC. Mechanistic experiments showed that abundant immune cell infiltration (macrophages showed the highest degree of infiltration) and increased genetic instability are traits of high lactylation scores. Immune checkpoint inhibitors (ICIs) demonstrated a reduced response rate in GC with high lactylation scores. At the same time, tumors with high lactylation scores had high Tumor Immune Dysfunction and Exclusion scores, which means that they had a higher risk of immune evasion and dysfunction.DiscussionThese findings indicate that the lactylation score can be used to predict the malignant progression and immune evasion of GC. This model also can guide the treatment response to ICIs of GC. The constructed model of the lactate gene is also expected to become a potential therapeutic target for GC and diagnostic marker.
Untargeted analysis in post-COVID-19 patients reveals dysregulated lipid pathways two years after recovery
Authors: López-Hernández Yamilé , Oropeza-Valdez Juan José , García Lopez David Alejandro , Borrego Juan Carlos , Murgu Michel , Valdez Jorge , López Jesús Adrián , Monárrez-Espino Joel 
Published: March 2023

Introduction: Similar to what it has been reported with preceding viral epidemics (such as MERS, SARS, or influenza), SARS-CoV-2 infection is also affecting the human immunometabolism with long-term consequences. Even with underreporting, an accumulated of almost 650 million people have been infected and 620 million recovered since the start of the pandemic; therefore, the impact of these long-term consequences in the world population could be significant. Recently, the World Health Organization recognized the post-COVID syndrome as a new entity, and guidelines are being established to manage and treat this new condition. However, there is still uncertainty about the molecular mechanisms behind the large number of symptoms reported worldwide.Aims and Methods: In this study we aimed to evaluate the clinical and lipidomic profiles (using non-targeted lipidomics) of recovered patients who had a mild and severe COVID-19 infection (acute phase, first epidemic wave); the assessment was made two years after the initial infection.Results: Fatigue (59%) and musculoskeletal (50%) symptoms as the most relevant and persistent. Functional analyses revealed that sterols, bile acids, isoprenoids, and fatty esters were the predicted metabolic pathways affected in both COVID-19 and post-COVID-19 patients. Principal Component Analysis showed differences between study groups. Several species of phosphatidylcholines and sphingomyelins were identified and expressed in higher levels in post-COVID-19 patients compared to controls. The paired analysis (comparing patients with an active infection and 2 years after recovery) show 170 dysregulated features. The relationship of such metabolic dysregulations with the clinical symptoms, point to the importance of developing diagnostic and therapeuthic markers based on cell signaling pathways.
Comparative efficacy and safety of antidepressant therapy for the agitation of dementia: A systematic review and network meta-analysis
Authors: Chen Kaili , Li Haiqi , Yang Le , Jiang Yan , Wang Qiaoli , Zhang Jiao , He Jinting 
Published: March 2023

BackgroundDementia is a clinical syndrome commonly seen in the elderly individuals. With the prevalence of dementia, the incidence of neuropsychiatric symptoms in dementia patients is increasing annually. Agitation, as one of the neuropsychiatric symptoms, has a serious impact on the quality of life of patients with dementia. Several antidepressant drugs have been shown to be effective for treating agitated behavior symptoms in patients with dementia, but there are no direct comparisons among those drugs. Therefore, we carried out a network meta-analysis (NMA) to examine the efficacy and safety of those antidepressant drugs.MethodsWe searched eight databases (PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, China National Knowledge Infrastructure, VIP Database and China biomedical literature service) from their inception to 6 November 2022. Randomized controlled trials (RCTs) reporting the efficacy and safety of antidepressant drugs in treating agitated behavior symptoms in patients with dementia were included in our analysis. The quality assessment was carried out by two researchers individually and the analysis was based on the frequency method.ResultsTwelve articles with 1,146 participants were included in our analysis. Based on the outcome of the agitation score, treatment with citalopram (standardized mean difference, SMD = −0.44, 95% confidence interval, 95% CI = −0.72 to −0.16) showed significant benefits over the placebo group. Treatment with trazodone (odds ratio, OR = 4.58, 95% CI = 1.12–18.69) was associated with a higher risk of total adverse events compared with a placebo treatment.ConclusionAmong the antidepressant drugs included in this study, treatment with citalopram was probably the only optimal intervention, when considering the improvement from baseline to the end of the intervention, and there was not a statistically significant difference in safety when compared with a placebo treatment.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, identifier: PROSPERO, CRD42022320932.
The diagnostic significance of cerebrospinal fluid cytology and circulating tumor DNA in meningeal carcinomatosis
Authors: Di Wei-Ying , Chen Ya-Nan , Cai Yun , Geng Qiang , Tan Yan-Li , Li Chun-Hui , Wang Ya-Nan , Shang Yan-Hong , Fang Chuan , Cheng Shu-Jie 
Published: March 2023

ObjectiveThe objective of this research is to investigate the clinical application value of cerebrospinal fluid (CSF) cytology and circulating tumor DNA (ctDNA) in lung adenocarcinoma (LUAD) meningeal metastasis-meningeal carcinomatosis (MC), and to further explore the possible molecular mechanisms and drug treatment targets of LUAD meningeal metastasis by next-generation sequencing (NGS).MethodsWe retrospectively analyzed LUAD with MC in 52 patients. CSF cytology was carried out using the slide centrifugation precipitation method and May-Grüwald-Giemsa (MGG) staining. Tumor tissue, plasma and CSF ctDNA of some MC patients were detected by NGS.ResultsOf the 52 MC patients, 46 (88.46%) were positive for CSF cytology and 34 (65.38%) were positive for imaging, with statistically significant differences in diagnostic positivity (P &lt; 0.05). In 32 of these patients, CSF cytology, cerebrospinal fluid ctDNA, plasma ctDNA and MRI examination were performed simultaneously, and the positive rates were 84.38, 100, 56.25, and 62.50% respectively, the difference was statistically significant (P &lt; 0.001). Analysis of the NGS profiles of tumor tissues, plasma and CSF of 12 MC patients: the mutated gene with the highest detection rate was epidermal growth factor receptor (EGFR) and the detection rate were 100, 58.33, and 100% respectively in tumor tissues, plasma and CSF, and there were 6 cases of concordance between plasma and tissue EGFR mutation sites, with a concordance rate of 50.00%, and 12 cases of concordance between CSF and tissue EGFR mutation sites, with a concordance rate of 100%. In addition, mutations not found in tissue or plasma were detected in CSF: FH mutation, SETD2 mutation, WT1 mutation, CDKN2A mutation, CDKN2B mutation, and multiple copy number variants (CNV), with the most detected being CDKN2A mutation and MET amplification.ConclusionCSF cytology is more sensitive than traditional imaging in the diagnosis of meningeal carcinomatosis and has significant advantages in the early screening and diagnosis of MC patients. CSF ctDNA can be used as a complementary diagnostic method to negative results of CSF cytology and MRI, and CSF ctDNA can be used as an important method for liquid biopsy of patients with MC, which has important clinical significance in revealing the possible molecular mechanisms and drug treatment targets of meningeal metastasis of LUAD.
Sex-dependent association analysis between serum uric acid and spontaneous hemorrhagic transformation in patients with ischemic stroke
Authors: Tang Ye , Liu Ming-Su , Fu Chong , Li Guang-Qin 
Published: March 2023

ObjectiveThe association between serum uric acid (UA) and spontaneous hemorrhagic transformation (HT) has been seldom studied, and the role of UA in spontaneous HT remains unclear. This study aims to investigate the sex-dependent association between UA and spontaneous HT in patients with ischemic stroke.MethodWe retrospectively included patients with ischemic stroke in a tertiary academic hospital between December 2016 and May 2020. Patients were included if they presented within 24 h after the onset of symptoms and did not receive reperfusion therapy. Spontaneous HT was determined by an independent evaluation of neuroimaging by three trained neurologists who were blinded to clinical data. A univariate analysis was performed to identify factors related to spontaneous HT. Four logistic regression models were established to adjust each factor and assess the association between UA and spontaneous HT.ResultsA total of 769 patients were enrolled (64.6% were male patients and 3.9% had HT). After adjusting the confounders with a P &lt; 0.05 (model A) in the univariate analysis, the ratio of UA and its interquartile range (RUI) was independently associated with spontaneous HT in male patients (OR: 1.85; 95% CI: 1.07–3.19; P = 0.028), but not in female patients (OR: 1.39; 95% CI: 0.28–6.82; P = 0.685). In models B–D, the results remain consistent with model A after the adjustment for other potential confounders.ConclusionsHigher serum UA was independently associated with a higher occurrence of spontaneous HT in male patients who were admitted within 24 h after the stroke onset without receiving reperfusion therapy.
A quantitative study of the effect of ICL orientation selection on post-operative vault and model-assisted vault prediction
Authors: Zhang Weijie , Li Fang , Li Lin , Zhang Jing 
Published: March 2023

BackgroundAppropriate vault height of implantable collamer lens (ICL) implantation matters for it has risks of corneal endothelial cell loss, cataract formation and intraocular pressure elevation, which could lead to irreversible damage to optic nerve. Therefore, pre-operative prediction for an ideal vault height is a hotspot. However, few data exist regarding quantitative effect of ICL orientation on vault height. This study is aimed to quantitatively investigate the effect of ICL implantation orientation on vault height, and built a machine-learning (ML)-based vault prediction model taking implantation orientation into account.Methods473 consecutive case series treated with ICL implantation were retrospectively analyzed (408 were horizontally implanted, and 65 were vertically implanted). Multivariable logistic regression analysis was performed to determine the association between ICL orientation and achieved vault. ML was performed to develop a new vault height prediction model taking ICL orientation into account. Receiver operating characteristic curve (ROC) and net reclassification index (NRI) were obtained to assess the prediction ability.Results95% of all the patients achieved 20/20 uncorrected distance visual acuity (UDVA) or better. No complications including cataract formation, dispersion or optic nerve injury were observed in any cases. Sex, sphere power, cylinder power, axis, ICL size and ICL orientation were all significant risk factors associated to vault height, and age was positively co-related. Of note, ICL size and ICL orientation were the top-ranking risk factors. Comparing to conventional horizontal implantation, vertical implantation could reduce the achieved vault by 81.187 μm (p &lt; 0.001). In regarding to different ICL sizes, vertical implantation had no good to vault reduction when using ICL of 12.1 mm. However, it could reduce the vault by 59.351 μm and 160.992 μm respectively when ICL of 12.6mm and 13.2 mm were implanted (p = 0.0097 and p = 0.0124). For prediction of vault height, ML based model significantly outperformed traditional multivariable regression model.ConclusionWe provide quantitative evidence that vertical implantation of ICL could effectively reduce the achieved vault height, especially when large size ICL was implanted, comparing to traditional horizontal implantation. ML is extremely applicable in development of vault prediction model.
Discovery of novel acetylcholinesterase inhibitors through integration of machine learning with genetic algorithm based in silico screening approaches
Authors: Khan Mohd Imran , Taehwan Park , Cho Yunseong , Scotti Marcus , Priscila Barros de Menezes Renata , Husain Fohad Mabood , Alomar Suliman Yousef , Baig Mohammad Hassan , Dong Jae-June 
Published: March 2023

IntroductionAlzheimer’s disease (AD) is the most studied progressive eurodegenerative disorder, affecting 40–50 million of the global population. This progressive neurodegenerative disease is marked by gradual and irreversible declines in cognitive functions. The unavailability of therapeutic drug candidates restricting/reversing the progression of this dementia has severed the existing challenge. The development of acetylcholinesterase (AChE) inhibitors retains a great research focus for the discovery of an anti-Alzheimer drug.Materials and methodsThis study focused on finding AChE inhibitors by applying the machine learning (ML) predictive modeling approach, which is an integral part of the current drug discovery process. In this study, we have extensively utilized ML and other in silico approaches to search for an effective lead molecule against AChE.Result and discussionThe output of this study helped us to identify some promising AChE inhibitors. The selected compounds performed well at different levels of analysis and may provide a possible pathway for the future design of potent AChE inhibitors.