bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy
Authors: Eschenhagen Patience N. , Bacher Petra , Grehn Claudia , Mainz Jochen G. , Scheffold Alexander , Schwarz Carsten 
Published: June 2023

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity.Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI.Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly.Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.
CL-705G: a novel chemical Kir6.2-specific KATP channel opener
Authors: Gando Ivan , Becerra Flores Manuel , Chen I.-Shan , Yang Hua-Qian , Nakamura Tomoe Y. , Cardozo Timothy J. , Coetzee William A. 
Published: June 2023

Background: KATP channels have diverse roles, including regulation of insulin secretion and blood flow, and protection against biological stress responses and are excellent therapeutic targets. Different subclasses of KATP channels exist in various tissue types due to the unique assemblies of specific pore-forming (Kir6.x) and accessory (SURx) subunits. The majority of pharmacological openers and blockers act by binding to SURx and are poorly selective against the various KATP channel subclasses.Methods and Results: We used 3D models of the Kir6.2/SUR homotetramers based on existing cryo-EM structures of channels in both the open and closed states to identify a potential agonist binding pocket in a functionally critical area of the channel. Computational docking screens of this pocket with the Chembridge Core chemical library of 492,000 drug-like compounds yielded 15 top-ranked “hits”, which were tested for activity against KATP channels using patch clamping and thallium (Tl+) flux assays with a Kir6.2/SUR2A HEK-293 stable cell line. Several of the compounds increased Tl+ fluxes. One of them (CL-705G) opened Kir6.2/SUR2A channels with a similar potency as pinacidil (EC50 of 9 µM and 11 μM, respectively). Remarkably, compound CL-705G had no or minimal effects on other Kir channels, including Kir6.1/SUR2B, Kir2.1, or Kir3.1/Kir3.4 channels, or Na+ currents of TE671 medulloblastoma cells. CL-705G activated Kir6.2Δ36 in the presence of SUR2A, but not when expressed by itself. CL-705G activated Kir6.2/SUR2A channels even after PIP2 depletion. The compound has cardioprotective effects in a cellular model of pharmacological preconditioning. It also partially rescued activity of the gating-defective Kir6.2-R301C mutant that is associated with congenital hyperinsulinism.Conclusion: CL-705G is a new Kir6.2 opener with little cross-reactivity with other channels tested, including the structurally similar Kir6.1. This, to our knowledge, is the first Kir-specific channel opener.
Oxycodone-induced dopaminergic and respiratory effects are modulated by deep brain stimulation
Authors: Yuen Jason , Goyal Abhinav , Rusheen Aaron E. , Kouzani Abbas Z. , Berk Michael , Kim Jee Hyun , Tye Susannah J. , Abulseoud Osama A. , Oesterle Tyler S. , Blaha Charles D. , Bennet Kevin E. , Lee Kendall H. , Oh Yoonbae , Shin Hojin 
Published: June 2023

Introduction: Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone.Methods: Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130 Hz, 0.2 ms, and 0.2 mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5 mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5 g/kg, i.p.).Results: I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0 nM) compared to baseline (150.7 ± 15.5 nM) and saline administration (152.0 ± 16.1 nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, p = 0.022, n = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6 min−1 vs. 67.9 ± 8.3 min−1; pre- vs. post-oxycodone; p &lt; 0.001). Continuous DBS targeted at the VTA (n = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7 min−1 vs. 105.2 ± 4.1 min−1; pre- vs. post-oxycodone; p = 0.072).Discussion: Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction.
Deciphering the role of NETosis-related signatures in the prognosis and immunotherapy of soft-tissue sarcoma using machine learning
Authors: Qi Lin , Chen Fangyue , Wang Lu , Yang Zhimin , Zhang Wenchao , Li Zhihong 
Published: June 2023

Background: Soft-tissue sarcomas (STSs) are a rare type of cancer, accounting for about 1% of all adult cancers. Treatments for STSs can be difficult to implement because of their diverse histological and molecular features, which lead to variations in tumor behavior and response to therapy. Despite the growing importance of NETosis in cancer diagnosis and treatment, researches on its role in STSs remain limited compared to other cancer types.Methods: The study thoroughly investigated NETosis-related genes (NRGs) in STSs using large cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and Support Vector Machine Recursive Feature Elimination (SVM-RFE) were employed for screening NRGs. Utilizing single-cell RNA-seq (scRNA-seq) dataset, we elucidated the expression profiles of NRGs within distinct cellular subpopulations. Several NRGs were validated by quantitative PCR (qPCR) and our proprietary sequencing data. To ascertain the impact of NRGs on the sarcoma phenotype, we conducted a series of in vitro experimental investigations. Employing unsupervised consensus clustering analysis, we established the NETosis clusters and respective NETosis subtypes. By analyzing DEGs between NETosis clusters, an NETosis scoring system was developed.Results: By comparing the outcomes obtained from LASSO regression analysis and SVM-RFE, 17 common NRGs were identified. The expression levels of the majority of NRGs exhibited notable dissimilarities between STS and normal tissues. The correlation with immune cell infiltration were demonstrated by the network comprising 17 NRGs. Patients within various NETosis clusters and subtypes exhibited different clinical and biological features. The prognostic and immune cell infiltration predictive capabilities of the scoring system were deemed efficient. Furthermore, the scoring system demonstrated potential for predicting immunotherapy response.Conclusion: The current study presents a systematic analysis of NETosis-related gene patterns in STS. The results of our study highlight the critical role NRGs play in tumor biology and the potential for personalized therapeutic approaches through the application of the NETosis score model in STS patients.
Relationship between hyperlipidemia and the risk of death in aneurysm: a cohort study on patients of different ages, genders, and aneurysm locations
Authors: Ding Dianzhu , Yang Yongbin , Jiang Guangwei , Peng Yanhui 
Published: June 2023

Aims: The study aimed to assess the association of hyperlipidemia and the risk of death in the aneurysm population, focusing on age, gender, and aneurysm location differences.Methods: All patients’ data on this retrospective cohort study were obtained from the Medical Information Mart for Intensive Care (MIMIC-III) database, and the baseline characteristics and laboratory parameters of all patients were collected. The COX regression model was established to explore the association of hyperlipidemia and the risk of death for patients with aneurysms. More importantly, subgroup analyses based on the age, gender, and aneurysm location differences were performed.Results: A total of 1,645 eligible patients were enrolled in this study. These patients were divided into the survival group (n = 1,098) and the death group (n = 547), with a total mortality rate of approximately 33.25%. The result displayed that hyperlipidemia was associated with a decreased death risk in aneurysm patients. In addition, we also found that hyperlipidemia was associated with a lower death risk of abdominal aortic aneurysm and thoracic aortic arch aneurysm among aneurysm patients aged ≥60 years; hyperlipidemia was only a protective factor for the death risk of male patients diagnosed with abdominal aortic aneurysm. For female patients diagnosed with abdominal aortic aneurysm and thoracic aortic arch aneurysm, hyperlipidemia was associated with a decreased death risk.Conclusion: The relationship of hyperlipidemia, hypercholesterolemia, and the risk of death for patients diagnosed with aneurysms was significantly associated with age, gender, and aneurysm location.
The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes
Authors: Ahmed Mohamed , Casanova Nancy G. , Zaghloul Nahla , Gupta Akash , Rodriguez Marisela , Robbins Ian R. , Kempf Carrie L. , Sun Xiaoguang , Song Jin H. , Hernon Vivian Reyes , Sammani Saad , Camp Sara M. , Moreira Alvaro , Hsu Chaur-Dong , Garcia Joe G. N. 
Published: June 2023

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes.Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb.Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a &gt; 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes.Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.
Analysis of the influences of social isolation on cognition and the therapeutic potential of deep brain stimulation in a mouse model
Authors: Hu Yun-Yun , Ding Xuan-Si , Yang Gang , Liang Xue-Song , Feng Lei , Sun Yan-Yun , Chen Rui , Ma Quan-Hong 
Published: June 2023

BackgroundSocial interaction is a fundamental human need. Social isolation (SI) can have negative effects on both emotional and cognitive function. However, it is currently unclear how age and the duration of SI affect emotion and recognition function. In addition, there is no specific treatment for the effects of SI.MethodsThe adolescence or adult mice were individually housed in cages for 1, 6 or 12 months and for 2 months to estabolish SI mouse model. We investigated the effects of SI on behavior in mice at different ages and under distinct durations of SI, and we explored the possible underlying mechanisms. Then we performed deep brain stimulation (DBS) to evaluate its influences on SI induced behavioral abnormalities.ResultsWe found that social recognition was affected in the short term, while social preference was damaged by extremely long periods of SI. In addition to affecting social memory, SI also affects emotion, short-term spatial ability and learning willingness in mice. Myelin was decreased significantly in the medial prefrontal cortex (mPFC) and dorsal hippocampus of socially isolated mice. Cellular activity in response to social stimulation in both areas was impaired by social isolation. By stimulating the mPFC using DBS, we found that DBS alleviated cellular activation disorders in the mPFC after long-term SI and improved social preference in mice.ConclusionOur results suggest that the therapeutic potential of stimulating the mPFC with DBS in individuals with social preference deficits caused by long-term social isolation, as well as the effects of DBS on the cellular activity and density of OPCs.
Associations of the perceived benefits and harms of COVID-19 with confidence in coping with the pandemic and mental health symptoms: a population-based survey in Hong Kong
Authors: Yao Ying , Gong Wei Jie , Lai Agnes Yuen Kwan , Wu Yongda Socrates , Sit Shirley Man Man , Wang Man Ping , Ho Sai Yin , Lam Tai Hing 
Published: June 2023

IntroductionBoth perceived benefits and harms of COVID-19 have been reported, but whether they affect confidence in coping with the pandemic and mental health remains uncertain.ObjectiveTo examine the association of perceived benefits and harms of COVID-19 with confidence in coping with the pandemic and mental health symptoms.MethodsA population-based survey was conducted on 7,535 Hong Kong adults from 22 February to 23 March 2021, when the 4th wave of COVID-19 was under control. Information on sociodemographic characteristics, perceived benefits (10 options) and harms (12 options) of COVID-19, confidence in coping with the pandemic (range 0–10), loneliness (range 0–4), anxiety (General Anxiety Disorders-2, range 0–6) and depression (Patient Health Questionnaire-2, range 0–6) was collected. Latent profile analysis was used to identify the combined patterns of perceived benefits and harms of COVID-19. The associations of combined patterns with confidence in coping with COVID-19, loneliness, anxiety, and depression were examined using linear regression (β coefficient) adjusting for sociodemographic characteristics.ResultsThe combined patterns of perceived benefits and harms were classified into benefit (n = 4,338, 59.3%), harm (n = 995, 14.0%), and ambivalent (n = 2,202, 26.7%) groups. Compared with the ambivalent group, the benefit group had a significantly higher level of confidence (adjusted β 0.46, 95% CI 0.33 to 0.58), and lower levels of loneliness (−0.35, −0.40 to-0.29), anxiety (−0.67, 0.76 to-0.59), and depression (−0.65, −0.73 to-0.57). The harm group had a significantly lower level of confidence (−0.35, −0.53 to-0.16), and higher levels of loneliness (0.38, 0.30 to 0.45), anxiety (0.84, 0.73 to 0.96), and depression (0.95, 0.84 to 1.07).ConclusionPerceived greater benefit from COVID-19 was associated with better mental health and stronger confidence in coping with the pandemic.
The implementation of community-based programs in Vietnam is promising in promoting health
Authors: Pardoel Zinzi E. , Reijneveld Sijmen A. , Lensink Robert , Postma Maarten , Thuy Tran B. , Viet Nga C. , Phuong Lien N. T. , Koot Jaap A. R. , Landsman Jeanet J. A. 
Published: June 2023

BackgroundLow-and middle-income countries mostly have ageing populations with many unmet economic, social, or health-related needs, Vietnam being an example. Community-based support in Vietnam, organized as Intergenerational Self-Help Clubs (ISHCs) based on the Older People Associations (OPA) model, can help to meet these needs by the provision of services for various aspects of life. This study aims to assess the implementation of the ISHCs and whether successful implementation is associated with more member-reported positive health.MethodsWe used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to evaluate the implementation using multiple data sources: ISHC board surveys (n = 97), ISHC member surveys (n = 5,080 in 2019 and n = 5,555 in 2020), focus group discussions (6; n = 44), and interviews with members and board leaders (n = 4).ResultsReach ranged between 46 and 83% of ISHCs reaching target groups, with a majority of women and older people participating. Regarding Effectiveness, members indicated high satisfaction with the ISHCs. Adoption scores were high, with 74%–99% for healthcare and community support activities, and in 2019, higher adoption scores were associated with more members reporting good positive health. In 2020, reported positive health slightly decreased, probably due to the influence of the COVID-19 pandemic. A total of 61 ISHCs had consistent or improving Implementation from 2019 to 2020, and confidence in Maintenance was high.ConclusionThe implementation of the OPA model in Vietnam is promising regarding its promotion of health and may help to tackle the needs of an ageing population. This study further shows that the RE-AIM framework helps to assess community health promotion approaches.
Trends in antimicrobial susceptibility patterns of bacterial isolates in Lahore, Pakistan
Authors: Khalid Nauman , Akbar Zunaira , Mustafa Nosheen , Akbar Jamshaid , Saeed Shanawar , Saleem Zikria 
Published: June 2023

BackgroundAntimicrobial resistance (AMR) has provoked a global health issue. Antimicrobial stewardship programs should be implemented to overcome this issue. The aim of this study was to determine the sensitivity patterns of the WHO Access, Watch, Reserve (AWaRe) group of antibiotics that assists in the selection of appropriate empiric antibiotic therapies.MethodA descriptive, cross-sectional study was conducted for 6 months, in which 422 culture sensitivity sample reports from the Ghurki Trust Teaching Hospital’s laboratory were obtained through a convenience sampling technique, and the sensitivity patterns of nine offending bacteria to the WHO AWaRe group antibiotics were determined. Descriptive statistics and differences in frequency distribution among the categorical variables were obtained using the Statistical Package for Social Sciences (SPSS) software, version 21.ResultsAmong 422 culture sensitivity sample reports,Escherichia coli(16.1%) was the most common Gram-negative pathogen.Acinetobacter, E. coli, Klebsiella, andPseudomonasshowed 100% sensitivity to polymyxin-b and colistin.Proteusshowed the highest sensitivity to meropenem (90%),Staphylococcus aureusshowed a 98% sensitivity to linezolid,Staphylococcus epidermidiswas 100% sensitive to vancomycin and linezolid, andStreptococcusshowed the highest sensitivity to penicillin (100%) and vancomycin (94.7%). Polymyxin b and colistin were found to be the most effective antibiotics against Gram-negative bacteria (100%). Gram-positive bacteria were highly sensitive to linezolid (99.4%), vancomycin (98.2%), chloramphenicol (89.5%), and tigecycline (82.6%).ConclusionCulture sensitivity reports help to rationalize the empirical use of antibiotics in clinical practice in addressing the challenge of antimicrobial resistance. This study showed that polymyxin-b and colistin were the most effective antibiotics against Gram-negative isolates and that Gram-positive bacteria were highly susceptible to linezolid. Updated antibiograms should be used by clinicians to evaluate bacterial susceptibility patterns and rationalize antibiotic empiric therapy.
Comparative Analysis of Water-Soluble Polysaccharides from Dendrobium Second Love ‘Tokimeki’ and Dendrobium nobile in Structure, Antioxidant, and Anti-Tumor Activity In Vitro
Authors: Ye Guangying , Zhang Jinhui , Xu Xiaoli , Zeng Canbiao , Ye Qingsheng , Wang Zaihua 
Published: June 2023

With potential anti-tumor and antioxidant properties, the polysaccharide content of D. nobile is relatively lower than that of the other medicinal Dendrobium. To find high-content polysaccharide resources, the polysaccharide (DHPP-Ⅰs) was prepared from D. Second Love ‘Tokimeki’ (a D. nobile hybrid) and compared with DNPP-Ⅰs from D. nobile. DHPP-Is (Mn 31.09 kDa) and DNPP-Is (Mn 46.65 kDa) were found to be O-acetylated glucomannans (-Glcp-(1,4) and O-acetylated-D-Manp-(1,4) backbones), analogous to other Dendrobium polysaccharides. DHPP-Ⅰs had higher glucose content (31.1%) and a lower degree (0.16) of acetylation than DNPP-Ⅰs (15.8%, 0.28). Meanwhile, DHPP-Ⅰs and DNPP-Ⅰs had the same ability in the radical scavenging assay, which was milder than the control of Vc. Both DHPP-Is and DNPP-Is inhibited SPC-A-1 cell proliferation in vitro, with obvious differences in dose concentrations (0.5–2.0 mg/mL) and treatment times (24–72 h). Therefore, the antioxidant activity of DHPP-Ⅰs and DNPP-Ⅰs is not associated with distinction in anti-proliferative activity. As a glucomannan derived from non-medicinal Dendrobium, DHPP-Ⅰs has similar bioactivity to other medicinal Dendrobium, and this could serve as a starting point for studying the conformational–bioactivity relationship of Dendrobium polysaccharides.