bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antifungal active ingredient from the twigs and leaves of Clausena lansium Lour. Skeels (Rutaceae)
Authors: Fu Xiaoxiang , Xiao Suling , Cao Duantao , Yuan Minxuan , Xiang Miaolian , Zhou Qinghong , Huang Yingjin , Wei Hongyi , Peng Wenwen 
Published: December 2022

Two novel amides, named clauphenamides A and B, and twelve other known compounds were isolated from the twigs and leaves of Clausena lansium Lour. Skeels (Rutaceae). Their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with data reported in the literature. Clauphenamide A (1) featured in the unit of N-2-(4,8-dimethoxyfuro [2,3-b]quinolin-7-yl)vinyl, and clauphenamide B (2) was a unprecedented N-phenethyl cinnamide dimer. Other known compounds belong to pyrrolidone amides (3 and 4), furacoumarins (7–10), simple coumarins (11–14), lignan (5) and sesquiterpene (6). Compounds 5, 6, 10 and 12 were separated from the genus (Clausena) for the first time, while 13 was isolated in the species (C. lansium) for the first time. The antifungal activities of the isolated compounds were assayed. As a result, at the concentration of 100 μg/ml, compared with the control (chlorothalonil, inhibition rate of 83.67%), compounds 1 and 2 were found to exhibit moderate antifungal activity against B. dothidea with inhibition rates of 68.39% and 52.05%, respectively. Compounds 11–14 also exhibited moderate activity against B. dothidea and F. oxysporum, with inhibition rates greater than 40%. In addition, compared with the control (chlorothalonil, inhibition rate of 69.02%), compounds 11–14 showed strong antifungal activity to P. oryzae, with inhibition rates greater than 55%. Among them, compound 14 has the strongest antifungal activity against P. oryzae, and the inhibition rate (65.44%) is close to that of the control chlorothalonil. Additionally, the structure-activity relationships of the separated compounds are also discussed preliminarily in this paper.
Cardiac geometry, as assessed by cardiac magnetic resonance, can differentiate subtypes of chronic thromboembolic pulmonary vascular disease
Authors: McGettrick Michael , Dormand Helen , Brewis Melanie , Johnson Martin K. , Lang Ninian N. , Church Alistair Colin 
Published: December 2022

BackgroundVentricular septal flattening reflects RV pressure overload in pulmonary arterial hypertension. Eccentricity index (EI) and pulmonary artery distensibility (PAD) correlate with pulmonary artery pressure. We assessed the utility of these using cardiac magnetic resonance (CMR) to assess for pulmonary hypertension (PH) in patients with chronic thromboembolic disease. This may allow non-invasive differentiation between patients who have chronic thromboembolic pulmonary hypertension (CTEPH) and those with pulmonary vascular obstructions without PH at rest, known as chronic thromboembolic pulmonary disease (CTEPD).MethodsTwenty patients without resting pulmonary hypertension, including ten with chronic thromboembolic disease, and thirty patients with CTEPH were identified from a database at the Scottish Pulmonary Vascular Unit. CMR and right heart catheter had been performed within 96 h of each other. Short-axis views at the level of papillary muscles were used to assess the EI at end-systole and diastole. Pulmonary artery distensibility was calculated using velocity-encoded images attained perpendicular to the main trunk.ResultsEccentricity index at end-systole and end-diastole were higher in CTEPH compared to controls (1.3 ± 0.5 vs. 1.0 ± 0.01; p ≤ 0.01 and (1.22 ± 0.2 vs. 0.98 ± 0.01; p ≤ 0.01, respectively) and compared to those with CTED. PAD was significantly lower in CTEPH compared to controls (0.13 ± 0.1 vs. 0.46 ± 0.23; p ≤ 0.01) and compared to CTED. End-systolic EI and end-diastolic EI correlated with pulmonary vascular hemodynamic indices and exercise variables, including mean pulmonary arterial pressure (R0.74 and 0.75, respectively), cardiac output (R-value −0.4 and −0.4, respectively) NTproBNP (R-value 0.3 and 0.3, respectively) and 6-min walk distance (R-value −0.7 and −0.8 respectively). Pulmonary artery distensibility also correlated with 6-min walk distance (R-value 0.8).ConclusionEccentricity index and pulmonary artery distensibility can detect the presence of pulmonary hypertension in chronic thromboembolic disease and differentiate between CTEPH and CTED subgroups. These measures support the use of non-invasive tests including CMR for the detection pulmonary hypertension and may reduce the requirement for right heart catheterization.
Heterogeneous circulating miRNA profiles of PBMAH
Authors: Hara Kazunari , Murakami Masanori , Niitsu Yoshihiro , Takeuchi Akira , Horino Masato , Shiba Kumiko , Tsujimoto Kazutaka , Komiya Chikara , Ikeda Kenji , Tsuiki Mika , Tanabe Akiyo , Tanaka Toshihiro , Yokoyama Minato , Fujii Yasuhisa , Naruse Mitsuhide , Yamada Tetsuya 
Published: December 2022

ObjectivePrimary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of Cushing syndrome, is often diagnosed as a bilateral adrenal incidentaloma with subclinical cortisol production. Circulating microRNAs (miRNAs) are a characteristic of adrenocortical adenomas, but miRNA expression in PBMAH has not been investigated. We aimed to evaluate the circulating miRNA expression in patients with PBMAH and compare them with those in patients with non-functioning adrenocortical adenoma (NFA) and cortisol-producing adrenocortical adenoma (CPA).MethodsmiRNA profiling of plasma samples from four, five, and five patients with NFA, CPA, and PBMAH, respectively, was performed. Selected miRNA expressions were validated using quantitative RT-PCR.ResultsPBMAH samples showed distinct miRNA expression signatures on hierarchical clustering while NFA and CPA samples were separately clustered. PBMAH was distinguished from the adenoma group of NFA and CPA by 135 differentially expressed miRNAs. Hsa-miR-1180-3p, hsa-miR-4732-5p, and hsa-let-7b-5p were differentially expressed between PBMAH and adenoma (P = 0.019, 0.006, and 0.003, respectively). Furthermore, PBMAH could be classified into two subtypes based on miRNA profiling: subtype 1 with a similar profile to those of adenoma and subtype 2 with a distinct profile. Hsa-miR-631, hsa-miR-513b-5p, hsa-miR-6805-5p, and hsa-miR-548av-5p/548k were differentially expressed between PBMAH subtype 2 and adenoma (P = 0.027, 0.027, 0.027, and 1.53E-04, respectively), but not between PBMAH, as a whole, and adenoma.ConclusionCirculating miRNA signature was identified specific for PBMAH. The existence of subtype-based miRNA profiles may be associated with the pathophysiological heterogeneity of PBMAH.
Secondary metabolites produced by endophytic fungi, Alternaria alternata, as potential inhibitors of the human immunodeficiency virus
Authors: Nzimande Bruce , Kumalo Hezekiel M. , Ndlovu Sizwe I. , Mkhwanazi Nompumelelo P. 
Published: December 2022

Antiretroviral treatment has significantly reduced human immunodeficiency virus infection and mortality. However, the current treatment regimen is limited by adverse side effects, the emergence of drug resistance, and the inability to eliminate viral reservoirs. Here, fifteen endophytic fungi were isolated from Sclerocarya birrea and Hypoxis plants. Crude extracts of Alternaria alternata (strain ID PO4PR1, PO4PR2, and PO2PL1) of the fifteen isolate’s crude extracts showed anti-HIV-1 activity in TZM-bl cell line at inhibitory concentration (IC50) values ranging from 0.017 to 1.170 μg/ml. The three crude extracts also maintained the virus replication inhibition profile on PBMCs and CD4+ T cells at concentrations ranging from 0.3 to 50.2 ng/ml. Partial purification using the solid phase extraction and analysis with Gas Chromatography-Mass spectrophotometry showed a diverse profile. The bioactive compounds were identified based on peak area, retention time, similarity index. The major compounds from GC-MS analysis of A. Alternata revealed the existence of cyclotrisiloxane octamethyl (22.92%); Propaninitrile (16,67%); Pyrrolol[1,2-a]pyrazine-1,4-dione, hexahydro-3-(2-methyl propyl) (10.42%); Silane, diethylethoxy(2-ethoxyethyloxy) (4.17%); Coumarin, 3,4-dihydro-4,5,7-trimethyl- 4,5,7-Trimethyl-2-chromanone (13.7%) and 1,2-Cyclobutanedicarbonitrile (2.08%) with previously reported biological activities such as antimicrobial, anti-inflammatory and antioxidant properties. Therefore, these bioactive compounds from A. alternata fungal endophytes could be repurposed as potential anti-HIV agents. This study showed the potential of endophytic fungi, Alternaria alternata from S. birrea, and Hypoxis species as producers of anti-HIV compounds.
A hypoxia risk score for prognosis prediction and tumor microenvironment in adrenocortical carcinoma
Authors: Deng Yuanyuan , Li Huihuang , Fu Jinglan , Pu Ying , Zhang Ying , Chen Shijing , Tong Shiyu , Liu Huixia 
Published: December 2022

Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction.Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients.Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy.Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.
Phenotype and genotype analyses of Chinese patients with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations
Authors: Wang Yanxin , Lv Yuqiang , Li Zilong , Gao Min , Yang Xiaomeng , Li Yue , Shi Jianguo , Gao Zaifen , Liu Yi , Gai Zhongtao 
Published: December 2022

Background: Autosomal dominant mental retardation type 5 (MRD5), a rare neurodevelopmental disorder (NDD) characterized by intellectual disability (ID), developmental delay (DD), and epilepsy predominantly, is caused by a heterozygous mutation in the SYNGAP1 gene. SYNGAP1 mutations have been rarely reported in the Chinese population. Here, we present an investigation of SYNGAP1 mutations in a clinical cohort with ID and DD in Shandong, a northern province in China, to further explore the genotype and phenotype correlations.Methods: A retrospective study was conducted on 10 children with SYNGAP1 mutations presenting ID, DD, and epilepsy who were diagnosed between January 2014 and May 2022. Clinical data and genetic tests were collected. Treatment and regular follow-ups were carried out to pay close attention to the prognosis of the patients.Results: We described 10 unrelated affected individuals with SYNGAP1 mutations, displaying ID, DD, epilepsy, or seizures. All mutations of SYNGAP1 in the 10 patients were de novo, except patient 3 whose father was unavailable, including five nonsense mutations, two frameshift mutations, two splicing mutations, and one codon deletion. Among these mutations, five were novel and the other five were previously reported. Significantly, all patients with epilepsy were sensitive to anti-seizure drugs, especially sodium valproate. Furthermore, rehabilitation training seemed to exert a more improved effect on motor development than language development for the patients.Conclusion The 10 patients carrying SYNGAP1 mutations were diagnosed as MRD5. Five novel genetic mutations were found, which expanded the mutational spectrum of the SYNGAP1 gene. The identification of these mutations in this study helps explore the relationship between genotypes and phenotypes and contributes to genetic counseling and therapeutic intervention for patients with MRD5.
Diagnostic gene signatures and aberrant pathway activation based on m6A methylation regulators in rheumatoid arthritis
Authors: Geng Qishun , Cao Xiaoxue , Fan Danping , Gu Xiaofeng , Zhang Qian , Zhang Mengxiao , Wang Zheng , Deng Tingting , Xiao Cheng 
Published: December 2022

PurposeRheumatoid arthritis (RA) is a chronic autoimmune disease (AD) characterized by persistent synovial inflammation, bone erosion and progressive joint destruction. This research aimed to elucidate the potential roles and molecular mechanisms of N6-methyladenosine (m6A) methylation regulators in RA.MethodsAn array of tissues from 233 RA and 126 control samples was profiled and integrated for mRNA expression analysis. Following quality control and normalization, the cohort was split into training and validation sets. Five distinct machine learning feature selection methods were applied to the training set and validated in validation sets.ResultsAmong the six models, the LASSO_λ-1se model not only performed better in the validation sets but also exhibited more stringent performance. Two m6A methylation regulators were identified as significant biomarkers by consensus feature selection from all four methods. IGF2BP3 and YTHDC2, which are differentially expressed in patients with RA and controls, were used to predict RA diagnosis with high accuracy. In addition, IGF2BP3 showed higher importance, which can regulate the G2/M transition to promote RA-FLS proliferation and affect M1 macrophage polarization.ConclusionThis consensus of multiple machine learning approaches identified two m6A methylation regulators that could distinguish patients with RA from controls. These m6A methylation regulators and their target genes may provide insight into RA pathogenesis and reveal novel disease regulators and putative drug targets.
Immune-mediated inflammatory diseases and risk of venous thromboembolism: A Mendelian randomization study
Authors: Lv Xiaoshuo , Gao Xixi , Liu Jingwen , Deng Yisen , Nie Qiangqiang , Fan Xueqiang , Ye Zhidong , Liu Peng , Wen Jianyan 
Published: December 2022

IntroductionImmune-mediated inflammatory diseases (IMIDs) have been associated with an increased risk of venous thromboembolism (VTE) in multiple observational studies. However, a direct causally relation between IMIDs and VTE remains unclear to date. Here, we used Mendelian randomization (MR) analysis to investigate causal associations between IMIDs and VTE.MethodsWe collected genetic data from published genome-wide association studies (GWAS) for six common IMIDs, specifically inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriasis (PSO), and systemic lupus erythematosus (SLE); and summary-level data for VTE, pulmonary embolism (PE), and deep vein thrombosis (DVT) from the FinnGen database. Two-sample MR analysis using inverse variance weighting (IVW) was performed to identify causal associations between IMIDs and VTE/DVT/PE, and sensitivity analyses were implemented for robustness.ResultsIVW analysis showed a causal relationship between genetically predicted UC (one type of IBD) and the risk of VTE (OR = 1.043, 95% CI: 1.013-1.073, p = 0.004) and DVT (OR = 1.088, 95% CI: 1.043-1.136, p &lt; 0.001), but we found no evidence of causality between UC and PE (OR = 1.029, 95% CI: 0.986-1.074, p = 0.19). In addition, no associations were observed between total IBD, CD, RA, SLE, or PSO and VTE/DVT/PE. Sensitivity analysis found no evidence for horizontal pleiotropy.ConclusionThis MR study provides new genetic evidence for the causal relationship between IMIDs and the risk of VTE. Our findings highlight the importance of active intervention and monitoring to mitigate VTE risk in patients with IBD, in particular those presenting with UC.
Using exergame-based exercise to prevent and postpone the loss of muscle mass, muscle strength, cognition, and functional performance among elders in rural long-term care facilities: A protocol for a randomized controlled trial
Authors: Tuan Sheng-Hui , Chang Ling-Hui , Sun Shu-Fen , Lin Ko-Long , Tsai Yi-Ju 
Published: December 2022

ObjectiveElderly individuals in long-term care facilities (LTCFs) have a higher prevalence of sarcopenia than those in the community. Exercise is the gold standard for preventing and treating sarcopenia. Regarding exercise, multicomponent exercises, including progressive resistance training (PRT), are beneficial. However, developing routine, structured exercise programs for the elderly in LTCFs is difficult because of a shortage of healthcare providers, particularly in rural regions. Exergame-based exercises can increase a player’s motivation and reduce staff time for an intervention. Nintendo Switch RingFit Adventure (RFA) is a novel exergame that combines resistance, aerobic, and balance exercises. In this study, we aim to investigate the clinical effectiveness of RFA on muscle and functional performance parameters among the elderly in LTCFs.MethodsThe EXPPLORE (using EXergame to Prevent and Postpone the LOss of muscle mass, muscle strength, and functional performance in Rural Elders) trial is a single-center randomized controlled trial involving elderly individuals (≥60 years) living in LTCFs in rural southern Taiwan. The participants will be equally randomized to the intervention group (exergame-based exercise plus standard care) or the control group (standard care alone). Both groups will receive standard care except that the intervention group will receive exergame-based exercises at the time previously scheduled for sedentary activities in the LTCFs. The exergame-based exercise will be performed using RFA in the sitting position with a specialized design, including arm fit skills and knee assist mode. Each session of the exercise lasts 30 mins and will be performed two times per week for 12 weeks. The primary outcomes will be the osteoporotic fracture index, appendicular skeletal muscle mass index, dominant handgrip strength, and gait speed. Meanwhile, the secondary outcomes will be the dexterity and agility, muscle strength and thickness, range of motion of the joints of the dominant upper extremity, Kihon checklist, Medical Outcomes Study 36-Item Short-Form Health Survey, and Brain Health Test.DiscussionThis trial will provide valuable knowledge on whether exergames using RFA can counteract physical decline and improve quality of life and cognition among the elderly in LTCFs.Clinical trial registration[www.ClinicalTrials.gov], identifier [NCT05360667].
Novel modular chimeric antigen receptor spacer for T cells derived from signal regulatory protein alpha Ig-like domains
Authors: Koski Jan , Jahan Farhana , Luostarinen Annu , Schenkwein Diana , Ylä-Herttuala Seppo , Göös Helka , Monzo Hector , Ojala Päivi M. , Maliniemi Pilvi , Korhonen Matti 
Published: December 2022

Background: T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG’s crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided.Methods: Two novel CARs targeting the CD19 antigen where the IgG1-CH2 and -CH3 domains were replaced with Ig-like domains from signal-regulatory protein α (SIRPα) were designed in silico. An IgG1-based CAR and a CAR lacking both SIRPα and IgG1 domains were used as comparators. The phenotype and memory phenotype of the expanded cells were analyzed by flow cytometry, and CAR T cell activation and cytotoxic efficacy were assessed in co-culture experiments in response to CD19+ target cells. Unwanted interactions with FcR-expressing myeloid cells were interrogated in co-culture assays with THP-1 monocytic cells.Results: T cells carrying the novel SIRPα-based CARs enacted potent in vitro cytotoxicity against CD19 positive B-lineage leukemia cells, comparable to traditional IgG1-based CAR T cells. Co-culture of IgG1-based CAR T cells with FcR-expressing THP-1 monocytic cells led to prominent cell surface expression of CD69 on T cells together with production of Interleukin (IL)-2 and Interferon-γ, and production of IL-1β, indicating activation of the T cells and monocytes, respectively. Longer co-culture led to killing of the monocytes. No signs of T cell nor monocyte activation were detected in co-cultures of SIRPα-based CAR T cells with THP-1 cells. Arming T cells with the SIRPα-based CARs favored differentiation towards CD4+ phenotype during expansion, while the effects on memory phenotype of the T cells were equivalent between the SIRPα- and IgG1-based CARs. In a pilot experiment, T cells modified with one of the SIRPα-based CARs showed dose dependent leukemia cell control.Conclusion: The novel SIRPα based spacers offer a suitable backbone for developing chimeric antigen receptors that evade the off-target binding to FcR while the cells retain a favorable memory phenotype and efficient cytotoxicity, establishing a promising candidate for future in vivo and clinical testing.
Methylmalonic acid levels in serum, exosomes, and urine and its association with cblC type methylmalonic acidemia-induced cognitive impairment
Authors: Sun Shuqi , Jin Hong , Rong Yu , Song Wenqi , Li Qiliang 
Published: December 2022

BackgroundThe cblC type methylmalonic acidemia is the most common methylmalonic acidemia (MMA) in China. The biochemical characteristics of this disease include elevated methylmalonic acid and homocysteine (HCY), increased propionylcarnitine (C3), decreased free carnitine (C0). In this study, we aimed to clarify the roles of these biomarkers in cblC-MMA induced cognitive impairment and evaluate the capacity of methylmalonic acid in different fluids or exosomes to distinguish cblC-MMA induced cognitive impairment.Methods15 non-inherited hyperhomocysteinemia (HHcy) patients, 42 cblC-MMA patients and 57 age- and sex-matched healthy children were recruited in this study. The levels of HCY were detected by an automatic immune analyzer. The levels of acylcarnitines and methylmalonic acid were detected by tandem mass spectrometer.ResultsThe main findings were all biomarkers as HCY, acylcarnitines and methylmalonic acid had capacities for distinguishing patients with cblC-MMA induced cognitive impairment from healthy children. The methylmalonic acid in different fluids or exosomes had good performances for distinguishing patients with cblC-MMA induced cognitive impairment from HHcy patients. The methylmalonic acid in serum exosomes and neuronal-derived exosomes were able to distinguishing cblC-MMA patients with cognitive impairment from patients without cognitive impairment. The methylmalonic acid in neuronal-derived exosomes might be helpful to evaluate the severity of cblC-MMA induced cognitive impairment.DiscussionMethylmalonic acid levels in serum exosomes, especially in serum neuronal-derived exosomes, serve as potential biomarkers for distinguishing cblC-MMA induced cognitive impairment.