bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of the Late Jurassic-Early Cretaceous Lamprophyres in Western Songliao Basin of Northeast China and Their Constraint on Regional Lithospheric Evolution
Authors: Yu Taiji , Wang Pujun , Zhang Yan , Gao Youfeng , Chen Chongyang 
Published: June 2022

Contrary to the commonly accepted notion that the lithosphere in NE China thinned from the Late Jurassic through to the Early Cretaceous period, we report the discovery of a thickening episode in the backdrop of this long-term thinning. A series of lamprophyre dikes have been recently discovered in the Tuquan Basin of the western Songliao Basin that have been dated to 156.0 ± 2.3 Ma, 132.9 ± 1.2 Ma, and 126.2 ± 2.5 Ma by using the zircon U–Pb technique. These lamprophyres are subdivided into biotite orthoclase lamprophyre (BOL) from the Late Jurassic and quartz magnetite lamprophyre (QML) from the Early Cretaceous. The BOL and QMLs are shoshonite and calc-alkaline in series, are characterized by large amounts of FeOT, TiO2, MgO, and Mg#, and are rich in LREEs and LILEs but poor in HREEs and HFSEs. They have high ratios of (La/Yb)N, La/Ta, La/Nb, Th/Y, Ba/Nb, Ba/Ta, and Ba/Th, and low ratios of Zr/Ba, La/Sm, and Nb/Zr. These features collectively point to the derivation of dike magmas from the partial melting of the enriched lithospheric mantle that had been previously metasomatized by subduction-related fluids. The BOL has high ratios of Rb/Sr (0.42) and K/Yb*1000 (28.3), and low ratios of Ba/Rb (13.5) and Dy/Yb (2.35), suggesting the derivation of magma from a high degree of partial melting of the phlogopite-bearing lherzolite mantle in the spinel–garnet transition zone at a depth of about 60 km. The QMLs have low ratios of Rb/Sr (0.02–0.06) and K/Yb*1000 (8.13–19.73), and high ratios of Ba/Rb (17.6–42.6) and Dy/Yb (3.48–4.09), indicating that the magmas were derived from a low degree of partial melting of the lherzolite mantle in the garnet zone at a depth of ca. 85 km. The younger QML (126.2 ± 2.5 Ma) has a lower Dy/Yb ratio (3.48–3.92) than the older QML (132.9 ± 1.2 Ma), with a Dy/Yb ratio of 4.09 implying that the younger magma was formed at a shallower depth of the mantle (&lt;85 km) than the older one. These observations indicate that in 156–132 Ma, the lithosphere thickened by approximately 25 km at a rate of approximately 1.0 km/Myr. This is used to propose a model of geodynamic evolution in three stages.
Comparison of the Reproductive Outcome Between 2 and 4 mg Daily Doses of Estradiol After Hysteroscopic Adhesiolysis: A Propensity Score Matching Analysis–Retrospective Cohort Study
Authors: Qiu Dan-Er , Zhang Wan-Lin , Liu Jin , Yang Fang , Miao Ye , Tong Ya-Fei , Xiao Xi-Feng , Wang Xiao-Hong 
Published: June 2022

ObjectiveTo investigate the effect of two postoperative doses of estradiol valerate (2 and 4 mg/day) on reproductive outcomes in patients with moderate to severe intrauterine adhesions (IUAs).MethodsA retrospective cohort study was conducted at a single tertiary reproductive medical center between January 2018 and December 2019 to compare the reproductive outcomes of two doses of estradiol valerate (2 and 4 mg daily) after hysteroscopic adhesiolysis. All patients received adjuvant postoperative treatment with a Foley catheter, hyaluronic acid gel, and medication therapy. Hysteroscopy was repeated every 7 days after surgery. Multivariate regression analysis and propensity score matching (PSM) were performed to minimize intrinsic bias.ResultsA total of 212 patients with moderate to severe IUAs were included: 74 patients received 2 mg of estradiol valerate daily and 138 patients received 4 mg of estradiol daily postoperatively. No significant differences were found in the reproductive outcomes between the two groups, including clinical pregnancy rates. The multivariable regression analyses both before and after PSM also showed that there was no significant difference in the menstrual improvement and clinical pregnancy rates between the two groups.ConclusionsWe suggest the use of a lower dose (2 mg/day) of estradiol valerate as an adjuvant therapy for IUAs to minimize estrogen-related side effects.
Effect of Growth Hormone Treatment on the Concentration of Selected Metabolic Markers in Girls With Turner Syndrome
Authors: Błaszczyk Ewa , Gawlik Jakub , Gieburowska Joanna , Tokarska Agnieszka , Kimsa-Furdzik Małgorzata , Hibner Grzegorz , Francuz Tomasz , Gawlik Aneta 
Published: June 2022

BackgroundAs Turner syndrome (TS) predisposes to obesity and metabolic disorders, and their complications, such as cardiovascular diseases, are the main causes of shortened life expectancy in patients with TS, new metabolic markers that could serve as early predictors of dysmetabolic state are sought.ObjectiveAssessment of MMP-1 (matrix metalloproteinase-1), MMP-2 (matrix metalloproteinase-2), MMP-9 (matrix metallopeptidase-9), BDNF (brain-derived neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), and VEGF (vascular endothelial growth factor) before the onset of growth hormone (GH) therapy and then during GH treatment as well as markers assessment during GH medication in girls with TS to establish marker stability and repeatability, and the impact of GH on markers concentration.MethodThe concentrations of circulating MMP-1, MMP-2, MMP-9, BDNF, GDNF, and VEGF were measured in nine girls with TS before the onset of GH therapy and then after at least 3 months of treatment period. Subsequently, markers concentration was determined in 17 girls during GH medication, with the first determination after at least a 3-month treatment period. The patients’ clinical and biochemical phenotypes were determined by weight, height, BMI, total cholesterol, HDL cholesterol, triglycerides, and glucose concentration.ResultsComparison of markers concentration revealed a significantly higher concentration of MMP-2 in patients undergoing GH treatment (132.1 ± 42.05) than before the onset of therapy (105.0 ± 45.5, p=0.045). The values of the first measurement of VEGF in girls with TS undergoing GH therapy were significantly higher than those during the second measurement (30.9 ± 33.4 vs. 12.5 ± 11.7, p=0.029). There were no statistically significant differences between the measurements of the remaining markers concentration at any stage of the analysis.ConclusionIncrease in MMP-2 concentration is visible during GH therapy in comparison to the pre-GH period in girls with TS which demands confirmation in subsequent tests. The role of VEGF requires further studies in the context of carbohydrate-lipid disturbances in girls with TS and its association with GH treatment.
Prevalence and Genetic Analysis of Thalassemia and Hemoglobinopathy in Different Ethnic Groups and Regions in Hainan Island, Southeast China
Authors: Wang Min , Zhang Xiaozhuang , Zhang Yubin , Xiao Meifang 
Published: June 2022

Background: There are limited studies on the molecular profile of thalassemia in Hainan, the free trade island in China. Our aim was to reveal the prevalence and molecular mutation spectrum of thalassemia in different ethnic groups and regions of Hainan through a large sample study for the first time.Methods: A total of 231,596 individuals from 19 cities and counties in Hainan were screened by hematological parameter analysis, and further genetic analysis was performed on individuals with MCV less than 82 fL.Results: Totally, 31,780 (13.72%) subjects were diagnosed as thalassemia carriers. The overall prevalence of α-thalassemia, β-thalassemia, and α+β-thalassemia were 11.04%, 1.48%, and 1.20%, respectively. We further analyzed the molecular profiles of thalassemia in various ethnic groups and mainly compared the difference between Han and Li. The results showed that the frequency of thalassemia in the Li population (47.03%) was much higher than that in Han (9.37%). Except for β-thalassemia (1.31% of Li vs. 1.47% of Han), the frequencies of α-thalassemia (39.59% of Li vs. 7.35% of Han) and α+β-thalassemia (6.13% of Li vs. 0.56% of Han) in the Li were obviously higher than those in Han. The high-frequent genotypes of α-thalassemia in Han were αα/--SEA (25.55%), -α3.7/αα (22.17%), -α4.2/αα (21.59%), αWSα/αα (8.93%), and -α3.7/-α4.2 (4.17%) and those of Li were -α4.2/αα (17.24%), -α3.7/αα (17.16%), -α3.7/-α4.2 (15.09%), αWSα/αα (9.69%), and αWSα/-α3.7 (8.06%), respectively. The αα/--SEA was the highest genotype of α-thalassemia in Han but only accounted for 1.87% in Li. For β-thalassemia, the top three high-frequent genotypes in both Han and Li were βCD41/42(-TTCT)/βN, β-28(A&gt;G)/βN, and βIVS-Ⅱ-654(C&gt;T)/βN, but the frequency of βCD41/42(-TTCT)/βN in Li (90.96%) was much higher than that in Han (56.32%) and the data reported in other provinces of China. Additionally, the prevalence of thalassemia ranged from 8.16% to 34.35% in Hainan, Wuzhishan, Baoting, Qiongzhong, and Baisha have a higher prevalence than other areas.Conclusion: Our study revealed the characteristics of ethnic and regional differences in the prevalence of thalassemia in the childbearing age population of Hainan for the first time, indicating that the prevalence of thalassemia among Li nationality is the highest in China. Those findings will be useful for genetic counseling and the prevention of thalassemia.
A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity
Authors: Vargas Juan Gamboa , Wagner Jennifer , Shaikh Haroon , Lang Isabell , Medler Juliane , Anany Mohamed , Steinfatt Tim , Mosca Josefina Peña , Haack Stephanie , Dahlhoff Julia , Büttner-Herold Maike , Graf Carolin , Viera Estibaliz Arellano , Einsele Hermann , Wajant Harald , Beilhack Andreas 
Published: June 2022

Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.MethodsSingle-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.ResultsSTAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by &gt; 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.ConclusionsNewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
To Be or Not to Be: The Case of Endoplasmic Reticulum Aminopeptidase 2
Authors: Kuśnierczyk Piotr 
Published: June 2022

To be, or not to be, that is the question. (William Shakespeare, Hamlet)Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2, respectively) play a role in trimming peptides that are too long to be bound and presented by class I HLA (HLA-I) molecules to CD8+T cells. They may also affect the HLA-I-presented peptide repertoire by overtrimming potential epitopes. Both enzymes may also be released from the cell to cleave cytokine receptors and regulate blood pressure. Both enzymes are polymorphic, which affects their expression, specificity, and activity, resulting in their role in diseases associated with HLA-I. In this brief review, we concentrate on ERAP2, less investigated because of its lack in laboratory mice and 25% of humans, as well as a lower polymorphism. ERAP2 was found to be associated with several diseases and to influence ERAP1 effects. It was discovered recently that the defectiveERAP2gene, not encoding functional aminopeptidase, may nevertheless, during viral infections, produce a truncated protein isoform of unknown function, possibly interfering with ERAP1 and full-length ERAP2 by heterodimer formation. The disease associations of ERAP2, alone or in combination with ERAP1, are reviewed.
Plasma Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in the Acute Respiratory Distress Syndrome
Authors: Metkus Thomas S. , Kim Bo Soo , Jones Steven R. , Martin Seth S. , Schulman Steven P. , Leucker Thorsten M. 
Published: June 2022

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is a mediator of the immune response to sepsis. PCSK9 is also highly expressed in pneumocytes and pulmonary endothelial cells. We hypothesized that serum PCSK9 levels would be associated with death and ICU outcomes in patients with ARDS.MethodsUsing data and plasma samples from the NIH BioLINCC data repository, we assembled a cohort of 1,577 patients with the acute respiratory distress syndrome (ARDS) enrolled in two previously completed clinical trials, EDEN and SAILS. We measured PCSK9 levels in plasma within 24 h of intubation using commercially available ELISA kits (R&amp;D Systems). We assessed the association of PCSK9 with mortality using Cox proportional hazard models. We also assessed clinical factors associated with PCSK9 level and the association of PCSK9 with the number of days free of mechanical ventilation and days free of ICU care.ResultsIn 1,577 ARDS patients, median age was 53 years (IQR 42–65 years) and median APACHE III score 91 (72–111) connoting moderate critical illness. PCSK9 levels were 339.3 ng/mL (IQR 248.0–481.0). In multivariable models, race, cause of ARDS, body mass index, pre-existing liver disease, body temperature, sodium, white blood cell count and platelet count were associated with PCSK9 level. Presence of sepsis, use of vasopressors and ventilator parameters were not associated with PCSK9 level. PCSK9 levels were not associated with in-hospital mortality (HR per IQR 0.96, 95% CI 0.84–1.08, P = 0.47). Higher PCSK9 levels were associated with fewer ICU and ventilator free days.ConclusionsPlasma PCSK9 is not associated with mortality in ARDS, however higher PCSK9 levels are associated with secondary outcomes of fewer ICU free and ventilator free days. Clinical factors associated with PCSK9 in ARDS are largely unmodifiable. Further research to define the mechanism of this association is warranted.
Exonuclease 1 is a Potential Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma
Authors: Ma Jiaxiu , Jin Jiapei , Lu Huishuang , Zhang Jin , Li Yalan , Cai Xuefei 
Published: June 2022

Background: Hepatocellular carcinoma (HCC) represents a global health challenge. Effective biomarkers are required for an early diagnosis to improve the survival rates of HCC patients. Exonuclease 1 (EXO1) plays a significant role in the DNA repair and recombination mechanisms. This study aimed to investigate the diagnostic and prognostic roles of EXO1 in HCC.Methods: We analyzed the EXO1 expression levels in various cancers including HCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA sequencing data were analyzed using the R packages to determine differentially expressed genes (DEGs) between high- and low-EXO1 expressing HCC tissues from the TCGA–LIHC database. A Spearman’s correlation analysis was performed to determine the association between EXO1 expression and immune cell infiltration, and immune checkpoint genes and TP53. MethSurv and CBioPortal databases were used to evaluate the DNA methylation changes and genetic alterations in the EXO1 gene. A logistic regression analysis was performed to determine the association between EXO1 expression and the clinicopathological characteristics of the HCC patients. The diagnostic and prognostic predictive values of EXO1 were evaluated using the Kaplan–Meier (K-M) survival curves, diagnostic receiver operating characteristic (ROC) curves, nomogram model, and Cox regression analysis.Results: EXO1 expression levels were significantly higher in the tumor tissues and serums of HCC patients compared to the corresponding controls. The DEGs associated with EXO1 were significantly enriched in the cell proliferation pathways. EXO1 expression levels significantly correlated with immune cell infiltration, immune checkpoint genes, and TP53 in the HCC tissues. The DNA methylation status in five CpG islands of the EXO1 gene was associated with the prognosis of HCC. EXO1 expression levels in the HCC tissues were associated with the tumor grades, alpha-fetoprotein (AFP) levels, and the tumor stages. Cox regression analysis showed that EXO1 was a potential independent risk factor for the overall survival (OS) and disease-specific survival (DSS) of HCC patients. ROC curve analysis showed that EXO1 expression levels accurately distinguished HCC tissues from the adjacent normal liver tissues.Conclusion: Our study demonstrated that EXO1 was a potential diagnostic and prognostic biomarker, and a promising therapeutic target in HCC.
Phosphorylated Tau 181 Serum Levels Predict Alzheimer’s Disease in the Preclinical Stage
Authors: Qin Wei , Li Fangyu , Jia Longfei , Wang Qi , Li Ying , Wei Yiping , Li Yan , Jin Hongmei , Jia Jianping 
Published: June 2022

BackgroundThere is an urgent need for cost-effective, easy-to-measure biomarkers to identify subjects who will develop Alzheimer’s disease (AD), especially at the pre-symptomatic stage. This stage can be determined in autosomal dominant AD (ADAD) which offers the opportunity to observe the dynamic biomarker changes during the life-course of AD stages. This study aimed to investigate serum biomarkers during different AD stages and potential novel protein biomarkers of presymptomatic AD.MethodsIn the first stage, 32 individuals [20 mutation carriers including 10 with AD, and 10 with mild cognitive impairment (MCI), and 12 healthy controls] from ADAD families were analyzed. All subjects underwent a complete clinical evaluation and a comprehensive neuropsychological battery. Serum samples were collected from all subjects, and antibody arrays were used to analyze 170 proteins in these samples. The most promising biomarkers were identified during this screening and were then measured in serum samples of 12 subjects with pre-MCI and 20 controls.ResultsThe serum levels of 13 proteins were significantly different in patients with AD or MCI compared to controls. Of the 13 proteins, cathepsin D, immunoglobulin E, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP-9), von Willebrand factor (vWF), haptoglobin, and phosphorylated Tau-181 (p-Tau181) correlated with all cognitive measures (R2 = −0.69–0.76). The areas under the receiver operating characteristic curve of these seven proteins were 0.71–0.93 for the classification of AD and 0.57–0.95 for the classification of MCI. Higher levels of p-Tau181 were found in the serum of pre-MCI subjects than in the serum of controls. The p-Tau181 serum level might detect AD before symptoms occur (area under the curve 0.85, sensitivity 75%, specificity 81.67%).ConclusionsA total of 13 serum proteins showed significant differences between subjects with AD and MCI and healthy controls. The p-Tau181 serum level might be a broadly available and cost-effective biomarker to identify individuals with preclinical AD and assess the severity of AD.
Clinical Value and Prognosis of C Reactive Protein to Lymphocyte Ratio in Severe Aneurysmal Subarachnoid Hemorrhage
Authors: Zhang Qingqing , Zhang Gaoqi , Wang Lintao , Zhang Wanwan , Hou Fandi , Zheng Zhanqiang , Guo Yong , Chen Zhongcan , Hernesniemi Juha , Andrade-Barazarte Hugo , Feng Guang , Gu Jianjun 
Published: June 2022

ObjectiveTo investigate the relationship between CLR and disease severity and clinical prognosis of aSAH.MethodsThe authors retrospectively analyzed the clinical data of 221 patients with aSAH, who were admitted to the intensive care unit from January 2017 to December 2020. The indicators of inflammatory factors in the first blood routine examination within 48 h of bleeding were obtained. The prognosis was evaluated by mRS score at discharge, mRS&gt;2 was a poor outcome. Through the receiver operating characteristic (ROC) curve, the area under the curve was calculated and the predicted values of inflammatory factors (CLR, CRP, WBC, and neutrophils) were compared. Univariate and multivariable logistic regression analyses were used to evaluate the relationship between CLR and the clinical prognosis of patients. ROC curve analysis was performed to determine the optimal cut-off threshold, sensitivity, and specificity of CLR in predicting prognosis at admission.ResultsAccording to the mRS score at discharge, 139 (62.90%) patients were classified with poor outcomes (mRS&gt;2). The inflammatory factor with the best predictive value was CLR, which had an optimal cut-off threshold of 10.81 and an area under the ROC curve of 0.840 (95%CI.788–0.892, P &lt; 0.001). Multivariable Logistic regression analysis showed that the Modified Fisher grade, Hunt-Hess grade, and CLR at admission were independent risk factors for poor outcomes of patients with aSAH (P &lt; 0.05). According to Hunt-Hess grade, patients were divided into a mild group (Hunt-Hess ≤ 3) and a severe group (Hunt-Hess &gt; 3), and the CLR value was significantly higher in severe patients with aSAH than in mild patients. The optimal cut-off threshold of CLR in the severe group was 6.87, and the area under the ROC curve was 0.838 (95% CI.752–0.925, P &lt; 0.001).ConclusionsThe CLR value at the admission of patients with aSAH was significantly associated with Hunt-Hess grade, The higher Hunt-Hess grade, the higher the CL R-value, and the worse the prognosis. Early CLR value can be considered as a feasible biomarker to predict the clinical prognosis of patients with aSAH.