bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
Authors: Wang Qi , Chen Yinghua , Readhead Benjamin , Chen Kewei , Su Yi , Reiman Eric M. , Dudley Joel T. 
Published: December 2020

Abstract
Background
While Alzheimer’s disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.

Methods
We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).

Results
When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.

Conclusions
Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.
Lean body weight versus total body weight to calculate the iodinated contrast media volume in abdominal CT: a randomised controlled trial
Authors: Zanardo Moreno , Doniselli Fabio Martino , Esseridou Anastassia , Agrò Massimiliano , Panarisi Nicol Antonina Rita , Monti Caterina Beatrice , Di Leo Giovanni , Sardanelli Francesco 
Published: December 2020

Abstract
Objectives
Iodinated contrast media (ICM) could be more appropriately dosed on patient lean body weight (LBW) than on total body weight (TBW).

Methods
After Ethics Committee approval, trial registration NCT03384979, patients aged ≥ 18 years scheduled for multiphasic abdominal CT were randomised for ICM dose to LBW group (0.63 gI/kg of LBW) or TBW group (0.44 gI/kg of TBW). Abdominal 64-row CT was performed using 120 kVp, 100–200 mAs, rotation time 0.5 s, pitch 1, Iopamidol (370 mgI/mL), and flow rate 3 mL/s. Levene, Mann–Whitney U, and χ2 tests were used. The primary endpoint was liver contrast enhancement (LCE).

Results
Of 335 enrolled patients, 17 were screening failures; 44 dropped out after randomisation; 274 patients were analysed (133 LBW group, 141 TBW group). The median age of LBW group (66 years) was slightly lower than that of TBW group (70 years). Although the median ICM-injected volume was comparable between groups, its variability was larger in the former (interquartile range 27 mL versus 21 mL, p = 0.01). The same was for unenhanced liver density (IQR 10 versus 7 HU) (p = 0.02). Median LCE was 40 (35–46) HU in the LBW group and 40 (35–44) HU in the TBW group, without significant difference for median (p = 0.41) and variability (p = 0.23). Suboptimal LCE (< 40 HU) was found in 64/133 (48%) patients in the LBW group and 69/141 (49%) in the TBW group, but no examination needed repeating.

Conclusions
The calculation of the ICM volume to be administered for abdominal CT based on the LBW does not imply a more consistent LCE.
Catecholaminergic polymorphic ventricular tachycardia in pregnancy: a case report
Authors: Schumer Amy , Contag Stephen 
Published: December 2020

Abstract
Introduction
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder that can cause fatal tachyarrhythmias brought on by physical or emotional stress. There is little reported in the literature regarding management of CPVT in pregnancy much less during labor.

Case presentation
A gravida 2, para 1 presented to our high-risk clinic at 15 weeks gestation with known CPVT. The Caucasian female patient had been diagnosed after experiencing a cardiac arrest following a motor vehicle accident and found to have a pathogenic cardiac ryanodine receptor mutation. An implantable cardioverter defibrillator was placed at that time. Her pregnancy was uncomplicated, and she was medically managed with metoprolol, flecainide, and verapamil. Her labor course and successful vaginal delivery were uncomplicated and involved a multidisciplinary team comprising specialists in electrophysiology, maternal fetal medicine, anesthesiology, general obstetrics, lactation, and neonatology.

Conclusions
CPVT is likely underdiagnosed and, given that cardiovascular disease is a leading cause of death in pregnancy, it is important to bring further awareness to the diagnosis and management of this inherited arrhythmia syndrome in pregnancy.
Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells
Authors: Obendorf Janine , Fabian Claire , Thome Ulrich H. , Laube Mandy 
Published: December 2020

AbstractBackgroundMesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as bronchopulmonary dysplasia (BPD), the most common sequel of preterm birth. In these studies, cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD.MethodsWe aimed to determine if the conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na+transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na+transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants.ResultsMSC-CM strongly increased the activity of the epithelial Na+channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’s actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na+transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na+transport.ConclusionThe results demonstrate that MSC-CM strongly stimulated functional and structural maturation of the fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus, MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.
Dissecting molecular mechanisms underlying H2O2-induced apoptosis of mouse bone marrow mesenchymal stem cell: role of Mst1 inhibition
Authors: Zhang Qian , Cheng Xianfeng , Zhang Haizhou , Zhang Tao , Wang Zhengjun , Zhang Wenlong , Yu Wancheng 
Published: December 2020

AbstractBackgroundBone marrow mesenchymal stem cell (BM-MSC) has been shown to treat pulmonary arterial hypertension (PAH). However, excessive reactive oxygen species (ROS) increases the apoptosis of BM-MSCs, leading to poor survival and engraft efficiency. Thus, improving the ability of BM-MSCs to scavenge ROS may considerably enhance the effectiveness of transplantation therapy. Mammalian Ste20-like kinase 1 (Mst1) is a pro-apoptotic molecule which increases ROS production. The aim of this study is to uncover the underlying mechanisms the effect of Mst1 inhibition on the tolerance of BM-MSCs under H2O2condition.MethodsMst1 expression in BM-MSCs was inhibited via transfection with adenoviruses expressing a short hairpin (sh) RNA directed against Mst1 (Ad-sh-Mst1) and exposure to H2O2. Cell viability was detected by Cell Counting Kit 8 (CCK-8) assay, and cell apoptosis was analyzed by Annexin V-FITC/PI, Caspase 3 Activity Assay kits, and pro caspase 3 expression. ROS level was evaluated by the ROS probe DCFH-DA, mitochondrial membrane potential (ΔΨm) assay, SOD1/2, CAT, and GPx expression. Autophagy was assessed using transmission electron microscopy, stubRFP-sensGFP-LC3 lentivirus, and autophagy-related protein expression. The autophagy/Keap1/Nrf2 signal in H2O2-treated BM-MSC/sh-Mst1 was also measured.ResultsMst1 inhibition reduced ROS production; increased antioxidant enzyme SOD1/2, CAT, and GPx expression; maintained ΔΨm; and alleviated cell apoptosis in H2O2-treated BM-MSCs. In addition, this phenomenon was closely correlated with the autophagy/Keap1/Nrf2 signal pathway. Moreover, the antioxidant pathway Keap1/Nrf2 was also blocked when autophagy was inhibited by the autophagy inhibitor 3-MA. However, Keap1 or Nrf2 knockout via siRNA had no effect on autophagy activation or suppression.ConclusionMst1 inhibition mediated the cytoprotective action of mBM-MSCs against H2O2-induced oxidative stress injury. The underlying mechanisms involve autophagy activation and the Keap1/Nrf2 signal pathway.Graphical abstract
Targeted expression profiling reveals distinct stages of early canine fibroblast reprogramming are regulated by 2-oxoglutarate hydroxylases
Authors: Tobias Ian C. , Kao Mian-Mian C. , Parmentier Thomas , Hunter Hailey , LaMarre Jonathan , Betts Dean H. 
Published: December 2020

Abstract
Background
Ectopic expression of a defined set of transcription factors allows the reprogramming of mammalian somatic cells to pluripotency. Despite continuous progress in primate and rodent reprogramming, limited attention has been paid to cell reprogramming in domestic and companion species. Previous studies attempting to reprogram canine cells have mostly assessed a small number of presumptive canine induced pluripotent stem cell (iPSC) lines for generic pluripotency attributes. However, why canine cell reprogramming remains extremely inefficient is poorly understood.

Methods
To better characterize the initial steps of pluripotency induction in canine somatic cells, we optimized an experimental system where canine fetal fibroblasts (cFFs) are transduced with the Yamanaka reprogramming factors by Sendai virus vectors. We use quantitative PCR arrays to measure the expression of 80 target genes at various stages of canine cell reprogramming. We ask how cFF reprogramming is influenced by small molecules affecting the epigenomic modification 5-hydroxymethylcytosine, specifically L-ascorbic acid and retinoic acid (AA/RA).

Results
We found that the expression and catalytic output of a class of 2-oxoglutarate-dependent (2-OG) hydroxylases, known as ten-eleven translocation (TET) enzymes, can be modulated in canine cells treated with AA/RA. We further show that AA/RA treatment induces TET1 expression and facilitates early canine reprogramming, evidenced by upregulation of epithelial and pluripotency markers. Using a chemical inhibitor of 2-OG hydroxylases, we demonstrate that 2-OG hydroxylase activity regulates the expression of a subset of genes involved in mesenchymal-to-epithelial transition (MET) and pluripotency in early canine reprogramming. We identify a set of transcription factors depleted in maturing reprogramming intermediates compared to pluripotent canine embryonic stem cells.

Conclusions
Our findings highlight 2-OG hydroxylases have evolutionarily conserved and divergent functions regulating the early reprogramming of canine somatic cells and show reprogramming conditions can be rationally optimized for the generation of maturing canine iPSC.
circAKT3 positively regulates osteogenic differentiation of human dental pulp stromal cells via miR-206/CX43 axis
Authors: Zhang Bo , Huo Sibei , Cen Xiao , Pan Xuefeng , Huang Xinqi , Zhao Zhihe 
Published: December 2020

Abstract
Background
Human dental pulp stromal cells (hDPSCs) are promising sources of mesenchymal stem cells (MSCs) for bone tissue regeneration. Circular RNAs (circRNAs) have been demonstrated to play critical roles in stem cell osteogenic differentiation. Herein, we aimed to investigate the role of circAKT3 during osteogenesis of hDPSCs and the underlying mechanisms of its function.

Methods
We performed circRNA sequencing to investigate the expression profiles of circular RNAs during osteogenesis of hDPSCs. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect the expression pattern of circAKT3 and miR-206 in hDPSCs during osteogenesis. We knocked down circAKT3 and interfered the expression of miR-206 to verify their regulatory role in hDPSC osteogenesis. We detected hDPSCs mineralization by alkaline phosphatase (ALP) and Alizarin Red S (ARS) staining and used dual-luciferase reporter assay to validate the direct binding between circAKT3 and miR-206. To investigate in vivo mineralization, we performed subcutaneous transplantation in nude mice and used hematoxylin and eosin, Masson’s trichrome, and immunohistochemistry staining.

Results
Totally, 86 circRNAs were differentially expressed during hDPSC osteogenesis, in which 29 were downregulated while 57 were upregulated. circAKT3 was upregulated while miR-206 was downregulated during hDPSC osteogenesis. Knockdown of circAKT3 inhibited ALP/ARS staining and expression levels of osteogenic genes. circAKT3 directly interacted with miR-206, and the latter one suppressed osteogenesis of hDPSCs. Silencing miR-206 partially reversed the inhibitory effect of circAKT3 knockdown on osteogenesis. Connexin 43 (CX43), which positively regulates osteogenesis of stem cells, was predicted as a target of miR-206, and overexpression or knockdown of miR-206 could correspondingly decrease and increase the expression of CX43. In vivo study showed knockdown of circAKT3 suppressed the formation of mineralized nodules and expression of osteogenic proteins.

Conclusion
During osteogenesis of hDPSCs, circAKT3 could function as a positive regulator by directly sponging miR-206 and arresting the inhibitive effect of miR-206 on CX43 expression.
Design, development, and evaluation of the efficacy of a nucleic acid-free version of a bacterial ghost candidate vaccine against avian pathogenic E. coli (APEC) O78:K80 serotype
Authors: Soleymani Safoura , Tavassoli Amin , Hashemi Tabar Gholamreza , Kalidari Gholam Ali , Dehghani Hesam 
Published: December 2020

AbstractOne of the major bacterial infectious diseases in the poultry industry is avian pathogenic Escherichia coli (APEC), which causes colibacillosis in chickens. To develop a novel nucleic acid-free bacterial ghost (BG) vaccine against the O78:K80 serotype of APEC, in this study we constructed a plasmid that harbored E-lysis and S nuclease (SNUC). Following the expression, the O78:K80 bacteria lost all of their cytoplasmic content and nucleic acids by enzymatic digestion. The functionality of these two proteins in the production procedure of bacterial ghosts was confirmed by monitoring the number of colonies, scanning electron microscopy imaging, gel electrophoresis of genomic DNA, and qPCR on the plasmid content of bacterial ghosts. The protective efficacy of the ghost vaccine generated from O78:K80 serotype of APEC was tested in chickens by injection and inhalation routes and compared with that in chickens that received the injection of a killed vaccine. The O78:K80 BG vaccine candidate, used as injection and inhalation, in comparison with the killed vaccine, triggered higher proinflammatory cytokine expression including IL-6, IL-1β, and TNFSF15; a higher level of antibody-dependent humoral (IgY and IgA) and cellular immune responses (IFNγ and lymphocyte proliferation); and lower lesion scores. According to the results of this study, we suggest that the bacterial ghost technology has the potential to be applied for the development of novel vaccines against avian colibacillosis. This technology provides an effective and reliable approach to make multivalent vaccines for more prevalent APEC strains involved in the establishment of this infectious disease in the poultry industry.
Regulatory effects of chicken TRIM25 on the replication of ALV-A and the MDA5-mediated type I interferon response
Authors: Zhou Jin-run , Liu Jun-hong , Li Hong-mei , Zhao Yue , Cheng Ziqiang , Hou Yan-meng , Guo Hui-jun 
Published: December 2020

AbstractThis study focuses on the immunoregulatory effects of chicken TRIM25 on the replication of subgroup A of avian leukosis virus (ALV-A) and the MDA5-mediated type I interferon response. The ALV-A-SDAU09C1 strain was inoculated into DF1 cells and 1-day-old SPF chickens, and the expression of TRIM25 was detected at different time points after inoculation. A recombinant overexpression plasmid containing the chicken TRIM25 gene (TRIM25-GFP) was constructed and transfected into DF1 cells to analyse the effects of the overexpression of chicken TRIM25 on the replication of ALV-A and the expression of MDA5, MAVS and IFN-β. A small interfering RNA targeting chicken TRIM25 (TRIM25-siRNA) was prepared and transfected into DF1 cells to assess the effects of the knockdown of chicken TRIM25 on the replication of ALV-A and the expression of MDA5, MAVS and IFN-β. The results showed that chicken TRIM25 was significantly upregulated at all time points both in ALV-A-infected cells and in ALV-A-infected chickens. Overexpression of chicken TRIM25 in DF1 cells dramatically decreased the antigenic titres of ALV-A in the cell supernatant and upregulated the relative expression of MDA5, MAVS and IFN-β induced by ALV-A or by poly(I:C); in contrast, knockdown of chicken TRIM25 significantly increased the antigenic titres of ALV-A and downregulated the relative expression of MDA5, MAVS and IFN-β. It can be concluded that chicken TRIM25 can inhibit the replication of ALV-A and upregulate the MDA5 receptor-mediated type I interferon response in chickens. This study can help improve the understanding of the antiviral activities of chicken TRIM25 and enrich the knowledge of antiviral responses in chickens.
Relationship between physical and biogeochemical parameters and the scenario dependence of the transient climate response to cumulative carbon emissions
Authors: Tachiiri Kaoru 
Published: December 2020

AbstractThe transient climate response to cumulative carbon emissions (TCRE) is a key metric in estimating the remaining carbon budget for given temperature targets. However, the TCRE has a small scenario dependence that can be non-negligible for stringent temperature targets. To investigate the parametric correlations and scenario dependence of the TCRE, the present study uses a 512-member ensemble of an Earth system model of intermediate complexity (EMIC) perturbing 11 physical and biogeochemical parameters under scenarios with steady increases of 0.25%, 0.5%, 1%, 2%, or 4% per annum (ppa) in the atmospheric CO2 concentration (pCO2), or an initial increase of 1% followed by an annual decrease of 1% thereafter. Although a small difference of 5% (on average) in the TCRE is observed between the 1-ppa and 0.5-ppa scenarios, a significant scenario dependence is found for the other scenarios, with a tendency toward large values in gradual or decline-after-a-peak scenarios and small values in rapidly increasing scenarios. For all scenarios, correlation analysis indicates a remarkably large correlation between the equilibrium climate sensitivity (ECS) and the relative change in the TCRE, which is attributed to the longer response time of the high ECS model. However, the correlations of the ECS with the TCRE and its scenario dependence for scenarios with large pCO2 increase rates are slightly smaller, and those of biogeochemical parameters such as plant respiration and the overall pCO2–carbon cycle feedback are larger, than in scenarios with gradual increases. The ratio of the TCREs under the overshooting (i.e., 1-ppa decrease after a 1-ppa increase) and 1-ppa increase only scenarios had a clear positive relation with zero-emission commitments. Considering the scenario dependence of the TCRE, the remaining carbon budget for the 1.5 °C target could be reduced by 17 or 22% (before and after considering the unrepresented Earth system feedback) for the most extreme case (i.e., the 67th percentile when using the 0.25-ppa scenario as compared to the 1-ppa increase scenario). A single ensemble EMIC is also used to indicate that, at least for high ECS (high percentile) cases, the scenario dependence of the TCRE should be considered when estimating the remaining carbon budget.
A dynamic causal model on self-regulation of aversive emotion
Authors: Yang Yang , Zhang Xiaofei , Peng Yue , Bai Jie , Lei Xiuya 
Published: December 2020

AbstractCognitive regulation of emotion has been proven to be effective to take control the emotional responses. Some cognitive models have also been proposed to explain the neural mechanism that underlies this process. However, some characteristics of the models are still unclear, such as whether the cognitive regulation will be spontaneously employed by participants implicitly. The present study recruited the fMRI experiment to focus on the discomfort induced by viewing aversive pictures, and the emotional self-regulation during picture viewing. By using the dynamic causal modeling (DCM), 50 putative models of brain functional networks were constructed, one optimal model that fitted the real data best won the comparison from the candidates. As a result, the optimal model suggests that both the ventral striatum (VS)-centric bottom-up and the dorsolateral prefrontal cortex (DLPFC)-centric top-down regulations are recruited for self-regulation on negative emotions. The DLPFC will exert modulatory influence on the VS only when the VS fails to suppress the induced emotions by self-inhibition.