bluuebunny/crossref_metadata_2025_split huggingface dataset:
P12.04.A Exosomes from glioma associated sphere forming cells induce a transition of invasive phenotype via transfer of EMP2 and CA9
Authors: Kang S , Ryu B , Sa J , Kim H , Park K , Yu S , Hong D , Kim K 
Published: September 2022

Abstract

Background
Glioblastoma multiforme (GBM) mostly occurs local recurrence at normal parenchyme adjacent tumor despite of conventional treatment. Glioma stem like cells (GSC) forming intratumoral heterogeneity within the GBM acquired the microenvironmental adaptation by inter-exosomal contents exchange between heterogenic cells. In addition, GSC has an invasive potential as like human GBM. Therefore, we investigate whether exosomal proteins of GSC affect the normal tissue invasion in GBM.

Material and Methods
Exosomes were isolated by Size-Exclusion method from conditioned media and validated by Electron microscope and Immunoblot assay. Exosomal proteomics were examined with Liquid Chromatography-Mass Spectrometry (LC/MS). To produce the fluorescent exosome, bi-cistron vectors were cloned with shRNA and CD63-GFP. To identify the effect of tranfected exosome, the isolated exosomes were treated to recipient cells and examined the invasion by 3D invasion assay and mouse intracranial model.

Results
Firstly, we dichotomized two groups following tumor invasion at matrigel assay and GSC derived orthotopic mouse model. CSC2 and X01 GSCs revealed highly invasive phenotype whereas 83NS and 528NS GSCs did not. Exosome was isolated in each group and identified by CD63 expression or electron microscopy. In proteomics analysis, hypoxia, extracellular matrix organization, GTPase cycle related proteins were enriched in highly invasive cell’s exosome. Among them, we focused the carbonic anhydrase IX (CA9) and the epithelial membrane protein 2 (EMP2) on its permissive role to glioblastoma invasion respectively. CA9 and EMP2 mRNA and protein levels were verified in GSCs and their exosomes and the high expression levels were detected in CSC2 and X01 compared to the low one in 83NS and 528NS GSCs. To evaluate the effects of CA9 and EMP2 on exosome mediated invasion potential, viral bi-cistron vectors was composed with the target gene knockdown and the CD63 fluorescence was used to detect intracellular exosome transfer. Interestingly, the decreased expression of phosphorylated FAK, a key invasive marker, was observed after Lentiviral mediated CA9- and EMP2-knockdown in highly invasive CSC2. To identify whether CA9 and EMP2 proteins are the intracellular effector protein responsible for exosome mediated glioma invasion, the donor exosomes (Exo-CSC2-sh-CA9 and Exo-CSC2-EMP2, after Lentiviral transfection to CSC2s) were isolated and treated to the non invasive 528NS cells as recipient cells. In 3D invasion assay, Exo-CSC2-shCA9 or Exo-CSC2-shEMP2 mediated tumor invasion was significantly decreased at 528NS GSCs compared to Exo-CSC2-shEV. These features were found at mouse intracranial model as well.

Conclusion
Together with these, we conclude that exosome derived from GSCs induces a transition of invasive phenotype via transfer of EMP2 and CA9 proteins.
An SNW/SKI-INTERACTING PROTEIN influences endoreduplication and cell growth in Arabidopsis
Authors: Jiang Shan , Meng Bolun , Zhang Yilan , Li Na , Zhou Lixun , Zhang Xuan , Xu Ran , Guo Siyi , Song Chun-Peng , Li Yunhai 
Published: September 2022

Abstract
Endoreduplication plays an important role in cell growth and differentiation, but the mechanisms regulating endoreduplication are still elusive. We have previously reported that UBIQUITIN-SPECIFIC PROTEASE14 (UBP14) encoded by DA3 interacts with ULTRAVIOLETB INSENSITIVE4 (UVI4) to influence endoreduplication and cell growth in Arabidopsis (Arabidopsis thaliana). The da3-1 mutant possesses larger cotyledons and flowers with higher ploidy levels than the wild-type. Here, we identify the suppressor of da3-1 (SUPPRESSOR OF da3-1 3; SUD3), which encodes SNW/SKI-INTERACTING PROTEIN (SKIP). Biochemical studies demonstrate that SUD3 physically interacts with UBP14/DA3 and UVI4 in vivo and in vitro. Genetic analyses support that SUD3 acts in a common pathway with UBP14/DA3 and UVI4 to control endoreduplication. Our findings reveal an important genetic and molecular mechanism by which SKIP/SUD3 associates with UBP14/DA3 and UVI4 to modulate endoreduplication.
Long-term outcomes in Rheumatoid Arthritis: Review of data from the ‘Basildon Inflammatory Arthritis Cohort’
Authors: Jain Kanishk , Laila Deena , Nandagudi Anupama , Bharadwaj Anurag 
Published: September 2022

Abstract

Objective
The aim was to determine outcomes in RA with long-term analysis of a real-world inception cohort.

Methods
We carried out a retrospective cohort analysis of 184 patients with a new diagnosis of RA (ACR/EULAR 2010 criteria) between 2009 and 2013. Measured parameters included patient demographics, serological markers, disease activity (DAS28-CRP), treatment regimen, development of new co-morbidities and all-cause mortality.

Results
Complete data were available for analysis in 171 patients, 60 men and 111 women, with a median age of 57 years and median follow-up time of 7.5 years. DAS-28 remission was achieved in 73%, with the majority continuing to require pharmacological therapy. Drug-free remission was achieved in 11.7%, whereas 3.5% remained refractory to treatment. Analysis of new co-morbidities revealed malignancy in 12.9% (n = 22), with lung cancer having the highest incidence (n = 9). Cardiovascular, pulmonary and cerebrovascular disease developed in 11.1% (n = 19), 5.8% (n = 10) and 5.3% (n = 9), respectively. The crude mortality rate was 19.3% (33 of 171), incidence mortality rate 174 per 10 000 person-years of follow-up and standardized mortality ratio 1.57 (95% CI 1.10, 2.17). More deaths were recorded from underlying malignancy [7.6% (n = 13)] than with cardiovascular disease [4.7% (n = 8)]. The majority of deaths occurred ≥5 years after initial diagnosis (67%).

Conclusion
Long-term analysis reveals that mortality in RA remains significantly elevated compared with the general population. Additionally, this real-world study underlines malignancy as the predominant cause of morbidity and mortality in RA.
Contribution of Organ-Based Tube Current Modulation to the Reduction of Lens Exposure Dose in Head 4D CT Imaging: A Phantom Study
Authors: Nagamoto Keisuke , Watanabe Ryo , Kawachino Tomonori , Ohishi Yoshitaka , Yamamoto Aina , Moritake Takashi , Nihei Shun-ichi , Kamochi Masayuki , Kunugita Naoki 
Published: September 2022

Abstract
The purpose of this study was to evaluate the effectiveness of organ effect modulation (OEM) in reducing the lens dose in 4D computed tomography (CT) of the head in volume-acquisition (NVA) mode. Six radiophotoluminescent dosemeters were placed on the head of a RANDO phantom. The doses absorbed by the organs and image noise change rate were determined. The lens doses without OEM (i.e. in the OEMoff case) were higher than those with the same target standard deviation and volume-computed tomography dose index (CTDIvol) as in the OEMoff case (p &lt; 0.01). The image noise change rate was 11%. OEM reduced the lens dose during head 4D CT imaging in the NVA mode by 18%. Furthermore, the feasibility of lens dose reduction while ensuring sufficient image quality was confirmed under the condition in which OEM was employed with the same CTDIvol as in the OEMoff case.
On Understanding in Mathematics
Authors: Schaathun Hans Georg 
Published: September 2022

Abstract
It is often difficult to teach mathematics for understanding. Many students seem to prefer to learn computational skills by rote, and seem to remember very little of the course contents the following semester. The reasons for this are surely manifold. This paper reviews the concept of understanding, looking particularly towards the meaning it has in hermeneutic philosophy. The known distinction between hermeneutical and epistemological understanding is resituated in mathematics, and we argue that it is the hermeneutic understanding which is most relevant when mathematics is taught as a support subject for engineering and other professions.
Resveratrol alleviates Ang II-induced vascular smooth muscle cell senescence by upregulating E2F1/SOD2 axis
Authors: Liu Lei , Yang Xiuhua , Liao Yiyang , Wang Chuanhua , Wang Yuanliang 
Published: September 2022

Abstract

Background
Vascular smooth muscle cells (VSMCs) senescence is a crucial factor relevant to accelerate cardiovascular diseases. Resveratrol (RES) has been reported that could obstruct vascular senescence. However, the detailed molecular mechanisms of RES in VSMCs senescence are still indistinct and deserve further investigations.

Methods and Results
In this study, VSMCs were treated with 100 nM angiotensin II (Ang II) for 3 days and then followed with a range of different concentrations of RES (0.5, 5, 15, 25, 35, 50 μM), and 25 μM of RES was chose for following experiments. We found that the E2F1 and SOD2 expressions were reduced in Ang II-induced VSMCs. RES treatment impeded Ang II-induced oxidative stress and mitochondrial dysfunction through elevating E2F1 and SOD2 expression, thereby alleviating VSMCs senescence. Additionally, E2F1 knockdown reversed the protective effects of RES on VSMCs senescence caused by Ang II administration. Ch-IP assay and dual luciferase reporter gene assay validated that E2F1 could bind to the promoter region of SOD2. Furthermore, E2F1 or SOD2 overexpression blocked Ang II-induced on VSMCs senescence.

Conclusion
In conclusion, RES mitigated Ang II-induced VSMCs senescence by suppressing oxidative stress and mitochondrial dysfunction through activating E2F1/SOD2 axis. Our study disclosed that RES might be a potential drug and the axis of its regulatory mechanism might be therapeutic targets for postponing vascular senescence.
RHEGMATOGENOUS RETINAL DETACHMENT AFTER INJECTION OF TISSUE PLASMINOGEN ACTIVATOR AND GAS FOR SUBMACULAR HEMORRHAGE SECONDARY TO AGE-RELATED MACULAR DEGENERATION
Authors: Manrique-Lipa Roslyn , Jasim Haneen , Safi Antoine , Liyanage Sidath E. , Keller Johannes 
Published: September 2022

Purpose:
The purpose of this study was to describe the rate, clinical characteristics, and outcomes of rhegmatogenous retinal detachment (RRD) after injection of tissue plasminogen activator (TPA) and gas for submacular hemorrhage displacement.

Methods:
Retrospective analysis of consecutive cases developing RRD after TPA injection and gas for submacular hemorrhage displacement. The rate of RRD was calculated, and a description of RRD clinical characteristics was performed. Anatomic and visual outcomes after RRD repair were analyzed.

Results:
Ninety eyes of 90 patients were analyzed. Tissue plasminogen activator was given intravitreally in 53 eyes (59%) and subretinally in 37 eyes (41%). RRD occurred in 6 of 90 eyes (7%). Of these, one had intravitreal TPA and five had vitrectomy with subretinal TPA (P = 0.04). The mean age was 75 (64–93) years. The median time of RRD occurrence was 42 (1–134) days. All cases had macular involvement. Two cases had PVR at presentation. Vitrectomy was performed in all cases and silicone oil used in five, all of which resulted in permanent silicone oil retention. One case (17%) achieved primary single surgery success. The median final visual acuity was 1.8 logMAR (20/1,260 Snellen).

Conclusion:
The RRD rate after submacular hemorrhage displacement was 7% in our case series. Rhegmatogenous retinal detachment occurred more commonly after vitrectomy with subretinal TPA injection. The visual and anatomic outcomes were poor, with a high rate of retained silicone oil and recurrent RRD.
Validation and update of a prediction model for risk of relapse after cessation of anti-TNF treatment in Crohn’s disease
Authors: ten Bokkel Huinink Sebastiaan , de Jong Djuna C. , Nieboer Daan , Thomassen Doranne , Steyerberg Ewout W. , Dijkgraaf Marcel G.W. , Bodelier Alexander G.L. , West Rachel L. , Römkens Tessa E.H. , Hoentjen Frank , Mallant Rosalie C. , van Tuyl Bas A.C. , Mares Wout G.N. , Wolfhagen Frank H.J. , Dijkstra Gerard , Reijnders Jurriën G.P. , de Boer Nanne K. , Tan Adriaan C.I.T.L. , van Boeckel Petra G.A. , Tack Greetje J. , van Asseldonk Dirk P. , D’Haens Geert R.A.M. , van der Woude C Janneke , Duijvestein Marjolijn , de Vries Annemarie C 
Published: September 2022

Background
Anti-tumor necrosis factor (TNF) therapy is effective for the treatment of Crohn’s disease. Cessation may be considered in patients with a low risk of relapse. We aimed to externally validate and update our previously developed prediction model to estimate the risk of relapse after cessation of anti-TNF therapy.

Methods
We performed a retrospective cohort study in 17 Dutch hospitals. Crohn’s disease patients in clinical, biochemical or endoscopic remission were included after anti-TNF cessation. Primary outcome was a relapse necessitating treatment. Discrimination and calibration of the previously developed model were assessed. After external validation, the model was updated. The performance of the updated prediction model was assessed in internal-external validation and by using decision curve analysis.

Results
486 patients were included with a median follow-up of 1.7 years. Relapse rates were 35 and 54% after 1 and 2 years. At external validation, the discriminative ability of the prediction model was equal to that found at the development of the model [c-statistic 0.58 (95% confidence interval (CI) 0.54–0.62)], though the model was not well-calibrated on our cohort [calibration slope: 0.52 (0.28–0.76)]. After an update, a c-statistic of 0.60 (0.58–0.63) and calibration slope of 0.89 (0.69–1.09) were reported in internal-external validation.

Conclusion
Our previously developed and updated prediction model for the risk of relapse after cessation of anti-TNF in Crohn’s disease shows reasonable performance. The use of the model may support clinical decision-making to optimize patient selection in whom anti-TNF can be withdrawn. Clinical validation is ongoing in a prospective randomized trial.
Validating the prognostic value of Freiburg index of posttransjugular intrahepatic portosystemic shunt survival score and classic scores in Chinese patients with implantation of transjugular intrahepatic portosystemic shunt
Authors: Song Jinlei , Wang Xiaoze , Yan Yuling , Xiang Tong , Luo Xuefeng 
Published: September 2022

Background and aims
It is important and challenging to evaluate the survival of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). We aimed to validate the Freiburg index of post-TIPS survival (FIPS) score and classic scores for predicting mortality in Chinese patients after TIPS creation.

Methods
A total of 709 consecutive patients with cirrhosis from December 2011 to July 2018 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the FIPS score, the model for end-stage liver disease (MELD) score, Child-Pugh score and Chronic Liver Failure Consortium Acute Decompensation score was validated with the receiver operating characteristic (ROC) curve and DeLong et al. test.

Results
The MELD-Na score was superior to the FIPS score in predicting 1-month mortality [AUROC, 0.727 (0.692–0.759) vs. 0.588 (0.551–0.625); P = 0.048]. The MELD and MELD-Na scores were significant superior to the FIPS score in predicting 3-month mortality [AUROC, 0.730 (0.696–0.762) vs. 0.598 (0.561–0.634); P = 0.044 and 0.740 (0.706–0.772) vs. 0.598 (0.561–0.634); P = 0.028]. Subgroup analyses revealed that Child-Pugh score was better than FIPS score in predicting 3-month mortality [AUROC, 0.797 (0.745–0.843) vs. 0.578 (0.517–0.637); P = 0.049] in nonviral cirrhosis group.

Conclusion
Classic scores still had good risk stratification and predictive ability of post-TIPS mortality. The FIPS score was not superior to the classic scores in the current Chinese cohort. The MELD and MELD-Na scores were significantly superior to the FIPS score in predicting 3-month mortality.
Comparison of the safety and efficacy of YEARS, PEGeD, 4PEPS or the sole item “PE is the most likely diagnosis” strategies for the diagnosis of pulmonary embolism in the emergency department: post-hoc analysis of two European cohort studies
Authors: Roussel Mélanie , Gorlicki Judith , Douillet Delphine , Moumneh Thomas , Bérard Laurence , Cachanado Marine , Chauvin Anthony , Roy Pierre-Marie , Freund Yonathan 
Published: September 2022

Background
The optimal strategy for the diagnosis of pulmonary embolism (PE) in the emergency department (ED) remains debated. To reduce the need of imaging testing, several rules have been recently validated using an elevated D-dimer threshold.

Objective:
To validate the safety of different diagnostic strategies and compare the efficacy in terms of chest imaging testing.

Design and patients:
Post-hoc analysis of individual data of 3330 adult patients without a high clinical probability of PE in the ED followed-up at 3 months in France and Spain (1916 from the PROPER cohort, 1414 from the MODIGLIANI cohort).

Exposure:
Four diagnostic strategies with an elevated D-dimer threshold if PE is unlikely. The YEARS combined with Pulmonary Embolism Rule-out Criteria (PERC) the pulmonary embolism graduated D-dimer (PEGeD) combined with PERC and the 4-level pulmonary embolism probability score (4PEPS) rules were assessed. A modified simplified (MODS) rule with a simplified YEARS reduced to the sole item of “Is PE the most likely diagnosis” combined with PERC was also tested.

Outcome measure and analysis:
The primary outcome was the proportion of diagnosed PE or deep venous thrombosis at 3 months in patients in whom PE could have been excluded without chest imaging according to the tested strategy. The safety of a strategy was confirmed if the failure rate was less than 1.85%. The secondary outcome was the use of imaging testing according to each rule.

Results:
Among 3330 analyzed patients, 150 (4.5%) had a PE. The number of missed PEs were 25, 29, 30 and 26 for the PERC+YEARS, PERC+PEGeD, 4PEPS and MODS rules respectively, with a failure rate of 0.75% (95% CI 0.51% to 1.10%), 0.87% (0.61% to 1.25%), 0.90% (0.63% to 1.28%) and 0.78% (0.53% to 1.14%) respectively. There was no significant difference in the failure rate between rules. Except for a significant lower use of chest imaging for 4PEPS compared to YEARS (14.9% vs 16.3%, difference -1.4% [95%CI -2.1% to -0.8%]), there was no difference in the proportion of imaging testing.

Conclusion:
In this post-hoc analysis of patients with suspicion of PE, YEARS and PEGeD combined with PERC, and 4PEPS were safe to exclude PE. The safety of the modified simplified MODS strategy was also confirmed. There was no significant difference of the failure rate between strategies.
Understanding emergence of antimycobacterial dose dependent resistance
Authors: Kloprogge Frank , Canseco Julio Ortiz , Phee Lynette , Sadouki Zahra , Kipper Karin , Witney Adam A. , Stoker Neil , McHugh Timothy D. 
Published: September 2022

AbstractConcentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of genotypic resistance only occurs when antibiotic levels fall below MIC although MICs are typically maintained following clinical dosing provided that adherence to the regimen is good. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides improved rational for drug and dose selection although further work on understanding underlying mechanisms is needed to improve the drug development pipeline.One Sentence SummaryDisentangling and quantifying concentration dependent emergence of resistance will contribute to better informed drug and dose selection for anti-mycobacterial combination therapy.
Unravelling drivers of local adaptation through Evolutionary Functional-Structural Plant modelling
Authors: de Vries Jorad , Fior Simone , Pålsson Aksel , Widmer Alex , Alexander Jake M. 
Published: September 2022

SummaryLocal adaptation to contrasting environmental conditions along environmental gradients is a widespread phenomenon in plant populations, yet we lack a mechanistic understanding of how individual agents of selection contribute to local adaptation.Here, we developed a novel evolutionary functional-structural plant (E-FSP) model that simulates local adaptation of virtual plants along an environmental gradient. First, we validate the model by testing if it can recreate two elevational ecotypes of Dianthus carthusianorum occurring in the Swiss Alps. Second, we use the E-FSP model to disentangle the relative contribution of abiotic (temperature) and biotic (competition and pollination) selection pressures to elevational adaptation in D. carthusianorum.The model reproduced the qualitative differences between the elevational ecotypes in two phenological (germination and flowering time) and one morphological trait (stalk height), as well as qualitative differences in four performance variables that emerge from GxE interactions (flowering time, number of stalks, rosette area and seed production). Our results suggest that elevational adaptation in D. carthusianorum is predominantly driven by the abiotic environment.Our approach shows how E-FSP models incorporating physiological, ecological and evolutionary mechanisms can be used in combination with experiments to examine hypotheses about patterns of adaptation observed in the field.
Three new genome assemblies of blue mussel lineages: North and South EuropeanMytilus edulisand MediterraneanMytilus galloprovincialis
Authors: Simon Alexis 
Published: September 2022

AbstractThe blue mussel species complex (Mytilus edulls) is of particular interest both as model species in population genetics and ecology, but also as an economic resource in many regions. Using 10X genomics pseudo-long reads, I assembled genomes of three closely related blue mussel lineages from theMytllusspecies complex in the Northern hemisphere. Given the huge diversity within and between lineages in this complex, the objective was to produce affordable genomic resources for population and evolutionary genomic studies to broaden the coverage of this diverse species complex. I used transcriptome guided corrections and scaffolding on a chromosome scale genome of a close species to reduce the fragmentation of the genomes. The result is a set of partially fragmented genomes of equivalent completeness to already published genomes. Three new draft genomes are added to the fast increasing genomic resources of this complex for the MediterraneanM. galloprovlnclalls, the South-EuropeanM. edullsand the the North-EuropeanM. edulls.