bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation and application of recombinant FVIII‐neutralising antibodies from haemophilia A inhibitor patients
Authors: Coxon Carmen H. , Yu Xinren , Beavis James , Diaz‐Saez Laura , Riches‐Duit Andrew , Ball Chris , Diamond Scott L. , Raut Sanj 
Published: May 2021

SummaryThe development of anti‐drug antibodies (ADAs) is a serious outcome of treatment strategies involving biological medicines. Coagulation factor VIII (FVIII) is used to treat haemophilia A patients, but its immunogenicity precludes a third of severe haemophiliac patients from receiving this treatment. The availability of patient‐derived anti‐drug antibodies can help us better understand drug immunogenicity and identify ways to overcome it. Thus, there were two aims to this work: (i) to develop and characterise a panel of recombinant, patient‐derived, monoclonal antibodies covering a range of FVIII epitopes with varying potencies, kinetics and mechanism of action, and (ii) to demonstrate their applicability to assay development, evaluation of FVIII molecules and basic research. For the first objective we used recombinant antibodies to develop a rapid, sensitive, flexible and reproducible ex vivo assay that recapitulates inhibitor patient blood using blood from healthy volunteers. We also demonstrate how the panel can provide important information about the efficacy of FVIII products and reagents without the need for patient or animal material. These materials can be used as experimental exemplars or controls, as well as tools for rational, hypothesis‐driven research and assay development in relation to FVIII immunogenicity and FVIII‐related products.
Inhaled bacteriophage therapy in a porcine model of pneumonia caused by Pseudomonas aeruginosa during mechanical ventilation
Authors: Guillon Antoine , Pardessus Jeoffrey , L'Hostis Guillaume , Fevre Cindy , Barc Celine , Dalloneau Emilie , Jouan Youenn , Bodier‐Montagutelli Elsa , Perez Yonatan , Thorey Camille , Mereghetti Laurent , Cabrera Maria , Riou Mickaël , Vecellio Laurent , Le Guellec Sandrine , Heuzé‐Vourc'h Nathalie 
Published: May 2021

Background and Purpose 255Pseudomonas aeruginosa is a main cause of ventilator‐associated pneumonia (VAP) with drug‐resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of pneumonia caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized‐phage therapy.Experimental Approach(i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled‐phage therapy was evaluated in pigs, which were anaesthetized, mechanically ventilated and infected with P. aeruginosa.Key ResultsBy selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5‐log reduction, p < .001). No infective phage was detected in the sera and urines throughout the experiment.Conclusion and ImplicationsOur findings demonstrated (i) the feasibility of delivering large amounts of active phages by nebulization during mechanical ventilation and (ii) rapid control of in situ infection by inhaled bacteriophage in an experimental model of P. aeruginosa pneumonia with high translational value.
Inactivation of soluble guanylyl cyclase in living cells proceeds without loss of haem and involves heterodimer dissociation as a common step
Authors: Dai Yue , Stuehr Dennis J. 
Published: May 2021

Background and PurposeNitric oxide (NO) activates soluble guanylyl cyclase (sGC) for cGMP production, but in disease, sGC becomes insensitive towards NO activation. What changes occur to sGC during its inactivation in cells is not clear.Experimental ApproachWe utilized HEK293 cells expressing sGC proteins to study the changes that occur regarding its haem content, heterodimer status and sGCβ protein partners when the cells were given the oxidant ODQ or the NO donor NOC12 to inactivate sGC. Haem content of sGCβ was monitored in live cells through use of a fluorescent‐labelled sGCβ construct, whereas sGC heterodimer status and protein interactions were studied by Western blot analysis. Experiments with purified proteins were also performed.Key ResultsODQ‐ or NOC12‐driven inactivation of sGC in HEK293 cells was associated with haem oxidation (by ODQ), S‐nitrosation of the sGCβ subunit (by NOC12), sGC heterodimer breakup and association of the freed sGCβ subunit with cell chaperone Hsp90. These changes occurred without detectable loss of haem from the sGCβ reporter construct. Treating a purified ferrous haem‐containing sGCβ with ODQ or NOC12 caused it to bind with Hsp90 without showing any haem loss.Conclusion and ImplicationsOxidative (ODQ) or nitrosative (NOC12) inactivation of cell sGC involves sGC heterodimer dissociation and rearrangement of the sGCβ protein partners without any haem loss from sGCβ. Clarifying what changes do and do not occur to sGC during its inactivation in cells may direct strategies to preserve or recover NO‐dependent cGMP signalling in health and disease.LINKED ARTICLESThis article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc
From deep roots to new blooms: The ever‐growing field of evo–devo across land plants
Authors: Smith Stacey D. , Blackman Benjamin K. 
Published: May 2021

HighlightsThis editorial synthesizes the contribution of the articles in the special issue on plant evo‐devo to our understanding of major themes, such as the evolution of developmental signaling, the co‐option and modification of shared genetic toolkits, and the link between microevolution and macroevolution.
Making the municipal capital market in nineteenth‐century England†
Authors: Webster Ian 
Published: May 2021

AbstractHow did local authorities in nineteenth‐century England raise the money to finance the building of roads, sewers, gasworks, schools, and hospitals? The literature on local government and capital markets is silent on this question. This article reveals the size of the municipal capital market, how and why it developed, and how it performed. It shows that most of the capital came from private individuals and institutions, with central government having only a modest role. Avoiding defaults, protecting lenders, the move towards standardization, and the development of open markets were all important in improving the credibility of borrowers and reducing the cost of debt. The article also reveals that the municipal capital market shared many similarities with the wider capital market.
Target enhancement or distractor suppression? Functionally distinct alpha oscillations form the basis of attention
Authors: Schneider Daniel , Herbst Sophie K. , Klatt Laura‐Isabelle , Wöstmann Malte 
Published: May 2021

AbstractRecent advances in attention research have been propelled by the debate on target enhancement versus distractor suppression. A predominant neural correlate of attention is the modulation of alpha oscillatory power (~10 Hz), which signifies shifts of attention in time, space and between sensory modalities. However, the underspecified functional role of alpha oscillations limits the progress of tracking down the neurocognitive basis of attention. In this short opinion article, we review and critically examine a synthesis of three conceptual and methodological aspects that are indispensable for a mechanistic understanding of the role of alpha oscillations for attention. (a) Precise mapping of the anatomical source and the temporal response profile of neural signals reveals distinct alpha oscillatory processes that implement facilitatory versus suppressive components of attention. (b) A testable framework enables unanimous association of alpha modulation with either target enhancement or different forms of distractor suppression (active vs. automatic). (c) Linking anatomically specified alpha oscillations to behavior reveals the causal nature of alpha oscillations for attention. The three reviewed aspects substantially enrich study design, data analysis and interpretation of results to achieve the goal of understanding how anatomically specified and functionally relevant neural oscillations contribute to the implementation of facilitatory versus suppressive components of attention.
Breast ultrasound tumour classification: A Machine Learning—Radiomics based approach
Authors: Mishra Arnab K. , Roy Pinki , Bandyopadhyay Sivaji , Das Sujit K. 
Published: May 2021

AbstractPrediction of breast tumour malignancy using ultrasound imaging, is an important step for early detection of breast cancer. An efficient prediction system can be a great help to improve the survival chances of the involved patients. In this work, a machine learning (ML)—radiomics based classification pipeline is proposed, to perform this predictive modelling task, in a much more efficient manner. Multiple different types of image features of the region of interests are considered in this work, followed by a recursive feature elimination based feature selection step. Furthermore, a synthetic minority oversampling technique based step is also included in the pipeline, to deal with the class imbalance problem, that is often present in medical imaging datasets. Various ML models are considered in the subsequent model training phase, on a publicly available breast ultrasound image dataset (BUSI). From experimental analysis it has been observed that, shape, texture and histogram oriented gradients related features are the most informative, with respect to the predictive modelling task. Furthermore, it was observed that ensemble learners such as random forest, gradient boosting and AdaBoost classifiers are able to achieve significant results with respect to multiple evaluation metrics. The proposed approach achieved the state‐of‐the‐art accuracy, area under the curve, F1‐score and Mathews correlation coefficient values of 0.974, 0.97, 0.94 and 0.959, respectively, on the BUSI dataset. Such kind of impressive results suggest that the proposed approach can have a very high practical utility, in real medical diagnostic settings.
Quantification of JAK2V617F mutation load by droplet digital PCR can aid in diagnosis of myeloproliferative neoplasms
Authors: Zheng Chao‐Feng , Zhao Xiao‐Xue , Chen Xiu‐Hua , Liu Zhuang , Wang Wen‐Jun , Luo Ming , Ren Yan , Wang Hong‐Wei 
Published: May 2021

AbstractIntroductionThis study developed a method for quantifying the JAK2V617F mutation load in patients with myeloproliferative neoplasm (MPN) using droplet digital PCR (ddPCR), which provides a new laboratory method for diagnosing polycythemia vera (PV), essential thrombocythemia (ET), and pre‐primary myelofibrosis (pre‐PMF).MethodsPatients with MPN who had JAK2V617F mutations from March 2013 to August 2019 were enrolled in this study. JAK2V617F mutation loads were quantified using ddPCR technology.ResultsThe study examined 225 patients, including 135 with ET, 58 with PV, and 32 with PMF. JAK2V617F mutation loads significantly differed (P < .001) between the ET and PV groups and between the ET and PMF groups. Bone marrow biopsies were reclassified in accordance with the 2016 World Health Organization diagnostic criteria, which revealed 132 patients with MPN: 62 with ET, 35 with PV, 17 with pre‐PMF, and 18 with overt‐PMF. JAK2V617F mutation loads significantly differed (P < .001) between the ET and PV groups and between the ET and pre‐PMF groups. The cutoff value between the ET and pre‐PMF groups was 49.9.ConclusionJAK2V617F mutation loads provide an additional basis for diagnosis of ET, PV, and PMF, particularly regarding differentiation between ET and pre‐PMF.
Applying index of circulating anticoagulant to mixing tests with lupus anticoagulant screen and confirm reagents can distinguish with high specificity between lupus anticoagulants and direct factor Xa inhibitors
Authors: Kumano Osamu , Amiral Jean , Dunois Claire , Peyrafitte Marie , Moore Gary W. 
Published: May 2021

AbstractBackgroundLupus anticoagulants (LA) are detected by prolongation of clotting times for dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) screening tests. Direct oral anticoagulants (DOACs) can interfere with both screening and confirmatory tests. The present study aimed to investigate the influence of direct factor Xa inhibitors (DiXaIs) on screen, confirm and mixing tests and establish a method for differentiation from other sample types.Materials and methodsA total of 257 samples including nonanticoagulated LA positive, LA positive with DiXaIs, factor deficiency, FVIII inhibitors, warfarin and non‐APS DiXaIs were tested. APTT reagents Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used, respectively, to screen/confirm the study group. Index of circulating anticoagulant (ICA) was calculated from clotting times based on the following formula as ICA screening and ICA confirmation. ICA= (1:1 Mix sample – Normal pooled plasma) / Screen patient x 100. An ICA matrix was established which suggested the presence of a DiXaI when both ICA screening and confirmation were above the cut‐off. When only ICA screening is elevated, LA is suspected.ResultsSensitivity and specificity of the ICA matrix were 52.2% and 92.8% for DiXaIs and 38.1% and 96.7% for LA in APTT, and 61.2% and 92.9% for DiXaIs and 22.2% and 88.4% for LA in dRVVT, respectively.ConclusionThe ICA matrix achieved high specificity with a lower apparent sensitivity for DiXaI samples comparatively to other devices but due only to less interferences: the matrix could contribute to differentiating DiXaIs from LA in samples where anticoagulation status is unknown.
Silicon attenuates abiotic stress caused by ammonium toxicity but not nitrogen deficiency in cotton plants
Authors: Leal Aguinaldo José Freitas , Barreto Rafael Ferreira , de Mello Prado Renato , da Silva Junior Gabriel Barbosa , Barreto Cláudio Ferreira , Santos Luiz Cláudio Nascimento dos , Campos Cid Naudi Silva 
Published: May 2021

AbstractAlthough predominates in many soils, compared to , the fluctuations in the forms and concentrations of N can expose to N deficiency in plants in general and toxicity in sensitive plants. However, a strategy to mitigate nutritional disorders of N is to utilize Si. We aimed to verify if Si attenuates N deficiency and toxicity in cotton plants grown in nutrient solution. The treatments followed a 5 × 2 factorial scheme, with five concentrations of (1.0; 7.5; 15.0; 22.5 and 30.0 mmol/L) combined with the absence and presence of Si (1 mmol/L), arranged in a completely randomized design with four replications. Without Si, the largest shoot dry mass occurred at 16 mmol/L , increased by 47%, compared to 1 mmol/L and decreased by 37% compared to 30 mmol/L . With Si, the largest shoot dry mass was observed at 20 mmol/L , increased by 52% compared to 1 mmol/L and decreased by 14% compared to 30 mmol/L . In addition, in the highest concentration of , plants with Si exhibited a higher shoot dry mass relative to plants with no Si supplementation due to decreased electrolyte leakage index and increased use efficiency of N and K. Cotton plants were tolerant to high concentrations (≈15 mmol/L). Si attenuates abiotic stress caused by toxicity (30 mmol/L) but not N deficiency in cotton plants.
Development of the prediction model for hypertension in patients with idiopathic inflammatory myopathies
Authors: Qin Li , Zhang Yiwen , Yang Xiaoqian , Wang Han 
Published: May 2021

AbstractCardiac involvement is an important cause of morbidity and mortality in patients with idiopathic inflammatory myopathies (IIMs). Hypertension, an important cardiovascular risk factor for the general population, has a crucial role in heart involvement. However, few studies have focused on the hypertension associated with IIMs. This study aimed to develop and assess the prediction model for incident hypertension in patients with IIMs. A retrospective cohort study was performed on 362 patients with IIMs, of whom 54 (14.9%) were given a diagnosis of new‐onset hypertension from January 2008 to December 2018. The predictors of hypertension in IIMs were selected by least absolute shrinkage and selection operator (LASSO) regression, multivariable logistic regression, and clinically relevance, and then these predictors were used to draw the nomogram. Discrimination, calibration and clinical usefulness of the model were evaluated using the C‐index, calibration plot, and decision curve analysis, respectively. The predicting model was validated by the bootstrapping validation. The nomogram mainly included predictors such as age, diabetes mellitus, triglyceride, low‐density lipoprotein‐cholesterol (LDL‐C), antinuclear antibodies (ANA), and smoking. This prediction model demonstrated good discrimination with a C‐index of 0.754 (95%CI, 0.684 to 0.824) and good calibration. The C‐index of internal validation was 0.728, and decision curve analysis demonstrated that this nomogram was clinically useful. Clinicians can use this prediction model to assess the risk of hypertension in IIMs patients, and early preventive measures should be taken to reduce the incidence of hypertension in high‐risk patients.
Gastrodin induces lysosomal biogenesis and autophagy to prevent the formation of foam cells via AMPK‐FoxO1‐TFEB signalling axis
Authors: Tao Jun , Yang Ping , Xie Liqiu , Pu Yuwei , Guo Jiazhi , Jiao Jianlin , Sun Lin , Lu Di 
Published: May 2021

AbstractAbnormal accumulation of lipids and massive deposition of foam cells is a primary event in the pathogenesis of atherosclerosis. Recent studies have demonstrated that autophagy and lysosomal function of atherosclerotic macrophages are impaired, which exacerbates the accumulation of lipid in macrophages and formation of foam cells. Gastrodin, a major active component of Gastrodia elata Bl., has exerted a protective effect on nervous system, but the effect of gastrodin on atherosclerotic vascular disease remains unknown. We aimed to evaluate the effect of gastrodin on autophagy and lysosomal function of foam cells and explored the mechanism underlying gastrodin's effect on the formation of foam cells. In an in vitro foam cell model constructed by incubating macrophages with oxygenized low‐density lipoproteins (ox‐LDL), our results showed that lysosomal function and autophagy of foam cells were compromised. Gastrodin restored lysosomal function and autophagic activity via the induction of lysosomal biogenesis and autophagy. The restoration of lysosomal function and autophagic activity enhanced cholesterol efflux from macrophages, therefore, reducing lipid accumulation and preventing formation of foam cells. AMP‐activated protein kinase (AMPK) was activated by gastrodin to promote phosphorylation and nuclear translocation of forkhead box O1 (FoxO1), subsequently resulting in increased transcription factor EB (TFEB) expression. TFEB was activated by gastrodin to promote lysosomal biogenesis and autophagy. Our study revealed that the effect of gastrodin on foam cell formation and that induction of lysosomal biogenesis and autophagy of foam cells through AMPK‐FoxO1‐TFEB signalling axis may be a novel therapeutic target of atherosclerosis.
Natural antioxidants to restore immediate bond strength to bleached enamel: Systematic review and meta‐analysis of in vitro studies
Authors: Rodríguez‐Barragué Juana , Vola‐Gelmini Joanna , Skuras‐Siedemburg Marcel , Rivera‐Gonzaga José Alejandro , Cuevas‐Suarez Carlos Enrique 
Published: May 2021

AbstractObjectiveTo evaluate whether natural antioxidant treatment would enhance the immediate bond strength of dental adhesives to bleached enamel through a systematic review and meta‐analysis.Materials and methodsTwo reviewers performed a literature search up to November 2019 in seven databases. Only in vitro studies that evaluated the effect of the application of natural antioxidants in the bond strength of dental adhesives to bleached enamel were included. Analyses were carried out using RevMan 5.3.5 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). A global analysis was performed with random‐effects models at a significance level of p < 0.05.ResultsTwenty‐four studies were included in the meta‐analysis. Both in‐office (p ˂ 0.001) and at‐home (p ˂ 0.001) bleaching reduced the immediate bond strength. When compared to bleached enamel, all antioxidants improved the bond strength, but only grape seed extract/proanthocyanidin and lycopene restored it to the control values (p ˃ 0.05).ConclusionIn vitro available evidence suggests that the use of natural antioxidants can be beneficial when performing immediate resin‐based restorations after bleaching, however, these results should be taken with caution since they are based on medium and high risk of bias studies; low bias studies are needed to draw relevant conclusions.Clinical significanceDespite the lack of clinical evidence, the present study confirms the benefits of applying natural antioxidant agents to enhance the in vitro bond strength when performing immediate esthetic restorations after bleaching. Since certain antioxidant agents proved more effective than others, clinical investigations may be focused on the ones that withhold the most promising results. The application of natural antioxidants after bleaching may enable immediate esthetic restorations to be performed.
Effect of splenectomy on the outcomes in patients with cirrhosis receiving transjugular intrahepatic portosystemic shunt
Authors: Yang Chongtu , Liu Jiacheng , Shi Qin , Huang Songjiang , Zhou Chen , Wang Yingliang , Li Tongqiang , Chen Yang , Xiong Bin 
Published: May 2021

AbstractBackground and AimPatients indicated to transjugular intrahepatic portosystemic shunt (TIPS) placement may have splenectomy history due to thrombocytopenia. This study aimed to evaluate the effect of prior splenectomy on TIPS procedure and post‐TIPS outcomes.MethodsWe conducted a longitudinal analysis based on a cohort of 284 patients with cirrhosis submitted to TIPS; 74 patients had splenectomy history (splenectomy group) and 210 did not (non‐splenectomy group). Cox proportional hazards models were used to evaluate the association between splenectomy and outcomes after TIPS. The primary outcome was shunt dysfunction. Secondary outcomes included all‐cause mortality, clinical recurrence of bleeding or ascites, and overt hepatic encephalopathy (OHE).ResultsDuring a median follow‐up of 16.2 months, the splenectomy group had significantly lower rates of postoperative shunt patency (85.5% vs 95.6% at 1 year and 75.2% vs 86.5% at 2 years; adjusted hazard ratio [HR] 2.53; 95% confidence interval [CI] 1.21–5.12; P = 0.01) and higher risk of OHE (adjusted HR 1.82; 95% CI 1.03–3.54; P = 0.04). But the risk of mortality (adjusted HR 0.87; 95% CI 0.41–1.87; P = 0.73) and recurrent bleeding or ascites (adjusted HR 1.17; 95% CI 0.53–2.35; P = 0.77) showed no statistical difference. Multivariate analysis confirmed splenectomy history and endoscopic therapy as independent predictors of shunt dysfunction. Besides, pre‐TIPS splenectomy increased the difficulty of TIPS procedure by complicating portal vein puncture.ConclusionsFor patients with cirrhosis submitted to TIPS, prior splenectomy complicated TIPS procedure and increased the risk of shunt dysfunction and OHE after TIPS, but was not significantly associated with the occurrence of mortality and recurrent bleeding or ascites.