bluuebunny/crossref_metadata_2025_split huggingface dataset:
Personalised medicine for Crohn’s disease is a cost-effective strategy
Authors: Buchanan Vanessa , Griffin Susan , Tahir Warda , Hills Karen , Parkes Miles , Smith Kenneth GC , Lyons Paul A , Lee James C , McKinney Eoin F 
Published: December 2022

ABSTRACTObjectiveTo evaluate the cost-effectiveness of a personalised medicine strategy for Crohn’s disease in the UK, using early targeted top-down therapy compared to standard of care.Materials & MethodsA decision tree leading into a Markov state-transition model was constructed, allowing comparison of two treatment approaches: 1) standard of care therapy following established UK clinical guidelines (‘step-up’ treatment) and 2) a personalised medicine strategy in which patients identified as high-risk of subsequent relapse using a prognostic biomarker receive ‘top-down’ anti-TNF treatment at diagnosis. The model facilitated comparison of both costs and Quality Adjusted Life Years (QALYs) in a hypothetical cohort of newly diagnosed Crohn’s disease patients with sensitivity analyses undertaken to model the impact of key assumptions.ResultsEarly personalised treatment with anti-TNF based combination therapy resulted in an incremental cost-effectiveness ratio (ICER) of £2,176 per quality-adjusted life year (QALY), with £717 incremental costs and 0.330 incremental QALYs, substantially below the NICE cost-effectiveness threshold of between £20,000 and £30,000 per QALY. Additional costs relating to earlier biologic use were offset by incremental QALYS and reductions in costs driven by fewer disease flares and hospitalisations. Sensitivity analysis across a wide range of parameter assumptions did not impact on the model’s conclusion.ConclusionA personalised medicine strategy using anti-TNF therapy at diagnosis in Crohn’s disease to patients at high risk of subsequent relapse is highly likely to be a cost-effective use of resources in the UK National Health Service.KEY SUMMARYEstablished KnowledgeCurrently there are no validated prognostic test that can stratify IBD patients based on long term outcomes at the point of diagnosis used routinely in the UKIt therefore remains unclear which patients with Crohn’s disease should be treated with early anti-TNF based therapy as part of a ‘top-down’ regimen.As a consequence, the majority of IBD patients in the UK are currently treated with an accelerated step-up approachSignificant new findingsWe show here that the use of biomarkers at diagnosis to guide personalised use of such treatment is a cost-effective approach for treatment of Crohn’s disease.Use of a prognostic test to deliver personalised medicine for Crohn’s disease results in positive QALY of 0.330The approach is cost effective with an incremental cost of £717 and an ICER of 2,176The model’s conclusions were unaffected by a wide range of sensitivity analyses
Aortic valve stenosis induced occult hemoglobin release promotes endothelial dysfunction
Authors: Quast Christine , Bönner Florian , Polzin Amin , Veulemans Verena , Poku Isabella Gyamfi , Chennupati Ramesh , Nankinova Magdalena , Staub Nicole , Jokiel Juliane , Keyser Fabian , Hoffe Jasmina , Becker Katrin , Leuders Pia , Zako Saif , Erkens Ralf , Jung Christian , Flögel Ulrich , Neidlin Michael , Steinseifer Ulrich , Niepmann Sven Thomas , Zimmer Sebastian , Feelisch Martin , Zeus Tobias , Kelm Malte 
Published: December 2022

AbstractRationaleThe impact of aortic valve stenosis (AS) on systemic endothelial function independent of standard modifiable risk factors (SMuRFs) is unknown.ObjectiveWe hypothesized that AS induces subclinical hemoglobin release from red blood cells (RBCs) following transvalvular passage due to post-stenotic aberrant blood flow and that cell-free hemoglobin (fHb) may limit endothelial NO bioavailability, affecting vascular function.Methods and ResultsAS induces swirling blood flow in the ascending aorta which impairs RBC integrity with consecutive release of fHb. Indeed, swirl flow magnitude assessed by 4D flow cardiac magnetic resonance correlates with fHb levels. Elevated systemic fHb reduces NO bioavailability and thus impairs endothelial cell function as evidenced by impaired flow mediated dilation (FMD). In addition, we here demonstrate impaired FMD in an experimental model of AS utilising C57BL/6 mice with preserved left ventricular function and without cardiovascular risk factors. In this model, endothelial dysfunction is accompanied by significantly increased fHb, exaggerated NO consumption and increased plasma levels of nitroso species and the final NO oxidation product, nitrate. Scavenging of fHb by infusion of haptoglobin reversed these deleterious effects. There observations were verified by transfer experiments with human plasma (sampled from patients with AS sheduled for TAVR) using a murine aortic ring bioassay system where the plasma from AS patients induced endothelial dysfunction when compared to plasma from control individuals without AS. Importantly, these deleterious effects were reversed by successful aortic valve replacement via TAVR independent of SMuRFs.ConclusionsIn aortic valve stenosis, increases in post-valvular swirl blood flow in the ascending aorta induces subclinical hemolysis that impairs NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement limits NO scavenging by realigning of postvalvular blood flow to normal physiological patterns.
Effects of breast fibroepithelial tumor associated retinoic acid receptor alpha ligand binding domain mutations on receptor function and retinoid signaling
Authors: Huang Xi Xiao , Ng Ley Moy , Lee Po-Hsien , Guan Peiyong , Chow Mun Juinn , Mohamed Bashir Aisyah Binte , Lau Meina , Shu Tan Kenric Yi , Li Zhimei , Chan Jason Yongsheng , Hong Jing Han , Ng Sheng Rong , Teo Hsiang Ling , Rhodes Daniela , Tan Patrick , Tan Puay Hoon , McDonnell Donald P. , Teh Bin Tean 
Published: December 2022

AbstractPoint mutations in the ligand binding domain of retinoic acid receptor alpha (RARα) have been implicated in breast fibroepithelial tumors development. However, their role in the tumorigenesis of solid tumors is currently unknown. In this study, using a combination of biochemical and cellular assays, we evaluated the functional consequences of known tumor associated RARα mutations on retinoic acid signaling. All of the clinically associated mutants tested showed diminished transcriptional activities compared to wild type RARα. These mutants also exhibited a dominant negative effect, an activity which has previously been linked to developmental defects and tumor formation in mice. X-ray crystallography showed that mutants remain relatively intact structurally and the loss of transcriptional activity is due to altered co-activator recruitment. In agreement with our biochemical analyses, transcriptomics and cell growth analysis showed that the mutant RARα proteins confer resistance to growth inhibition in the presence of its ligand in phyllodes tumor cells. Although the mutations impair the receptor responses to retinoic acid, certain mutant RARα are partially reactivatable with alternative synthetic agonists. Our data provide insights into the mechanisms by which RARα mutations impact tumorigenesis.
Investigation of whether oxytocin and trust play a role in placebo effects of marketing actions
Authors: Schelski Daniela S. , Scheele Dirk , Schmidt Liane , Hurlemann René , Weber Bernd , Plassmann Hilke 
Published: December 2022

AbstractExpectations about the quality of a medical treatment influence how much an inert treatment helps to improve patient well-being. Similarly, expectations about the quality of products influence how identical goods and services are evaluated differently after their consumption. One driver for such “placebo effects” in medical treatments is social cognition in the form of trust, which may be influenced by the hormone oxytocin. An open question is whether trust and oxytocin play similar roles in marketing placebo effects. To answer this question, we combined oxytocin administration (24 IU) and trust questionnaires in a pre-registered double-blind randomized between-subjects study design (Nfoodtastingtask= 223;Ncognitiveperformancetask= 202). We could not find evidence that oxytocin and trust play a role in placebo effects of marketing actions. Together with other recent null findings from oxytocin administration studies, these findings question the role trust might play in different types of placebo effects.
Parabens Promote Pro-Tumorigenic Effects in Luminal Breast Cancer Cell Lines with Diverse Genetic Ancestry
Authors: Tapia Jazma L. , McDonough Jillian C. , Cauble Emily L. , Gonzalez Cesar G. , Teteh Dede K. , Treviño Lindsey S. 
Published: December 2022

AbstractOne in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate compared to White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing EDCs. Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expressionin vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote pro-tumorigenic effects in breast cancer cell lines of West African ancestry. Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben. Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben- and cell-line specific. This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.
Circular single-stranded DNA is a superior homology-directed repair donor template for efficient genome engineering
Authors: Xie Keqiang , Starzyk Jakob , Majumdar Ishita , Rincones Katerina , Tran Thao , Lee Danna , Niemi Sarah , Famiglietti John , Suter Bernhard , Shan Richard , Wu Hao 
Published: December 2022

AbstractThe toolbox for genome editing in basic research and therapeutic applications is rapidly expanding. While efficient targeted gene ablation using nuclease editors has been demonstrated from bench to bedside, precise transgene integration remains a technical challenge. AAV6 has been a prevalent donor carrier for homology-directed repair (HDR) mediated genome engineering but has reported safety issues, manufacturing constraints, and restricted applications due to its 4.5 Kb packaging limit. Non-viral targeted genetic knock-ins rely primarily on double-stranded DNA (dsDNA) and linear single-stranded DNA (lssDNA) donors. Both dsDNA and lssDNA have been previously demonstrated to have low efficiency and cytotoxicity. Here, we developed a non-viralgenome writingcatalyst(GATALYST™) system which allows production of ultrapure, minicirclesingle-strandedDNAs(cssDNAs) up to ∼20 Kb as donor templates for highly efficient precision transgene integration. cssDNA donors enable knock-in efficiency of up to 70% in induced pluripotent stem cells (iPSCs), superior efficiency in multiple clinically relevant primary cell types, and at multiple genomic loci implicated for clinical applications with various nuclease editor systems. When applied to immune cell engineering, cssDNA engineered CAR-T cells exhibit more potent and durable anti-tumor efficacy than those engineered from AAV6 viral vectors. The exceptional precision and efficiency, improved safety, payload flexibility, and scalable manufacturability of cssDNA unlocks the full potential of genome engineering with broad applications in therapeutic development, disease modeling and other research areas.HighlightsScalable production of minicirclessDNA(cssDNA) with highly engineered phagemid systemGenome writingcatalyst(GATALYST™) system with cssDNA donor template demonstrates superior efficiency and safety in various cell types and genomic lociGATALYST gene writing system enables ultra-large transgene integrationcssDNA engineered CAR-T outperforms AAV engineered CAR-T with superior anti-tumor function
Quantitatively mapping local quality of super-resolution microscopy by rolling Fourier ring correlation
Authors: Zhao Weisong , Huang Xiaoshuai , Yang Jianyu , Qiu Guohua , Qu Liying , Zhao Yue , Zhao Shiqun , Luo Ziying , Wang Xinwei , Jiu Yaming , Mao Heng , Ding Xumin , Tan Jiubin , Hu Ying , Pan Leiting , Chen Liangyi , Li Haoyu 
Published: December 2022

ABSTRACTIn fluorescence microscopy, computational algorithms have been developed to suppress noise, enhance contrast, and even enable super-resolution (SR). However, the local quality of the images may vary on multiple scales, and these differences can lead to misconceptions, which is especially intractable in emerging deep-learning ones. Current mapping methods fail to finely estimate the local quality, challenging to associate the SR scale content. Here, we develop a rolling Fourier ring correlation (rFRC) framework to evaluate the reconstruction uncertainties down to SR scale. To visually pinpoint regions with low reliability, a filtered rFRC is combined with a modified resolution scaled error map (RSM), offering a comprehensive and concise map for further examination. We demonstrate their performances on various SR imaging modalities, and the resulting quantitative maps enable better SR images integrated from different reconstructions. Beyond that, we provide a strategy for learning-based restorations, allowing a direct detection of both data and model uncertainties, and expect the representative cases can inspire further advances in this rapidly developing field.
Metacell projection for interpretable and quantitative use of transcriptional atlases
Authors: Ben-Kiki Oren , Bercovich Akhiad , Lifshitz Aviezer , Tanay Amos 
Published: December 2022

ABSTRACTWe describe MCProj - an algorithm for analyzing query scRNA-seq data by projections over reference single cell atlases. We represent the reference as a manifold consisting of annotated metacell gene expression distributions. We then infer query metacells as mixtures of atlas distributions while correcting for technology-specific gene biases. This approach distinguishes and tags query cells that are consistent with existing atlas states from novel or artifactual behaviors that are not observed in the atlas. It also identifies significant expression differences observed in query states that are mapped coherently onto the atlas. We showcase MCProj functionality by analyzing blood gene expression from multiple sources and technologies, suggesting it as a method of choice for scRNA-seq analysis following extensive cell atlas projects.
An epitope-enriched immunogen increases site targeting in germinal centers
Authors: Caradonna Timothy M. , Windsor Ian W. , Roffler Anne A. , Song Shengli , Watanabe Akiko , Kelsoe Garnett , Kuraoka Masayuki , Schmidt Aaron G. 
Published: December 2022

ABSTRACTAntibody immunodominance is the asymmetric elicitation of responses against protein antigens. For influenza hemagglutinin (HA), antibody responses often target variable regions on HA and do not provide lasting protection. Next-generation influenza vaccines should elicit antibodies targeting conserved regions such as the receptor binding site (RBS). Understanding how presenting an epitope on a rationally-designed immunogen influences immune responses could help achieve this goal. Here, we compared an engineered RBS-enriched immunogen and its non-enriched counterparts to characterize RBS-directed responses. We found that enriching the RBS-epitope on a single immunogen preferentially expands RBS-directed responses relative to a cocktail of the non-epitope-enriched immunogens. Single B cell analyses showed a genetically diverse RBS-directed population that structural characterization showed engagement of the RBS with canonical features shared with both its receptor and human broadly neutralizing antibodies. These data show how epitope-enriched immunogens can expand responses to a conserved viral site, while maintaining genetic and structural diversity.
Chimeric U-Net – Modifying the standard U-Net towards Explainability
Authors: Schulze Kenrick , Peppert Felix , Schütte Christof , Sunkara Vikram 
Published: December 2022

Healthcare guided by semantic segmentation has the potential to improve our quality of life through early and accurate disease detection. Convolutional Neural Networks, especially the U-Net-based architectures, are currently the state-of-the-art learningbased segmentation methods and have given unprecedented performances. However, their decision-making processes are still an active field of research. In order to reliably utilize such methods in healthcare, explainability of how the segmentation was performed is mandated. To date, explainability is studied and applied heavily in classification tasks. In this work, we propose the Chimeric U-Net, a U-Net architecture with an invertible decoder unit, that inherently brings explainability into semantic segmentation tasks. We find that having the restriction of an invertible decoder does not hinder the performance of the segmentation task. However, the invertible decoder helps to disentangle the class information in the latent space embedding and to construct meaningful saliency maps. Furthermore, we found that with a simple k-Nearest-Neighbours classifier, we could predict the Intersection over Union scores of unseen data, demonstrating that the latent space, constructed by the Chimeric U-Net, encodes an interpretable representation of the segmentation quality. Explainability is an emerging field, and in this work, we propose an alternative approach, that is, rather than building tools for explaining a generic architecture, we propose constraints on the architecture which induce explainability. With this approach, we could peer into the architecture to reveal its class correlations and local contextual dependencies, taking an insightful step towards trustworthy and reliable A.I.Code to build and utilize the Chimeric U-Net is made available under:https://github.com/kenrickschulze/Chimeric-UNet---Half-invertible-UNet-in-Pytorch
The oncogenic fusion protein TAZ-CAMTA1 promotes genomic instability and senescence through hypertranscription
Authors: Neil Emily , Rubin Brian , Kouskoff Valerie 
Published: December 2022

AbstractTAZ-CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ-CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ-CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ-CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ-CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ-CAMTA1-expressing cells enter senescence. Knockout ofCdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.
Blochmanniaendosymbionts reduce brood rearing success in a carpenter ant (Camponotussp.)
Authors: Preuss Anika , Czuppon Peter , Ernst Ulrich R. , Gadau Jürgen 
Published: December 2022

AbstractAll ants of the species rich genusCamponotus(‘carpenter ants’) possess the obligate intracellular bacterial mutualistBlochmannia. We tested the relevance of the endosymbiontBlochmanniafor offspring rearing using cross-fostering experiments betweenCamponotussp. colonies and subcolonies (worker groups), which were either treated with antibiotics to removeBlochmanniaor untreated. Our antibiotic treatment reduced the level ofBlochmanniaendosymbionts in eggs, larvae and workers significantly. Corroborating previous results, we found that eggs from treated colonies had a significantly reduced probability to develop into larvae and almost zero probability to become adults. Surprisingly, subcolonies treated with antibiotics had a significantly higher success in raising their own and foreign eggs from treated and untreated colonies than untreated subcolonies. This might indicate that theBlochmanniasymbiosis entails significant costs for the host in terms of brood rearing, i.e., symbiont-free workers are more successful in brood rearing than untreated workers. If confirmed, this would be a rare case where the costs of a symbiosis can be empirically measured and quantified. Alternatively, the antibiotic treatment increased as a side effect the brood rearing effort of workers leading to the differences in brood rearing success of treated workers. But even if that would be the case, it still indicates that workers that have either lost or have a significantly reduced number of endosymbionts can still raise brood from antibiotic-treated and untreated colonies better than untreated workers. ThusBlochmannia, although crucial for brood development, may reduce the amount of brood a colony can raise.
Genome-wide Identification and Expression Profile Analysis of Laccase Family Genes in theHypsizygus marmoreus
Authors: Wang Gang , Wang Cheng , Wang HongBo , Zhu Ying , Wang Yuanyuan , chen Yu , Ma Lin , Sun Zijun , Liu Bobin , Liu Fang 
Published: December 2022

AbstractLaccase exists widely in plants and fungi. It is a copper-containing polyphenol oxidase that can degrade lignin, oxidate, and phenolic substances, inhibit heterophytes, promote fruiting body formation, and improve the quality of mushrooms. In this study, 18 laccase genes were identified from the whole genome of a white strain (HM62) ofHypsizygus marmoreus, and the mapping, structure, and evolution of laccase genes were analyzed at the whole genome level, while the spatiotemporal expression was evaluated at different developmental stages. The laccase genes mainly distributed on chromosomes 1, 2, 3, 4, 6, 9, and 10, and 9 genes were clustered linearly on chromosome 6, indicating gene doubling. Phylogenetic tree analysis showed that the laccase gene family was divided into three subfamilies. The spatiotemporal expression analysis of the laccase gene family showed thatHmLac09andHmLac10were highly expressed in different periods and might be involved in lignin degradation and fruit body formation, respectively. The expression levels ofHmLac02, HmLac05, HmLac08, andHmLac17genes in gray or gray and white heterozygous strains were higher than those in white strains, which might be related to the difference in lignin decomposition in gray strains, and one of the factors leading to different growth rates. The present study investigated the characterization of theH. marmoreuslaccase gene family, extending our understanding of laccase mediated fruiting body development and growth rate mechanisms in this fungi.