bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction
Authors: Tombor Lukas S. , John David , Glaser Simone F. , Luxán Guillermo , Forte Elvira , Furtado Milena , Rosenthal Nadia , Baumgarten Nina , Schulz Marcel H. , Wittig Janina , Rogg Eva-Maria , Manavski Yosif , Fischer Ariane , Muhly-Reinholz Marion , Klee Kathrin , Looso Mario , Selignow Carmen , Acker Till , Bibli Sofia-Iris , Fleming Ingrid , Patrick Ralph , Harvey Richard P. , Abplanalp Wesley T. , Dimmeler Stefanie 
Published: January 2021

AbstractEndothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.
H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
Authors: Cai Yichao , Zhang Ying , Loh Yan Ping , Tng Jia Qi , Lim Mei Chee , Cao Zhendong , Raju Anandhkumar , Lieberman Aiden Erez , Li Shang , Manikandan Lakshmanan , Tergaonkar Vinay , Tucker-Kellogg Greg , Fullwood Melissa Jane 
Published: January 2021

AbstractThe mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping.
Real-time interleaved spectroscopic photoacoustic and ultrasound (PAUS) scanning with simultaneous fluence compensation and motion correction
Authors: Jeng Geng-Shi , Li Meng-Lin , Kim MinWoo , Yoon Soon Joon , Pitre John J. , Li David S. , Pelivanov Ivan , O’Donnell Matthew 
Published: January 2021

AbstractFor over two decades photoacoustic imaging has been tested clinically, but successful human trials have been limited. To enable quantitative clinical spectroscopy, the fundamental issues of wavelength-dependent fluence variations and inter-wavelength motion must be overcome. Here we propose a real-time, spectroscopic photoacoustic/ultrasound (PAUS) imaging approach using a compact, 1-kHz rate wavelength-tunable laser. Instead of illuminating tissue over a large area, the fiber-optic delivery system surrounding an US array sequentially scans a narrow laser beam, with partial PA image reconstruction for each laser pulse. The final image is then formed by coherently summing partial images. This scheme enables (i) automatic compensation for wavelength-dependent fluence variations in spectroscopic PA imaging and (ii) motion correction of spectroscopic PA frames using US speckle tracking in real-time systems. The 50-Hz video rate PAUS system is demonstrated in vivo using a murine model of labelled drug delivery.
DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously
Authors: Beckmann Roland , Jensen Kristian , Fenn Sebastian , Speck Janina , Krause Katrin , Meier Anastasia , Röth Melanie , Fauser Sascha , Kimbung Raymond , Logan Derek T. , Steegmaier Martin , Kettenberger Hubert 
Published: January 2021

AbstractWe report the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops: the so-called H-side paratope encompassing HCDR1, HCDR3 and LCDR2, and the L-side paratope encompassing LCDR1, LCDR3 and HCDR2. Both paratopes can be independently selected and combined into the desired bispecific DutaFabs in a modular manner. X-ray crystal structures illustrate that DutaFabs are able to bind two target molecules simultaneously at the same Fv region comprising a VH-VL heterodimer. In the present study, this platform is applied to generate DutaFabs specific for VEGFA and PDGF-BB, which show high affinities, physico-chemical stability and solubility, as well as superior efficacy over anti-VEGF monotherapy in vivo. These molecules exemplify the usefulness of DutaFabs as a distinct class of antibody therapeutics, which is currently being evaluated in patients.
Deep convolutional neural networks to predict cardiovascular risk from computed tomography
Authors: Zeleznik Roman , Foldyna Borek , Eslami Parastou , Weiss Jakob , Alexander Ivanov , Taron Jana , Parmar Chintan , Alvi Raza M. , Banerji Dahlia , Uno Mio , Kikuchi Yasuka , Karady Julia , Zhang Lili , Scholtz Jan-Erik , Mayrhofer Thomas , Lyass Asya , Mahoney Taylor F. , Massaro Joseph M. , Vasan Ramachandran S. , Douglas Pamela S. , Hoffmann Udo , Lu Michael T. , Aerts Hugo J. W. L. 
Published: January 2021

AbstractCoronary artery calcium is an accurate predictor of cardiovascular events. While it is visible on all computed tomography (CT) scans of the chest, this information is not routinely quantified as it requires expertise, time, and specialized equipment. Here, we show a robust and time-efficient deep learning system to automatically quantify coronary calcium on routine cardiac-gated and non-gated CT. As we evaluate in 20,084 individuals from distinct asymptomatic (Framingham Heart Study, NLST) and stable and acute chest pain (PROMISE, ROMICAT-II) cohorts, the automated score is a strong predictor of cardiovascular events, independent of risk factors (multivariable-adjusted hazard ratios up to 4.3), shows high correlation with manual quantification, and robust test-retest reliability. Our results demonstrate the clinical value of a deep learning system for the automated prediction of cardiovascular events. Implementation into clinical practice would address the unmet need of automating proven imaging biomarkers to guide management and improve population health.
Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth
Authors: Munir Hafsa , Jones James O. , Janowitz Tobias , Hoffmann Markus , Euler Maximilien , Martins Carla P. , Welsh Sarah J. , Shields Jacqueline D. 
Published: January 2021

AbstractTumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses
Authors: Li Shuo , Raychaudhuri Sumana , Lee Stephen Alexander , Brockmann Marisa M. , Wang Jing , Kusick Grant , Prater Christine , Syed Sarah , Falahati Hanieh , Ramos Raul , Bartol Tomas M. , Hosy Eric , Watanabe Shigeki 
Published: January 2021

AbstractNeurotransmitter is released synchronously and asynchronously following an action potential. Our recent study indicates that the release sites of these two phases are segregated within an active zone, with asynchronous release sites enriched near the center in mouse hippocampal synapses. Here we demonstrate that synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement of release can lead to maximal membrane depolarization through AMPA receptors, alleviating the pore-blocking magnesium leading to greater activation of NMDA receptors. Together, these results suggest that release sites are likely organized to activate NMDA receptors efficiently.
Influence of cytochrome P450 2D6 polymorphism on hippocampal white matter and treatment response in schizophrenia
Authors: Shin Wonsuk , Bang Minji , Kim Anhye , Cho Doo-Yeoun , Lee Sang-Hyuk 
Published: January 2021

AbstractCytochrome P450 2D6 (CYP2D6) is expressed at high levels in the brain and plays a considerable role in the biotransformation and neurotransmission of dopamine. This raises the question of whether CYP2D6 variations and its impact on the brain can confer susceptibility to schizophrenia. We investigated the possible links among the CYP2D6 genotype, white matter (WM) integrity of the hippocampus, and the treatment response to antipsychotic drugs in Korean patients with schizophrenia (n = 106). Brain magnetic resonance imaging and genotyping for CYP2D6 were conducted at baseline. The severity of clinical symptoms and the treatment response were assessed using the Positive and Negative Syndrome Scale (PANSS). After genotyping, 43 participants were classified as intermediate metabolizers (IM), and the remainder (n = 63) were classified as extensive metabolizers (EM). IM participants showed significantly higher fractional anisotropy (FA) values in the right hippocampus compared to EM participants. Radial diffusivity (RD) values were significantly lower in the overlapping region of the right hippocampus in the IM group than in the EM group. After 4 weeks of antipsychotic treatment, the EM group showed more improvements in positive symptoms than the IM group. FAs and RDs in the CYP2D6-associated hippocampal WM region were significantly correlated with a reduction in the positive symptom subscale of the PANSS. Greater improvements in positive symptoms were negatively associated with FAs, and positively associated with RDs in the right hippocampal region. The findings suggest that CYP26D-associated hippocampal WM alterations could be a possible endophenotype for schizophrenia that accounts for individual differences in clinical features and treatment responses.
Hepatitis A virus knowledge and immunization attitudes and practices in the United Arab Emirates community
Authors: Samara Kamel A. , Barqawi Hiba J. , Aboelsoud Basant H. , AlZaabi Moza A. , Alraddawi Fay T. , Mannaa Ayten A. 
Published: January 2021

AbstractAnnually, 1.5 million cases of hepatitis A infection occur worldwide. The United Arab Emirates (U.A.E.) has seen a decrease in infection rates and seroprevalence coupled with an increase in the average age of infection. This study aimed to assess the U.A.E. society’s hepatitis A knowledge, and attitudes and vaccination practices, with the applicability of its introduction into the local immunization schedule. A self-administered, 50-item questionnaire was used to collect data from the four most populous cities in the U.A.E., between January and March 2020. A total of 458 responses were collected and analysed using IBM-SPSS-26, R-4.0.0 and Matplotlib-v3.2.1. Females had better attitudes (P = 0.036), practices (P < 0.0005), immunization schedule knowledge (AOR = 3.019; CI 1.482–6.678), and appreciation of the immunization schedule (AOR = 2.141; CI 1.310–3.499). A higher level of perceived knowledge was associated with an actual better knowledge (P < 0.0005), better practices (P = 0.011), and increased willingness to get vaccinated (AOR = 1.988; CI 1.032–3.828). Respondents were more likely to vaccinate their children against HAV if the vaccine were introduced into the National Immunization Program (P < 0.0005). Overall, disease knowledge was lacking but with positive attitudes and poor practices. There is high trust in the National Immunization Program and a potential for improving poor practices through local awareness campaigns.
Towards a mechanistic understanding of particle shrinkage during biomass pyrolysis via synchrotron X-ray microtomography and in-situ radiography
Authors: Barr Meredith Rose , Jervis Rhodri , Zhang Yeshui , Bodey Andrew J. , Rau Christoph , Shearing Paul R. , Brett Dan J. L. , Titirici Maria‐Magdalena , Volpe Roberto 
Published: January 2021

AbstractAccurate modelling of particle shrinkage during biomass pyrolysis is key to the production of biochars with specific morphologies. Such biochars represent sustainable solutions to a variety of adsorption-dependent environmental remediation challenges. Modelling of particle shrinkage during biomass pyrolysis has heretofore been based solely on theory and ex-situ experimental data. Here we present the first in-situ phase-contrast X-ray imaging study of biomass pyrolysis. A novel reactor was developed to enable operando synchrotron radiography of fixed beds of pyrolysing biomass. Almond shell particles experienced more bulk shrinkage and less change in porosity than did walnut shell particles during pyrolysis, despite their similar composition. Alkaline pretreatment was found to reduce this difference in feedstock behaviour. Ex-situ synchrotron X-ray microtomography was performed to study the effects of pyrolysis on pore morphology. Pyrolysis led to a redistribution of pores away from particle surfaces, meaning newly formed surface area may be less accessible to adsorbates.
Design of epidermal growth factor immobilization on 3D biocompatible scaffolds to promote tissue repair and regeneration
Authors: Bavaro Teodora , Tengattini Sara , Rezwan Refaya , Chiesa Enrica , Temporini Caterina , Dorati Rossella , Massolini Gabriella , Conti Bice , Ubiali Daniela , Terreni Marco 
Published: January 2021

AbstractExogenous application of human epidermal growth factor (hEGF) stimulates epidermal wound healing. The aim of this study was to develop bioconjugates based on hEGF mimicking the protein in its native state and thus suitable for tissue engineering applications, in particular for treating skin-related disorders as burns. Ribonuclease A (RNase A) was used to investigate a number of different activated-agarose carriers: cyanogen bromide (CNBr)-activated-agarose and glyoxyl-agarose showed to preserve the appropriate orientation of the protein for receptor binding. EGF was immobilized on these carriers and immobilization yield was evaluated (100% and 12%, respectively). A peptide mapping of unbound protein regions was carried out by LC–MS to take evidence of the residues involved in the immobilization and, consequently, the flexibility and surface accessibility of immobilized EGF. To assess cell proliferative activities, 10, 25, 50, and 100 ng/mL of each immobilized EGF sample were seeded on fibroblast cells and incubated for 24, 48 and 72 h. The immobilized growth factor showed significantly high cell proliferative activity at 50 and 100 ng/mL compared to control and soluble EGF. Although both of the immobilized samples show dose-dependency when seeded with high number of fibroblast cells, CNBr-agarose-EGF showed a significantly high activity at 100 ng/mL and 72 h incubation, compared to glyoxyl-agarose-EGF.
Signalling pathways and mechanistic cues highlighted by transcriptomic analysis of primordial, primary, and secondary ovarian follicles in domestic cat
Authors: Kehoe Shauna , Jewgenow Katarina , Johnston Paul R. , Mbedi Susan , Braun Beate C. 
Published: January 2021

AbstractIn vitro growth (IVG) of dormant primordial ovarian follicles aims to produce mature competent oocytes for assisted reproduction. Success is dependent on optimal in vitro conditions complemented with an understanding of oocyte and ovarian follicle development in vivo. Complete IVG has not been achieved in any other mammalian species besides mice. Furthermore, ovarian folliculogenesis remains sparsely understood overall. Here, gene expression patterns were characterised by RNA-sequencing in primordial (PrF), primary (PF), and secondary (SF) ovarian follicles from Felis catus (domestic cat) ovaries. Two major transitions were investigated: PrF-PF and PF-SF. Transcriptional analysis revealed a higher proportion in gene expression changes during the PrF-PF transition. Key influencing factors during this transition included the interaction between the extracellular matrix (ECM) and matrix metalloproteinase (MMPs) along with nuclear components such as, histone HIST1H1T (H1.6). Conserved signalling factors and expression patterns previously described during mammalian ovarian folliculogenesis were observed. Species-specific features during domestic cat ovarian folliculogenesis were also found. The signalling pathway terms “PI3K-Akt”, “transforming growth factor-β receptor”, “ErbB”, and “HIF-1” from the functional annotation analysis were studied. Some results highlighted mechanistic cues potentially involved in PrF development in the domestic cat. Overall, this study provides an insight into regulatory factors and pathways during preantral ovarian folliculogenesis in domestic cat.
The usefulness of SwiftScan technology for bone scintigraphy using a novel anthropomorphic phantom
Authors: Shibutani Takayuki , Onoguchi Masahisa , Naoi Yuka , Yoneyama Hiroto , Konishi Takahiro , Tatami Ringo , Nakajima Kenichi 
Published: January 2021

AbstractThe aim of this study was to demonstrate the usefulness of SwiftScan with a low-energy high-resolution and sensitivity (LEHRS) collimator for bone scintigraphy using a novel bone phantom simulating the human body. SwiftScan planar image of lateral view was acquired in clinical condition; thereafter, each planar image of different blend ratio (0–80%) of Crality 2D processing were created. SwiftScan planar images with reduced acquisition time by 25–75% were created by Poisson’s resampling processing. SwiftScan single photon emission computed tomography (SPECT) was acquired with step-and-shoot and continuous mode, and SPECT images were reconstructed using a three-dimensional ordered subset expectation maximization incorporating attenuation, scatter and spatial resolution corrections. SwiftScan planar image showed a high contrast to noise ratio (CNR) and low percent of the coefficient of variance (%CV) compared with conventional planar image. The CNR of the tumor parts in SwiftScan SPECT was higher than that of the conventional SPECT image of step and shoot acquisition, while the %CV showed the lowest value in all systems. In conclusion, SwiftScan planar and SPECT images were able to reduce the image noise compared with planar and SPECT image with a low-energy high-resolution collimator, so that SwiftScan planar and SPECT images could be obtained a high CNR. Furthermore, the SwiftScan planar image was able to reduce the acquisition time by 25% when the blend ratio of Clarity 2D processing set to more than 40%.
A multilayer multimodal detection and prediction model based on explainable artificial intelligence for Alzheimer’s disease
Authors: El-Sappagh Shaker , Alonso Jose M. , Islam S. M. Riazul , Sultan Ahmad M. , Kwak Kyung Sup 
Published: January 2021

AbstractAlzheimer’s disease (AD) is the most common type of dementia. Its diagnosis and progression detection have been intensively studied. Nevertheless, research studies often have little effect on clinical practice mainly due to the following reasons: (1) Most studies depend mainly on a single modality, especially neuroimaging; (2) diagnosis and progression detection are usually studied separately as two independent problems; and (3) current studies concentrate mainly on optimizing the performance of complex machine learning models, while disregarding their explainability. As a result, physicians struggle to interpret these models, and feel it is hard to trust them. In this paper, we carefully develop an accurate and interpretable AD diagnosis and progression detection model. This model provides physicians with accurate decisions along with a set of explanations for every decision. Specifically, the model integrates 11 modalities of 1048 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) real-world dataset: 294 cognitively normal, 254 stable mild cognitive impairment (MCI), 232 progressive MCI, and 268 AD. It is actually a two-layer model with random forest (RF) as classifier algorithm. In the first layer, the model carries out a multi-class classification for the early diagnosis of AD patients. In the second layer, the model applies binary classification to detect possible MCI-to-AD progression within three years from a baseline diagnosis. The performance of the model is optimized with key markers selected from a large set of biological and clinical measures. Regarding explainability, we provide, for each layer, global and instance-based explanations of the RF classifier by using the SHapley Additive exPlanations (SHAP) feature attribution framework. In addition, we implement 22 explainers based on decision trees and fuzzy rule-based systems to provide complementary justifications for every RF decision in each layer. Furthermore, these explanations are represented in natural language form to help physicians understand the predictions. The designed model achieves a cross-validation accuracy of 93.95% and an F1-score of 93.94% in the first layer, while it achieves a cross-validation accuracy of 87.08% and an F1-Score of 87.09% in the second layer. The resulting system is not only accurate, but also trustworthy, accountable, and medically applicable, thanks to the provided explanations which are broadly consistent with each other and with the AD medical literature. The proposed system can help to enhance the clinical understanding of AD diagnosis and progression processes by providing detailed insights into the effect of different modalities on the disease risk.