bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective large-scale evaluation of an AI system as an independent reader for double reading in breast cancer screening
Authors: Sharma Nisha , Ng Annie Y. , James Jonathan J. , Khara Galvin , Ambrozay Eva , Austin Christopher C. , Forrai Gabor , Fox Georgia , Glocker Ben , Heindl Andreas , Karpati Edit , Rijken Tobias M. , Venkataraman Vignesh , Yearsley Joseph E. , Kecskemethy Peter D. 
Published: March 2021

AbstractImportanceScreening mammography with two human readers increases cancer detection and lowers recall rates, but workforce shortages make double reading unsustainable in many countries. Artificial intelligence (AI) as an independent reader in double reading may support screening performance while improving cost-effectiveness. The clinical validation of AI requires large-scale, multi-vendor studies on unenriched cohorts.ObjectiveTo evaluate the performance of the Mia® AI system on data that the AI system would process in real-world deployments.DesignA retrospective study simulating the impact of AI on an unenriched screening sample.SettingSeven European breast screening sites representing four centers: three from the UK and one in Hungary (HU), between 2009 and 2019.ParticipantsThe sample included 275,900 cases (177,882 participants) from seven screening sites, involving two countries and four hardware vendors from 2009 to 2019.InterventionSimulation of double reading using AI as an independent reader in breast cancer screening on historical data.Main Outcomes and MeasuresPerformance was determined for standalone AI compared to the historical single reader and for simulated double reading with AI compared to historical double reading, assessing non-inferiority and superiority on relevant screening metrics using a non-inferiority margin of 10% relative difference and a one-sided alpha of 2.5% for both tests.ResultsStandalone AI detected 29.8% of missed interval cancers. When compared with historical double reading, double reading with AI showed non-inferiority for sensitivity and superiority for recall rate, specificity and positive predictive value. AI as an independent reader reduced the workload for the second human reader but increased the arbitration rate from 3.3% to 12.3%. Applying the AI system could have reduced the human reading time required by up to 44.8% and reduced the recall rate by a relative 7.7% (from 5.2% to 4.8%).Conclusions and RelevanceUsing the AI system as an independent reader maintains or improves the double reading standard of care, while substantially reducing the workload. Thus, it has the potential to provide operational and economic benefits.Trial RegistrationRegistered on ISRCTN, study ID: ISRCTN18056078
Rapid stress hardening in the Antarctic midge improves male fertility by increasing courtship success and preventing the decline of accessory gland proteins following cold exposure
Authors: Ajayi Oluwaseun M. , Gantz J. D. , Finch Geoffrey , Lee Richard E. , Denlinger David L. , Benoit Joshua B. 
Published: March 2021

AbstractRapid hardening is a process that quickly improves an animal’s performance following exposure to a potentially damaging stress. Features of reproduction can be improved by rapid hardening, but little is known about how rapid hardening may contribute to physiological responses in the cold environment of Antarctica. In this study of the Antarctic midge,Belgica antarctica(Diptera, Chironomidae), we examine how rapid hardening in response to dehydration (RDH) or cold (RCH) improves male pre- and post-copulatory function related to fertility when the insects are subsequently subjected to a damaging cold exposure. Neither RDH nor RCH improved survival in response to lethal cold stress, but male activity following sublethal cold exposure was enhanced. Both RCH and RDH improved mating success of males compared to those subjected directly to a sublethal bout of cold. Egg viability decreased following direct exposure to sublethal cold, but improved following RCH and RDH. Sublethal cold exposure reduced expression of four accessory gland proteins, while expression remained high in males exposed to RCH. Though rapid hardening may be cryptic in males, this study shows that it can be revealed by pre- and post-copulatory interactions with females.
Visual stimulation with blue wavelength light drives V1 effectively eliminating stray light contamination during two-photon calcium imaging
Authors: Kuznetsova Tatiana , Antos Kamil , Malinina Evgenya , Papaioannou Stylianos , Medini Paolo 
Published: March 2021

AbstractBACKGROUNDBrain visual circuits are often studiedin vivoby imaging Ca2+indicators with green-shifted emission spectra. Polychromatic white visual stimuli have a spectrum that partially overlaps indicators’ emission spectra, resulting in significant contamination of calcium signals.NEW METHODTo overcome light contamination problems we choose blue visual stimuli, having a spectral composition not overlapping with Ca2+indicator’s emission spectrum. To compare visual responsiveness to blue and white stimuli we used electrophysiology (visual evoked potentials–VEPs) and 3D acousto-optic two-photon(2P) population Ca2+imaging in mouse primary visual cortex (V1).RESULTSVEPs in response to blue and white stimuli had comparable peak amplitudes and latencies. Ca2+imaging revealed that the populations of neurons responding to blue and white stimuli were largely overlapping, that their responses had similar amplitudes, and that functional response properties such as orientation and direction selectivities were also comparable.COMPARISON WITH EXISTING METHODSMasking or shielding the microscope are often used to minimize the contamination of Ca2+signal by white light, but they are time consuming, bulky and thus can limit experimental design, particularly in the more and more frequently used awake set-up. Blue stimuli not interfering with imaging allow to omit shielding without affecting V1 physiological responsiveness.CONCLUSIONSOur results show that the selected blue light stimuli evoke physiological responses comparable to those evoked by white stimuli in mouse V1. This will make complex designs of imaging experiments in behavioral set-ups easier, and facilitate the combination of Ca2+imaging with electrophysiology and optogenetics.HighlightsWhite and blue light trigger VEPs with similar amplitudes and latencies in mouse V1Blue-and white-responding neurons are two largely overlapping neuronal populationsBlue and white evoke Ca2+responses similar in magnitude and latencyBlue and white evoke Ca2+responses similar in orientation/direction selectivityBlue stimuli could be an alternative to white ones in behavior and opto-physiological testsAbstract Figure
Effect of SARS-CoV-2 proteins on vascular permeability
Authors: Rauti Rossana , Shahoha Meishar , Leichtmann-Bardoogo Yael , Nasser Rami , Tamir Rina , Miller Victoria , Babich Tal , Shaked Kfir , Ehrlich Avner , Ioannidis Konstantinos , Nahmias Yaakov , Sharan Roded , Ashery Uri , Maoz Ben M. 
Published: March 2021

AbstractSARS-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5) and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by COVID-19. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.
GPRuler: metabolic Gene-Protein-Reaction rules automatic reconstruction
Authors: Di Filippo Marzia , Damiani Chiara , Pescini Dario 
Published: March 2021

AbstractBackgroundMetabolic network models are increasingly being used in health care and industry. As a consequence, many tools have been released to automate their reconstruction processde novo. In order to enable gene deletion simulations and integration of gene expression data, these networks must include gene-protein-reaction (GPR) rules, which describe with a Boolean logic relationships between the gene products (e.g., enzyme isoforms or subunits) associated with the catalysis of a given reaction. Nevertheless, the reconstruction of GPRs still remains a largely manual and time consuming process. Aiming at fully automating the reconstruction process of GPRs for any organism, we propose the open-source python-based frameworkGPRuler.ResultsBy mining text and data from 9 different biological databases,GPRulercan reconstruct GPRs starting either from just the name of the target organism or from an existing metabolic model. The performance of the developed tool is evaluated at small-scale level for a manually curated metabolic model, and at genome-scale level for three metabolic models related toHomo sapiensandSaccharomyces cerevisiaeorganisms. By exploiting these models as benchmarks, the proposed tool shown its ability to reproduce the original GPR rules with a high level of accuracy. In all the tested scenarios, after a manual investigation of the mismatches between the rules proposed byGPRulerand the original ones, the proposed approach revealed to be in many cases more accurate than the original models.ConclusionsBy complementing existing tools for metabolic network reconstruction with the possibility to reconstruct GPRs quickly and with a few resources,GPRulerpaves the way to the study of context-specific metabolic networks, representing the active portion of the complete network in given conditions, for organisms of industrial or biomedical interest that have not been characterized metabolically yet.
HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver
Authors: Deans Jonathan R. , Deol Poonamjot , Titova Nina , Radi Sarah H. , Vuong Linh M. , Evans Jane R. , Pan Songqin , Fahrmann Johannes , Yang Jun , Hammock Bruce D. , Fiehn Oliver , Fekry Baharan , Eckel-Mahan Kristin , Sladek Frances M. 
Published: March 2021

AbstractHepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2- HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. We demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4α exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. Taken together, we propose that the highly conserved two-promoter structure of theHnfagene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.
Brain Dynamics of Spatial Reference Frame Proclivity in Active Navigation
Authors: Yang Che-Sheng , Liu Jia , Singh Avinash Kumar , Huang Kuan-Chih , Lin Chin-Teng 
Published: March 2021

AbstractRecent research into navigation strategy of different spatial reference frame proclivities (RFPs) has revealed that the parietal cortex plays an important role in processing allocentric information to provide a translation function between egocentric and allocentric spatial reference frames. However, most studies merely focused on a passive experimental environment, which is not truly representative of our daily spatial learning/navigation tasks. This study investigated the factor associated with brain dynamics that causes people to switch their preferred spatial strategy in different environments in virtual reality (VR) based active navigation task to bridge the gap. High-resolution electroencephalography (EEG) signals were recorded to monitor spectral perturbations on transitions between egocentric and allocentric frames during a path integration task. Our brain dynamics results showed navigation involved areas including the parietal cortex with modulation in the alpha band, the occipital cortex with beta and low gamma band perturbations, and the frontal cortex with theta perturbation. Differences were found between two different turning-angle paths in the alpha band in parietal cluster event-related spectral perturbations (ERSPs). In small turning-angle paths, allocentric participants showed stronger alpha desynchronization than egocentric participants; in large turning-angle paths, participants for two reference frames had a smaller difference in the alpha frequency band. Behavior results of homing errors also corresponded to brain dynamic results, indicating that a larger angle path caused the allocentric to have a higher tendency to become egocentric navigators in the active navigation environment.
Infusion of CCR5 Gene-Edited T Cells Allows Immune Reconstitution, HIV Reservoir Decay, and Long-Term Virological Control
Authors: Zeidan Joumana , Sharma Ashish A. , Lee Gary , Raad Angie , Fromentin Remi , Fourati Slim , Ghneim Khader , Sanchez Gabriela P. , Benne Clarisse , Canderan Glenda , Procopio Francesco A. , Balderas Robert , Monette Georges , Lalezari Jacob P. , Heffernan Jane M. , Sabbagh Laurent , Chomont Nicolas , Ando Dale , Deeks Steven G. , Sekaly Rafick-Pierre 
Published: March 2021

AbstractAntiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4+T cells (SB-728-T) led to sustained increases in CD4+T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4+T memory stem cell (CD45RAintROintTSCM) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RAintROintTSCMcells are transcriptionally distinct from the previously described CD45RA+TSCMand are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited TSCMand their TEMprogeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4+and CD8+T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4+T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.
Development of a chemiluminescence immunoassay to accurately detect African swine fever virus antibodies in serum
Authors: Yang Yong , Lv Changjie , Fan Junqing , Zhao Ya , Jiang Lili , Sun Xiaomei , Zhang Qiang , Jin Meilin 
Published: March 2021

AbstractThe outbreak of African swine fever (ASF) has caused significant economic losses to animal husbandry worldwide. Currently, there is no effective vaccine or treatment available to control the disease, and therefore, efficient disease control is dependent on early detection and diagnosis of ASF virus (ASFV). In this study, a chemiluminescent immunoassay (CLIA) was developed using the ASFV protein p54 as a serum diagnostic antigen and an anti-p54 monoclonal antibody. After optimizing the working parameters of the CLIA, the sensitivity of the established CLIA was 1:128, ASFV-specific serum antibody was identified, and there was no cross-reaction with other swine virus antibodies. After testing 49 clinical serum samples, the consistency rate between the CLIA and the World Organization for Animal Health (OIE) recommended commercial kit was 100%. Thus, this CLIA had a high degree of specificity, sensitivity, and reliability, and could be used as a rapid detection method for epidemiological investigations of ASFV infection.
The Mechanism of Neurite Outgrowth Induction by Novel Synthetic Retinobenzoic Acids
Authors: Zhang Yang , Yoshimi Yoji , Funatsu Osamu , Hayashi Ryuto , Komagawa Shinsuke , Saito Shinichi , Nagahara Yukitoshi , Ikekita Masahiko 
Published: March 2021

AbstractRetinoids are a family of vitamin A-derived molecules and include the biologically active metabolite, retinoic acid (RA). RA acts as a specific modulator of neuronal differentiation and proliferation. However, teratogenicity and a large excess of RA have been found in animal studies. Thus, development of effective and stable retinoids is desirable. In this study, we showed that treatment with novel synthetic retinobenzoic acids promotes neurite outgrowth in a selected subpopulation of the human neuroblastoma cell line SK-N-SH. Furthermore, we found that, although acting via a different mechanism, retinobenzoic acids have the same neurite outgrowth-inducing effect as RA. Retinoids, including RA, bind to nuclear retinoic acid receptors (RARs). Therefore, we examined the expression of RARs in retinobenzoic acid-treated cells. Similar to already known retinoids, novel synthetic retinobenzoic acids promote the upregulation of RARβ and have no effect on RARα or γ. These results suggest that retinobenzoic acids act via RARβ during neurite outgrowth. Moreover, stimulation with RA or retinobenzoic acids significantly increased the phosphorylation levels of both ERK1/2 and mTOR. ERK1/2 and mTOR inhibition blocked the retinobenzoic acid-induced increase in neurite outgrowth, suggesting that retinobenzoic acids promoted neurite outgrowth by activating the ERK1/2 and mTOR signaling pathways. Notably, the RA-induced increase in neurite outgrowth was blocked by the ERK1/2 inhibitor U0126, but not by the mTOR inhibitor rapamycin. In addition, ERK1/2 inhibition blocked the upregulation of RARβ promoted by RA and retinobenzoic acids. In contrast, mTOR inhibition had no effect on upregulation of RARβ. Our results show that novel synthetic retinobenzoic acids induce neurite outgrowth by a different mechanism than RA. These findings suggest that activation of both ERK1/2, which results in downstream regulation of RARβ, and mTOR, are responsible for the novel synthetic retinobenzoic acid-induced neurite outgrowth in human neuroblastoma cells.
Placental uptake and metabolism of 25(OH)Vitamin D determines its activity within the fetoplacental unit
Authors: Ashley Brogan , Simner Claire , Manousopoulou Antigoni , Jenkinson Carl , Hey Felicity , Frost Jennifer M , Rezwan Faisal I , White Cory H , Lofthouse Emma , Hyde Emily , Cooke Laura , Barton Sheila , Mahon Pamela , Curtis Elizabeth M , Moon Rebecca J , Crozier Sarah R , Inskip Hazel M , Godfrey Keith M , Holloway John W , Cooper Cyrus , Jones Kerry S , Lewis Rohan M , Hewison Martin , Garbis Spiros D , Branco Miguel R , Harvey Nicholas C , Cleal Jane K 
Published: March 2021

AbstractPregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.
Biological networks with singular Jacobians: their origins and adaptation criteria
Authors: Oellerich Tracey , Emelianenko Maria , Liotta Lance , Araujo Robyn P. 
Published: March 2021

ABSTRACTThis work is focused on Ordinary Differential Equations(ODE)-based models of biochemical systems that possess a singular Jacobian manifesting in non-hyperbolic equilibria. We show that there are several classes of systems that exhibit this behavior: a)systems with monomial-type interaction terms and b)systems with linear or nonlinear conservation laws. While models derived from mass-action principles often present with linear conservation laws stemming from the underlying biologic rationale, nonlinear conservation laws are more subtle and harder to detect. Nevertheless, in both situations the corresponding ODE system will contain non-hyperbolic equilibria. While having a potentially more complex dynamics and falling outside of the scope of existing theoretical frameworks, this class of systems can still exhibit adapting behavior associated with certain nodes and inputs. We derive a generalized adaptation condition that extends to singular systems and is compatible with both single-input/single-output and multiple-input/multiple-output settings. The approach explored herein, based on the notion of Moore-Penrose pseudoinverse, is tested on several synthetic systems that are shown to exhibit homeostatic behavior but are not covered by existing methods. These results highlight the role of the network structure and modeling assumptions when understanding system response to input and can be helpful in discovering intrinsic relationships between the nodes.