bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving challenges in deep learning-based analyses of histopathological images using explanation methods
Authors: Hägele Miriam , Seegerer Philipp , Lapuschkin Sebastian , Bockmayr Michael , Samek Wojciech , Klauschen Frederick , Müller Klaus-Robert , Binder Alexander 
Published: April 2020

AbstractDeep learning has recently gained popularity in digital pathology due to its high prediction quality. However, the medical domain requires explanation and insight for a better understanding beyond standard quantitative performance evaluation. Recently, many explanation methods have emerged. This work shows how heatmaps generated by these explanation methods allow to resolve common challenges encountered in deep learning-based digital histopathology analyses. We elaborate on biases which are typically inherent in histopathological image data. In the binary classification task of tumour tissue discrimination in publicly available haematoxylin-eosin-stained images of various tumour entities, we investigate three types of biases: (1) biases which affect the entire dataset, (2) biases which are by chance correlated with class labels and (3) sampling biases. While standard analyses focus on patch-level evaluation, we advocate pixel-wise heatmaps, which offer a more precise and versatile diagnostic instrument. This insight is shown to not only be helpful to detect but also to remove the effects of common hidden biases, which improves generalisation within and across datasets. For example, we could see a trend of improved area under the receiver operating characteristic (ROC) curve by 5% when reducing a labelling bias. Explanation techniques are thus demonstrated to be a helpful and highly relevant tool for the development and the deployment phases within the life cycle of real-world applications in digital pathology.
Surface analysis of an eagle talon from Krapina
Authors: Radovčić Davorka , Birarda Giovanni , Sršen Ankica Oros , Vaccari Lisa , Radovčić Jakov , Frayer David W. 
Published: April 2020

AbstractThe Krapina white-tailed eagle talons represent a kind of jewelry worn by Krapina Neandertals some 130,000 years ago. New inspection of one Krapina talon (386.1) revealed a fiber, sealed by a thin silicate coating, adhering to the surface within a wide cut mark, as well as concentrated traces of occasional spots of red and yellow pigment and some black stains. We analyzed the fiber and small portions of pigmented areas by non-invasive, infrared synchrotron beam. Different areas were targeted, revealing the protein nature of the fiber, identified as of animal origin. Targeted areas revealed intra- and inter-strand aggregation indicating the fiber to be collagen losing its original triple α-helix conformation, further confirming the diagenetic decay of the original collagen structure and the antiquity of the fiber. It is possible that the fiber is a remnant of the leather or sinew string binding the talons together. Spectroscopic analysis of the pigments in two isolated areas confirmed two types of ochre and that the dark spots are charcoal remnants. Applying novel non-invasive technologies provides new possibilities to further test the hypothesis of using prehistoric objects for symbolic purposes.
Female horses spontaneously identify a photograph of their keeper, last seen six months previously
Authors: Lansade Léa , Colson Violaine , Parias Céline , Trösch Miléna , Reigner Fabrice , Calandreau Ludovic 
Published: April 2020

AbstractHorses are capable of identifying individual conspecifics based on olfactory, auditory or visual cues. However, this raises the questions of their ability to recognize human beings and on the basis of what cues. This study investigated whether horses could differentiate between a familiar and unfamiliar human from photographs of faces. Eleven horses were trained on a discrimination task using a computer-controlled screen, on which two photographs were presented simultaneously (32 trials/session): touching one was rewarded (S+) and the other not (S−). In the training phase, the S+ faces were of four unfamiliar people which gradually became familiar over the trials. The S− faces were novel for each trial. After the training phase, the faces of the horses’ keepers were presented opposite novel faces to test whether the horses could identify the former spontaneously. A reward was given whichever face was touched to avoid any possible learning effect. Horses touched the faces of keepers significantly more than chance, whether it was their current keeper or one they had not seen for six months (t = 3.65; p < 0.004 and t = 6.24; p < 0.0001). Overall, these results show that horses have advanced human face-recognition abilities and a long-term memory of those human faces.
Delaying the first grapevine fungicide application reduces exposure on operators by half
Authors: Chen Mathilde , Brun François , Raynal Marc , Makowski David 
Published: April 2020

AbstractDowny mildew is a severe disease of grapevines treated by repeated fungicide applications during the growing season. The impact of these treatments on human health is currently under scrutiny. Fungicide application long before disease onset is not thought to be greatly beneficial for grape production, but the first fungicide treatment is applied at least six weeks before disease onset in more than 50% of the vineyards in the Bordeaux region, a major French vine-growing area. We estimate that applying one fungicide every two weeks at disease onset would reduce fungicide applications against downy mildew by 56% (95%IC = [51.0%, 61.3%]), on average, relative to current levels. This decrease is slightly greater than the level of exposure reduction resulting from the random suppression of one out of every two fungicide treatments (i.e. 50%). The reduction is lower when treatments are sprayed weekly but still reaches at least 12.4% (95%IC = [4.3%, 20.8%]) in this case. We show that this and other strategies reducing the number of treatments would decrease operator exposure to pesticides as effectively as the use of various types of personal protective equipments in the Bordeaux region. The implementation of this strategy would significantly decrease fungicide use, health risks, and adverse environmental impacts of vineyards.
Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells
Authors: Maruoka Hiroki , Yamazoe Ryosuke , Takahashi Ryota , Yatsuo Keisuke , Ido Daiki , Fuchigami Yuki , Hoshikawa Fumiya , Shimoke Koji 
Published: April 2020

AbstractForskolin promotes neuronal differentiation of PC12 cells via the PKA-CREB-dependent signaling pathway. Activation of PKA by forskolin phosphorylates CREB, which then binds to CRE sites in numerous gene promoters. However, it is unclear which gene contains the CRE sites responsible for forskolin-induced neuronal differentiation. In this study, we investigated how an immediate early gene, nur77, which has CRE sites in the promoter region, contributes to the early stage of differentiation of forskolin-treated PC12 cells. After treatment with forskolin, expression of Nur77 was upregulated within 1 hr. In addition, knockdown of nur77 inhibited neurite outgrowth induced by forskolin. We also revealed that the specific four CRE sites near the transcriptional start site (TSS) of nur77 were strongly associated with phosphorylated CREB within 1 hr after treatment with forskolin. To analyze the roles of these four sites, reporter assays using the nur77 promoter region were performed. The results showed that nur77 expression was mediated through three of the CRE sites, −242, −222, and −78, and that −78, the nearest of the three to the TSS of nur77, was particularly important. An analysis of neuronal markers controlled by Nur77 after A-CREB-Nur77-Synapsin1 signaling pathway plays a pivotal role in differentiation of forskolin-induced PC12 cells.
Minimally altering a critical kinase for low-phytate maize
Authors: Singh Alla , Karjagi Chikkappa , Rakshit Sujay 
Published: April 2020

AbstractNutritional security is of vital importance for combating malnutrition and catering to increasing energy demands. Phytic acid is considered an anti-nutrient, which sequesters important metal ions, limiting their bioavailability. The lpa mutants of maize contain reduced phytate, thus increase its nutritive value. But low phytate is accompanied by negative pleiotropic effects. This article discusses the importance of lpa2 gene amongst available options, for precise DNA editing to simultaneously improve nutrition and avoid pleiotropic effects.
Immunomodulatory role of Interleukin-33 in large vessel vasculitis
Authors: Desbois Anne-Claire , Cacoub Patrice , Leroyer Aurélie S. , Tellier Edwige , Garrido Marlène , Maciejewski-Duval Anna , Comarmond Cloé , Barete Stéphane , Arock Michel , Bruneval Patrick , Launay Jean-Marie , Fouret Pierre , Blank Ulrich , Rosenzwajg Michelle , Klatzmann David , Jarraya Mohamed , Cluzel Philippe , Koskas Fabien , Kaplanski Gilles , Saadoun David 
Published: April 2020

AbstractThe mechanisms regulating inflammation in large vessels vasculitis (LVV) are poorly understood. Interleukin 33 (IL-33) has been shown to license innate and adaptive immunity by enhancing Th2 cytokines production. We aimed to examine the role of IL-33 in the immunomodulation of T cell activation in LVV. T cell homeostasis and cytokines production were determined in peripheral blood from 52 patients with giant cell arteritis (GCA) and 50 healthy donors (HD), using Luminex assay, flow cytometry, quantitative RT-PCR and by immunofluorescence analysis in inflammatory aorta lesions. We found increased level of IL-33 and its receptor ST2/IL-1R4 in the serum of patient with LVV. Endothelial cells were the main source of IL-33, whereas Th2 cells, Tregs and mast cells (MC) express ST2 in LVV vessels. IL-33 had a direct immunomodulatory impact by increasing Th2 and Tregs. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs (p = 0.008). Stimulation of MC by IL-33 increased indoleamine 2 3-dioxygenase (IDO) activity and IL-2 secretion. IL-33 mRNA expression was significantly correlated with the expression of IL-10 and TGF-β within aorta inflammatory lesions. To conclude, our findings suggest that IL-33 may exert a critical immunoregulatory role in promoting Tregs and Th2 cells in LVV.
R-loop-forming Sequences Analysis in Thousands of Viral Genomes Identify A New Common Element in Herpesviruses
Authors: Wongsurawat Thidathip , Gupta Arundhati , Jenjaroenpun Piroon , Owens Shana , Forrest James Craig , Nookaew Intawat 
Published: April 2020

AbstractR-loops are RNA-DNA hybrid sequences that are emerging players in various biological processes, occurring in both prokaryotic and eukaryotic cells. In viruses, R-loop investigation is limited and functional importance is poorly understood. Here, we performed a computational approach to investigate prevalence, distribution, and location of R-loop forming sequences (RLFS) across more than 6000 viral genomes. A total of 14637 RLFS loci were identified in 1586 viral genomes. Over 70% of RLFS-positive genomes are dsDNA viruses. In the order Herpesvirales, RLFS were presented in all members whereas no RLFS was predicted in the order Ligamenvirales. Analysis of RLFS density in all RLFS-positive genomes revealed unusually high RLFS densities in herpesvirus genomes, with RLFS densities particularly enriched within repeat regions such as the terminal repeats (TRs). RLFS in TRs are positionally conserved between herpesviruses. Validating the computationally-identified RLFS, R-loop formation was experimentally confirmed in the TR and viral Bcl-2 promoter of Kaposi sarcoma-associated herpesvirus (KSHV). These predictions and validations support future analysis of RLFS in regulating the replication, transcription, and genome maintenance of herpesviruses.
Viscosity of hcp iron at Earth’s inner core conditions from density functional theory
Authors: Ritterbex Sebastian , Tsuchiya Taku 
Published: April 2020

AbstractThe inner core, extending to 1,221 km above the Earth’s center at pressures between 329 and 364 GPa, is primarily composed of solid iron. Its rheological properties influence both the Earth’s rotation and deformation of the inner core which is a potential source of the observed seismic anisotropy. However, the rheology of the inner core is poorly understood. We propose a mineral physics approach based on the density functional theory to infer the viscosity of hexagonal close packed (hcp) iron at the inner core pressure (P) and temperature (T). As plastic deformation is rate-limited by atomic diffusion under the extreme conditions of the Earth’s center, we quantify self-diffusion in iron non-empirically. The results are applied to model steady-state creep of hcp iron. Here, we show that dislocation creep is a key mechanism driving deformation of hcp iron at inner core conditions. The associated viscosity agrees well with the estimates from geophysical observations supporting that the inner core is significantly less viscous than the Earth’s mantle. Such low viscosity rules out inner core translation, with melting on one side and solidification on the opposite, but allows for the occurrence of the seismically observed fluctuations in inner core differential rotation.
Evaluation of cell metabolic adaptation in wound and tumour by Fluorescence Lifetime Imaging Microscopy
Authors: Morone Diego , Autilia Francesca D’ , Schorn Tilo , Erreni Marco , Doni Andrea 
Published: April 2020

AbstractAcidic pH occurs in acute wounds progressing to healing as consequence of a cell metabolic adaptation in response to injury-induced tissue hypoperfusion. In tumours, high metabolic rate leads to acidosis affecting cancer progression. Acidic pH affects activities of remodelling cells in vitro. The pH measurement predicts healing in pathological wounds and success of surgical treatment of burns and chronic ulcers. However, current methods are limited to skin surface or based on detection of fluorescence intensity of specific sensitive probes that suffer of microenvironment factors. Herein, we ascertained relevance in vivo of cell metabolic adaptation in skin repair by interfering with anaerobic glycolysis. Moreover, a custom-designed skin imaging chamber, 2-Photon microscopy (2PM), fluorescence lifetime imaging (FLIM) and data mapping analyses were used to correlate maps of glycolytic activity in vivo as measurement of NADH intrinsic lifetime with areas of hypoxia and acidification in models of skin injury and cancer. The method was challenged by measuring the NADH profile by interfering with anaerobic glycolysis and oxidative phosphorylation in the mitochondrial respiratory chain. Therefore, intravital NADH FLIM represents a tool for investigating cell metabolic adaptation occurring in wounds, as well as the relationship between cell metabolism and cancer.
Infant Corpus Callosum Size After Surgery and Critical Care for Long-Gap Esophageal Atresia: Qualitative and Quantitative MRI
Authors: Mongerson Chandler R. L. , Jaimes Camilo , Zurakowski David , Jennings Russell W. , Bajic Dusica 
Published: April 2020

AbstractPrevious studies in preterm infants report white matter abnormalities of the corpus callosum (CC) as an important predictor of neurodevelopmental outcomes. Our cross-sectional study aimed to describe qualitative and quantitative CC size in critically ill infants following surgical and critical care for long-gap esophageal atresia (LGEA) – in comparison to healthy infants – using MRI. Non-sedated brain MRI was acquired for full-term (n = 13) and premature (n = 13) patients following treatment for LGEA, and controls (n = 20) <1 year corrected age. A neuroradiologist performed qualitative evaluation of T1-weighted images. ITK-SNAP was used for linear, 2-D and 3-D manual CC measures and segmentations as part of CC size quantification. Qualitative MRI analysis indicated underdeveloped CC in both patient groups in comparison to controls. We show no group differences in mid-sagittal CC length. Although 2-D results were inconclusive, volumetric analysis showed smaller absolute (F(2,42) = 20.40, p < 0.001) and normalized (F(2,42) = 16.61, p < 0.001) CC volumes following complex perioperative treatment for LGEA in both full-term and premature patients, suggesting delayed or diminished CC growth in comparison to controls, with no difference between patient groups. Future research should look into etiology of described differences, neurodevelopmental outcomes, and role of the CC as an early marker of neurodevelopment in this unique infant population.
Phoenixin-20 Stimulates mRNAs Encoding Hypothalamo-Pituitary-Gonadal Hormones, is Pro-Vitellogenic, and Promotes Oocyte Maturation in Zebrafish
Authors: Rajeswari Jithine Jayakumar , Unniappan Suraj 
Published: April 2020

AbstractPhoenixin-20 (PNX-20) is a bioactive peptide with hormone-like actions in vertebrates. In mammals, PNX stimulates hypothalamo-pituitary-gonadal hormones and regulate reproductive processes. Our immunohisto/cytochemical studies show PNX-like and the putative PNX receptor, SREB3-like immunoreactivity in the gonads of zebrafish, and in zebrafish liver (ZFL) cells. Intraperitoneal injection of zebrafish PNX-20 upregulates mRNAs encoding both salmon gonadotropin-releasing hormone (GnRH), and chicken GnRH-II and kisspeptin and its receptor in zebrafish hypothalamus. Similarly, luteinizing hormone receptor mRNA expression in the testis, follicle-stimulating hormone receptor in the ovary, and the kisspeptin system were upregulated in the gonads of PNX-20 injected fish. We also observed the upregulation of genes involved in the sex steroidogenic pathway (cyp11a1, cyp17a1, 17βhsd, cyp19a1a) in the gonads of PNX-20 administered fish. PNX-20 upregulates the expression of vitellogenin isoforms and estrogen receptor (esr2a and 2b) mRNAs in ZFL cells in vitro. Meanwhile, siRNA-mediated knockdown of PNX-20 resulted in the downregulation of all vitellogenin transcripts, further suggesting its possible role in vitellogenesis. PNX-20 treatment resulted in a significant increase in germinal vesicle breakdown in zebrafish follicles in vitro. Collectively, these results provide strong evidence for PNX-20 effects on the HPG axis and liver to promote reproduction in zebrafish.
Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression
Authors: Yagi Hiroaki , Nishigori Mitsuhiro , Murakami Yusuke , Osaki Tsukasa , Muto Sayaka , Iba Yutaka , Minatoya Kenji , Ikeda Yoshihiko , Ishibashi-Ueda Hatsue , Morisaki Takayuki , Ogino Hitoshi , Tanaka Hiroshi , Sasaki Hiroaki , Matsuda Hitoshi , Minamino Naoto 
Published: April 2020

AbstractSince aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues. To discover diagnostic biomarkers for AA, we performed proteome analysis of aortic media from patients with thoracic atherosclerotic AA (TAAA), comparing protein levels between the aneurysm and normal tissue areas. After hierarchical clustering analysis of the proteome analysis data, tissue samples were classified into three groups, regardless of morphological features. This classification was shown to reflect disease progression stage identified by pathological examination. This proteomics-based staging system enabled us to identify more significantly altered proteins than the morphological classification system. In subsequent data analysis, Niemann-Pick disease type C2 protein (NPC2) and insulin-like growth factor-binding protein 7 (IGFBP7) were selected as novel biomarker candidates for AA and were compared with the previously reported biomarker, thrombospondin 1 (THBS1). Blood concentrations of NPC2 and IGFBP7 were significantly increased, while THBS1 levels were decreased in TAAA and abdominal atherosclerotic AA patients. Receiver operating characteristic analysis of AA patients and healthy controls showed that NPC2 and IGFBP7 have higher specificity and sensitivity than THBS1. Thus, NPC2 and IGFBP7 are promising biomarkers for the detection and progression evaluation of AA.
The combined effects of motor and social goals on the kinematics of object-directed motor action
Authors: Gigliotti Maria Francesca , Sampaio Adriana , Bartolo Angela , Coello Yann 
Published: April 2020

AbstractVoluntary actions towards manipulable objects are usually performed with a particular motor goal (i.e., a task-specific object-target-effector interaction) and in a particular social context (i.e., who would benefit from these actions), but the mutual influence of these two constraints has not yet been properly studied. For this purpose, we asked participants to grasp an object and place it on either a small or large target in relation to Fitts’ law (motor goal). This first action prepared them for a second grasp-to-place action which was performed under temporal constraints, either by the participants themselves or by a confederate (social goal). Kinematic analysis of the first preparatory grasp-to-place action showed that, while deceleration time was impacted by the motor goal, peak velocity was influenced by the social goal. Movement duration and trajectory height were modulated by both goals, the effect of the social goal being attenuated by the effect of the motor goal. Overall, these results suggest that both motor and social constraints influence the characteristics of object-oriented actions, with effects that combine in a hierarchical way.
C-reactive protein (CRP) recognizes uric acid crystals and recruits proteases C1 and MASP1
Authors: Alberts Anika , Klingberg Annika , Wessig Anne Kathrin , Combes Christèle , Witte Torsten , Brand Korbinian , Pich Andreas , Neumann Konstantin 
Published: April 2020

AbstractGout is caused by crystallization of uric acid in the form of monosodium urate (MSU) crystals, which induce a sterile inflammatory response that is hardly distinguishable from microbe-induced inflammatory responses. It is unclear, if MSU crystals (like microbes) are recognized by specific pattern recognition receptors. To identify possible soluble pattern recognition molecules for MSU crystals, we purified MSU-binding proteins from human body fluids. We identified C-reactive protein (CRP) as a major MSU-binding protein. Binding of CRP was strong enough to specifically deplete CRP from human serum. We found that CRP was required for fixation of complement components C1q, C1r, C1s and MASP1. Thus, we have identified a pattern recognition molecule for MSU crystals that links to the activation of complement. Notably, CRP does not show an even binding to the complete surface of the crystals. It rather binds to edges or distinct faces of the crystals.