bluuebunny/crossref_metadata_2025 huggingface dataset:
Cobalt-catalyzed deoxygenative triborylation of allylic ethers to access 1,1,3-triborylalkanes
Authors: Teo Wei Jie , Yang Xiaoxu , Poon Yeng Yeng , Ge Shaozhong
Published: October 2020

Polyborylated organic compounds have been emerging as versatile building blocks in chemical synthesis. Here we report a selective cobalt-catalyzed deoxygenative 1,1,3-triborylation reaction of allylic ethers with pinacolborane to prepare 1,1,3-triborylalkane compounds. With naturally abundant and/or synthetic cinnamic methyl ethers as starting materials, we have achieved the synthesis of a variety of 1,1,3-triborylalkanes (25 examples). The synthetic utility of these 1,1,3-triborylalkanes is demonstrated through site-selective allylation, protodeborylation, and consecutive carbon-carbon bond-forming reactions. Mechanistic studies including deuterium-labeling and control experiments suggest that this 1,1,3-triborylation reaction proceeds through initial cobalt-catalyzed deoxygenative borylation of allylic ethers to form allylic boronates followed by cobalt-catalyzed 1,1-diborylation of the resulting allylic boronates.
Training high-strength aluminum alloys to withstand fatigue
Authors: Zhang Qi , Zhu Yuman , Gao Xiang , Wu Yuxiang , Hutchinson Christopher
Published: October 2020

The fatigue performance of high strength aluminum alloys used in planes, trains, trucks and automobiles is notoriously poor. Engineers must design around this important limitation to use Al alloys for light-weighting of transportation structures. An alternative concept for microstructure design for improved fatigue strength is demonstrated in this work. Microstructures are designed to exploit the mechanical energy imparted during the initial cycles of fatigue to dynamically heal the inherent weak points in the microstructure. The fatigue life of the highest strength Aluminum alloys is improved by 25x, and the fatigue strength is raised to ~1/2 the tensile strength. The approach embraces the difference between static and dynamic loading and represents a conceptual change in microstructural design for fatigue.
Compact representations of microstructure images using triplet networks
Authors: Larmuseau Michiel , Sluydts Michael , Theuwissen Koenraad , Duprez Lode , Dhaene Tom , Cottenier Stefaan
Published: October 2020

The microstructure of a material, typically characterized through a set of microscopy images of two-dimensional cross-sections, is a valuable source of information about the material and its properties. Every pixel of the image is a degree of freedom causing the dimensionality of the information space to be extremely high. This makes it difficult to recognize and extract all relevant information from the images. Human experts circumvent this by manually creating a lower-dimensional representation of the microstructure. However, the question of how a microstructure image can be best represented remains open. From the field of deep learning, we present triplet networks as a method to build highly compact representations of the microstructure, condensing the relevant information into a much smaller number of dimensions. We demonstrate that these representations can be created even with a limited amount of example images, and that they are able to distinguish between visually very similar microstructures. We discuss the interpretability and generalization of the representations. Having compact microstructure representations, it becomes easier to establish processing–structure–property links that are key to rational materials design.
Flexible biodegradable transparent heaters based on fractal-like leaf skeletons
Authors: Sharma Vipul , Koivikko Anastasia , Yiannacou Kyriacos , Lahtonen Kimmo , Sariola Veikko
Published: October 2020

We present a facile method to prepare flexible, transparent, biodegradable, and fast resistive heaters by applying silver (Ag) nanowires onto fractal-like leaf skeletons. The fractal-like structure of the leaf skeleton maximizes its surface area, improving the transfer of heat to its surroundings and thus making the heater fast, without compromising transparency. Ag ion layer on the leaf skeleton helps to conformally cover the surface with Ag nanowires. The sheet resistance of the heater can be controlled by the loading of Ag nanowires, without sacrificing the optical transmittance (~80% at 8 Ω sq−1). The heating is uniform and the surface temperature of a 60 mm × 60 mm heater (8 Ω sq−1) can quickly (5–10 s) raise to 125 °C with a low voltage (6 V). The heater displays excellent mechanical flexibility, showing no significant change in resistance and heating temperature when bent up to curvature of 800 m−1. Finally, we demonstrate the potential of the bioinspired heater as a thermotherapy patch by encapsulating it in a biodegradable tape and mounting it on the human wrist and elbow. This study shows that fractal-like structures from nature can be repurposed as fractal designs for flexible electronics.
A new comprehensive trait database of European and Maghreb butterflies, Papilionoidea
Authors: Middleton-Welling Joseph , Dapporto Leonardo , García-Barros Enrique , Wiemers Martin , Nowicki Piotr , Plazio Elisa , Bonelli Simona , Zaccagno Michele , Šašić Martina , Liparova Jana , Schweiger Oliver , Harpke Alexander , Musche Martin , Settele Josef , Schmucki Reto , Shreeve Tim
Published: October 2020

Trait-based analyses explaining the different responses of species and communities to environmental changes are increasing in frequency. European butterflies are an indicator group that responds rapidly to environmental changes with extensive citizen science contributions to documenting changes of abundance and distribution. Species traits have been used to explain long- and short-term responses to climate, land-use and vegetation changes. Studies are often characterised by limited trait sets being used, with risks that the relative roles of different traits are not fully explored. Butterfly trait information is dispersed amongst various sources and descriptions sometimes differ between sources. We have therefore drawn together multiple information sets to provide a comprehensive trait database covering 542 taxa and 25 traits described by 217 variables and sub-states of the butterflies of Europe and Maghreb (northwest Africa) which should serve for improved trait-based ecological, conservation-related, phylogeographic and evolutionary studies of this group of insects. We provide this data in two forms; the basic data and as processed continuous and multinomial data, to enhance its potential usage.
Differential susceptibility of retinal ganglion cell subtypes in acute and chronic models of injury and disease
Authors: VanderWall Kirstin B. , Lu Bin , Alfaro Jorge S. , Allsop Anna R. , Carr Alexa S. , Wang Shaomei , Meyer Jason S.
Published: October 2020

Retinal ganglion cells (RGCs) are a heterogeneous population of neurons, comprised of numerous subtypes that work synchronously to transmit visual information to the brain. In blinding disorders such as glaucoma, RGCs are the main cell type to degenerate and lead to loss of vision. Previous studies have identified and characterized a variety of RGC subtypes in animal models, although only a handful of studies demonstrate the differential loss of these RGC subtypes in response to disease or injury. Thus, efforts of the current study utilized both chronic (bead occlusion) and acute (optic nerve crush, ONC) rat models to characterize disease response and differential loss of RGC subtypes. Bead occlusion and ONC retinas demonstrated significant RGC loss, glial reactivity and apoptosis compared to control retinas. Importantly, bead occlusion and ONC retinas resulted in differential subtype-specific loss of RGCs, with a high susceptibility for alpha- and direction selective-RGCs and preferential survival of ipRGCs. Results of this study serve as an important foundation for future experiments focused on the mechanisms resulting in the loss of RGCs in optic neuropathies, as well as the development of targeted therapeutics for RGC subtype-specific neuroprotection.
Identifying a nasal gene expression signature associated with hyperinflation and treatment response in severe COPD
Authors: Faiz Alen , Imkamp Kai , van der Wiel Erica , Boudewijn Ilse M. , Koppelman Gerard H. , Brandsma Corry-Anke , Kerstjens Huib A. M. , Timens Wim , Vroegop Sebastiaan , Pasma Henk R. , Boersma Wim G. , Wielders Pascal , van den Elshout Frank , Mansour Khaled , Steiling Katrina , Spira Avrum , Lenburg Marc E. , Heijink Irene H. , Postma Dirkje S. , van den Berge Maarten
Published: October 2020

Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting β2-agonist (LABA) treatment on both lung function measures of hyperinflation, and the nasal epithelial gene-expression profile in severe COPD. 117 patients were screened and 60 COPD patients entered a 1-month run-in period on low-dose ICS/LABA budesonide/formoterol (BUD/F) 200/6 one inhalation b.i.d. Patients were then randomly assigned to 3-month treatment with either a high dose BDP/F 100/6 two inhalations b.i.d. (n = 31) or BUD/F 200/6 two inhalations b.i.d. (n = 29). Lung function measurements and nasal epithelial gene-expression were assessed before and after 3-month treatment and validated in independent datasets. After 3-month ICS/LABA treatment, residual volume (RV)/total lung capacity (TLC)% predicted was reduced compared to baseline (p < 0.05). We identified a nasal gene-expression signature at screening that associated with higher RV/TLC% predicted values. This signature, decreased by ICS/LABA treatment was enriched for genes associated with increased p53 mediated apoptosis was replicated in bronchial biopsies of COPD patients. Finally, this signature was increased in COPD patients compared to controls in nasal, bronchial and small airways brushings. Short-term ICS/LABA treatment improves RV/TLC% predicted in severe COPD. Furthermore, it decreases the expression of genes involved in the signal transduction by the p53 class mediator, which is a replicable COPD gene expression signature in the upper and lower airways.

Trial registration: ClinicalTrials.gov registration number NCT01351792 (registration date May 11, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 20, 2009), ClinicalTrials.gov registration number NCT00158847 (registration date September 12, 2005).
First use of artificial canopy bridge by the world’s most critically endangered primate the Hainan gibbon Nomascus hainanus
Authors: Chan Bosco Pui Lok , Lo Yik Fui Philip , Hong Xiao-Jiang , Mak Chi Fung , Ma Ziyu
Published: October 2020

All gibbon species (Primates: Hylobatidae) are facing high extinction risk due to habitat loss and hunting. The Hainan gibbonNomascus hainanusis the world’s most critically endangered primate, and one of the priority conservation actions identified is to establish artificial canopy corridors to reconnect fragmented forests. The effectiveness of artificial canopy bridge as a conservation tool for wild gibbons has not been widely tested, and the results are rarely published. We constructed the first canopy bridge for Hainan gibbon in 2015 to facilitate passage at a natural landslide; mountaineering-grade ropes were tied to sturdy trees with the help of professional tree climbers and a camera trap was installed to monitor wildlife usage. Hainan gibbon started using the rope bridge after 176 days, and usage frequency increased with time. All members in the gibbon group crossed the 15.8 m rope bridge except adult male. Climbing was the predominant locomotor mode followed by brachiation. This study highlights the use and value of rope bridges to connect forest gaps for wild gibbons living in fragmented forests. While restoring natural forest corridors should be a priority conservation intervention, artificial canopy bridges may be a useful short-term solution.
Dissecting the roles of GRK2 and GRK3 in μ-opioid receptor internalization and β-arrestin2 recruitment using CRISPR/Cas9-edited HEK293 cells
Authors: Møller Thor C. , Pedersen Mie F. , van Senten Jeffrey R. , Seiersen Sofie D. , Mathiesen Jesper M. , Bouvier Michel , Bräuner-Osborne Hans
Published: October 2020

Most G protein-coupled receptors (GPCRs) recruit β-arrestins and internalize upon agonist stimulation. For the μ-opioid receptor (μ-OR), this process has been linked to development of opioid tolerance. GPCR kinases (GRKs), particularly GRK2 and GRK3, have been shown to be important for μ-OR recruitment of β-arrestin and internalization. However, the contribution of GRK2 and GRK3 to β-arrestin recruitment and receptor internalization, remain to be determined in their complete absence. Using CRISPR/Cas9-mediated genome editing we established HEK293 cells with knockout of GRK2, GRK3 or both to dissect their individual contributions in β-arrestin2 recruitment and μ-OR internalization upon stimulation with four different agonists. We showed that GRK2/3 removal reduced agonist-induced μ-OR internalization and β-arrestin2 recruitment substantially and we found GRK2 to be more important for these processes than GRK3. Furthermore, we observed a sustained and GRK2/3 independent component of β-arrestin2 recruitment to the plasma membrane upon μ-OR activation. Rescue expression experiments restored GRK2/3 functions. Inhibition of GRK2/3 using the small molecule inhibitor CMPD101 showed a high similarity between the genetic and pharmacological approaches, cross-validating the specificity of both. However, off-target effects were observed at high CMPD101 concentrations. These GRK2/3 KO cell lines should prove useful for a wide range of studies on GPCR function.
Role of myo-inositol during skotomorphogenesis in Arabidopsis
Authors: Sharma Naveen , Chaudhary Chanderkant , Khurana Paramjit
Published: October 2020

Myo-inositol is a ubiquitous metabolite of plants. It is synthesized by a highly conserved enzyme L-myo-inositol phosphate synthase (MIPS; EC 5.5.1.4). Myo-inositol is well characterized during abiotic stress tolerance but its role during growth and development is unclear. In this study, we demonstrate that the apical hook maintenance and hypocotyl growth depend on myo-inositol. We discovered the myo-inositol role during hook formation and its maintenance via ethylene pathway in Arabidopsis by supplementation assays and qPCR. Our results suggest an essential requirement of myo-inositol for mediating the ethylene response and its interaction with brassinosteroid to regulate the skotomorphogenesis. A model is proposed outlining how MIPS regulates apical hook formation and hypocotyl growth.
Dissection of hyperspectral reflectance to estimate nitrogen and chlorophyll contents in tea leaves based on machine learning algorithms
Authors: Yamashita Hiroto , Sonobe Rei , Hirono Yuhei , Morita Akio , Ikka Takashi
Published: October 2020

Nondestructive techniques for estimating nitrogen (N) status are essential tools for optimizing N fertilization input and reducing the environmental impact of agricultural N management, especially in green tea cultivation, which is notably problematic. Previously, hyperspectral indices for chlorophyll (Chl) estimation, namely a green peak and red edge in the visible region, have been identified and used for N estimation because leaf N content closely related to Chl content in green leaves. Herein, datasets of N and Chl contents, and visible and near-infrared hyperspectral reflectance, derived from green leaves under various N nutrient conditions and albino yellow leaves were obtained. A regression model was then constructed using several machine learning algorithms and preprocessing techniques. Machine learning algorithms achieved high-performance models for N and Chl content, ensuring an accuracy threshold of 1.4 or 2.0 based on the ratio of performance to deviation values. Data-based sensitivity analysis through integration of the green and yellow leaves datasets identified clear differences in reflectance to estimate N and Chl contents, especially at 1325–1575 nm, suggesting an N content-specific region. These findings will enable the nondestructive estimation of leaf N content in tea plants and contribute advanced indices for nondestructive tracking of N status in crops.
Clusterin overexpression protects against western diet-induced obesity and NAFLD
Authors: Park Jin-Sung , Lee Woon-Kyu , Kim Hyeon Soo , Seo Ji A. , Kim Dong-Hoon , Han Hee Chul , Min Bon-Hong
Published: October 2020

Obesity is a significant risk factor for various metabolic diseases and is closely related to non-alcoholic fatty liver disease (NAFLD) characterized by inflammation and oxidative stress. Clusterin is a multi-functional protein that is up-regulated in the pathogenesis of various metabolic diseases, including obesity and NAFLD. Our previous studies indicated that hepatocyte-specific overexpression of clusterin alleviates methionine choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Here we generated transgenic mice with whole-body clusterin overexpression (wCLU-tg) and investigated the role of clusterin in Western diet-induced obesity and NAFLD. We confirmed that obesity parameters and the spectrum of NAFLD of wCLU-tg mice were improved compared to wild type mice. Contrarily, clusterin deficiency deteriorated metabolic disruptions. We also found that clusterin activates target molecules for obesity and NAFLD, namely Nrf2 and AMPK, suggesting that clusterin protects against Western diet-induced obesity and NAFLD by activating Nrf2 and AMPK.
Structural basis of peroxidase catalytic cycle of human Prdx6
Authors: Chowhan Rimpy Kaur , Rahaman Hamidur , Singh Laishram Rajendrakumar
Published: October 2020

Peroxiredoxin 6 (Prdx6) is a ubiquitously expressed antioxidant non-selenium glutathione peroxidase that is known to play a major role in various physiological and pathological processes. It belongs to the family of peroxidases (referred to as Peroxiredoxins, Prdx’s) that work independently of any prosthetic groups or co-factors, and instead utilize a peroxidatic thiol residue for peroxide reduction. Mammalian Prdx’s are classified according to the number of Cys implicated in their catalytic activity by the formation of either inter-molecular (typical 2-Cys, Prdx1–4) or intra-molecular (atypical 2-Cys, Prdx5) disulfide bond, or non-covalent interactions (1-Cys, Prdx6). The typical and atypical 2-Prdx’s have been identified to show decamer/dimer and monomer/dimer transition, respectively, upon oxidation of their peroxidatic cysteine. However, the alterations in the oligomeric status of Prdx6 as a function of peroxidatic thiol’s redox state are still ambiguous. While the crystal structure of recombinant human Prdx6 is resolved as a dimer, the solution structures are reported to have both monomers and dimers. In the present study, we have employed several spectroscopic and electrophoretic probes to discern the impact of change in the redox status of peroxidatic cysteine on conformation and oligomeric status of Prdx6. Our study indicates Prdx6′s peroxidase activity to be a redox-based conformation driven process which essentially involves monomer–dimer transition.
Heterogeneous leaves of predominant trees species enhance decomposition and nutrient release in the riparian zone of the Three Gorges Reservoir
Authors: Chen Zhangting , Wang Chaoying , Chen Xuemei , Yuan Zhongxun , Song Hong , Li Changxiao
Published: October 2020

The leaves of riparian plants are the main source of energy and nutrients in riparian ecosystems. In order to evaluate the nutrient release of reforested trees in a riparian zone, a field litterbag experiment involving three foliar types (the leaves of either coniferous and broadleaf trees as single-leaf treatment, or a mixture of coniferous and broadleaf leaves as a heterogenous-leaf treatment) and different submergence depths [no submergence (CK), shallow submergence (SS), and deep submergence (DS)] was conducted in situ in the Three Gorges Reservoir (TGR) for one year. The results showed that, when compared to the single-leaf treatment, the heterogenous-leaf treatment exhibited greater mass loss at both SS and DS, in contrast to a greater nitrogen release rate only at DS and a greater phosphorous release rate only at SS. Overall, submergence facilitated decomposition and nutrient release, although the decomposition rate was higher in SS than in DS. The results suggested that the decomposition and nutrient release of the three foliar types may increase the potential pollution risk to the TGR water environment. Thus, we propose that the leaves of the reforested riparian stands be harvested prior to submergence to preserve the water quality of the TGR.
Transitions between phyllotactic lattice states in curved geometries
Authors: Ansell H. S. , Tomlinson A. A. , Wilkin N. K.
Published: October 2020

Phyllotaxis, the regular arrangement of leaves or other lateral organs in plants including pineapples, sunflowers and some cacti, has attracted scientific interest for centuries. More recently there has been interest in phyllotaxis within physical systems, especially for cylindrical geometry. In this letter, we expand from a cylindrical geometry and investigate transitions between phyllotactic states of soft vortex matter confined to a conical frustum. We show that the ground states of this system are consistent with previous results for cylindrical confinement and discuss the resulting defect structures at the transitions. We then eliminate these defects from the system by introducing a density gradient to create a configuration in a single state. The nature of the density gradient limits this approach to a small parameter range on the conical system. We therefore seek a new surface, the horn, for which a defect-free state can be maintained for a larger range of parameters.
Numerical model of hybrid mode-locked Tm-doped all-fibre laser
Authors: Donodin Aleksandr , Voropaev Vasilii , Batov Daniil , Vlasov Dmitrii , Lazarev Vladimir , Tarabrin Mikhail , Khegai Aleksandr , Likhachev Mikhail
Published: October 2020

Ultrafast Tm-doped fibre lasers have been actively studied for the last decade due to their potential applications in precise mid-IR spectroscopy, LIDARs, material processing and more. The majority of research papers is devoted to the comparison between a numerical modelling and experimental results; however, little attention is being paid to the comprehensive description of the mathematical models and parameters of the active and passive components forming cavities of Tm-doped all-fibre lasers. Thus, here we report a numerical model of a stretched-pulsed Tm-doped fibre laser with hybrid mode-locking and compare it with experimental results. The key feature of the developed numerical model is employment of the experimentally measured dispersion coefficients and optimisation of some model parameters, such as the bandwidth of the spectral filter spectral filtering and the saturation power of the active fibre, for a conformity with the experiment. The developed laser emits 331.7 fs pulses with a 23.8 MHz repetition rate, 6 mW of average power, 0.25 nJ of pulse energy, and a 21.66 nm spectral bandwidth at a peak wavelength of 1899.5 nm. The numerical model characteristics coincide with experimentally achieved spectral width, pulse duration, and average power with inaccuracy of 4.7%, 5.4%, and 22.9%, respectively. Moreover, in the discussion of the work the main possible reasons influencing this inaccuracy are highlighted. Elimination of those factors might allow to increase accuracy even more. We show that numerical model has a good agreement with the experiment and can be used for development of ultrafast Tm-doped fibre laser systems.
A neuroimaging marker for predicting longitudinal changes in pain intensity of subacute back pain based on large-scale brain network interactions
Authors: Park Bo-yong , Lee Jae-Joong , Kim Hong Ji , Woo Choong-Wan , Park Hyunjin
Published: October 2020

Identification of predictive neuroimaging markers of pain intensity changes is a crucial issue to better understand macroscopic neural mechanisms of pain. Although a single connection between the medial prefrontal cortex and nucleus accumbens has been suggested as a powerful marker, how the complex interactions on a large-scale brain network can serve as the markers is underexplored. Here, we aimed to identify a set of functional connections predictive of longitudinal changes in pain intensity using large-scale brain networks. We re-analyzed previously published resting-state functional magnetic resonance imaging data of 49 subacute back pain (SBP) patients. We built a network-level model that predicts changes in pain intensity over one year by combining independent component analysis and a penalized regression framework. Connections involving top-down pain modulation, multisensory integration, and mesocorticolimbic circuits were identified as predictive markers for pain intensity changes. Pearson’s correlations between actual and predicted pain scores were r = 0.33–0.72, and group classification results between SBP patients with persisting pain and recovering patients, in terms of area under the curve (AUC), were 0.89/0.75/0.75 for visits four/three/two, thus outperforming the previous work (AUC 0.83/0.73/0.67). This study identified functional connections important for longitudinal changes in pain intensity in SBP patients, providing provisional markers to predict future pain using large-scale brain networks.
Evolutionary motor biases and cognition in children with and without autism
Authors: Forrester Gillian S. , Davis Rachael , Malatesta Gianluca , Todd Brenda K.
Published: October 2020

Evolution has endowed vertebrates with a divided brain that allows for processing of critical survival behaviours in parallel. Most humans possess astandardfunctional brain organisation for these ancient sensory-motor behaviours, favouring the right hemisphere for fight-or-flight processes and the left hemisphere for performing structured motor sequences. However, a significant minority of the population possess an organisational phenotype that represents crowding of function in one hemisphere, or a reversal of the standard functional organisation. Using behavioural biases as a proxy for brain organisation, results indicate that reversed brain organisation phenotype increases in populations with autism and is associated with weaker cognitive abilities. Moreover, this study revealed that left-handedness, alone, is not associated with decreased cognitive ability or autism. Rather, left-handedness acts as a marker for decreased cognitive performance when paired with the reversed brain phenotype. The results contribute to comparative research suggesting that modern human abilities are supported by evolutionarily old, lateralised sensory-motor processes. Systematic, longitudinal investigations, capturing genetic measures and brain correlates, are essential to reveal how cognition emerges from these foundational processes. Importantly, strength and direction of biases can act as early markers of brain organisation and cognitive development, leading to promising, novel practices for diagnoses and interventions.
Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing
Authors: Hurbain Julien , Labavić Darka , Thommen Quentin , Pfeuty Benjamin
Published: October 2020

Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.
Effects of processing conditions on stability of immune analytes in human blood
Authors: Gottfried-Blackmore Andres , Rubin Samuel J. S. , Bai Lawrence , Aluko Sheun , Yang Yujun , Park Walter , Habtezion Aida
Published: October 2020

Minimizing variability in collection and processing of human blood samples for research remains a challenge. Delaying plasma or serum isolation after phlebotomy (processing delay) can cause perturbations of numerous analytes. Thus, a comprehensive understanding of how processing delay affects major endpoints used in human immunology research is necessary. Therefore, we studied how processing delay affects commonly measured cytokines and immune cell populations. We hypothesized that short-term time delays inherent to human research in serum and plasma processing impact commonly studied immunological analytes. Blood from healthy donors was subjected to processing delays commonly encountered in sample collection, and then assayed by 62-plex Luminex panel, 40-parameter mass cytometry panel, and 540,000 transcript expression microarray. Variance for immunological analytes was estimated using each individual’s baseline as a control. In general, short-term processing delay led to small changes in plasma and serum cytokines (range − 10.8 to 43.5%), markers and frequencies of peripheral blood mononuclear cell phenotypes (range 0.19 to 3.54 fold), and whole blood gene expression (stable for > 20 K genes)—with several exceptions described herein. Importantly, we built an open-access web application allowing investigators to estimate the degree of variance expected from processing delay for measurements of interest based on the data reported here.
Mechanism of delayed seed germination caused by high temperature during grain filling in rice (Oryza sativa L.)
Authors: Suriyasak Chetphilin , Oyama Yui , Ishida Toshiaki , Mashiguchi Kiyoshi , Yamaguchi Shinjiro , Hamaoka Norimitsu , Iwaya-Inoue Mari , Ishibashi Yushi
Published: October 2020

High temperature during grain filling considerably reduces yield and quality in rice (Oryza sativa L.); however, how high temperature affects seed germination of the next generation is not yet well understood. Here, we report that seeds from plants exposed to high temperature during the grain filling stage germinated significantly later than seeds from unstressed plants. This delay remained even after dormancy release treatments, suggesting that it was not due to primary seed dormancy determined during grain filling. In imbibed embryos of heat-stressed seeds, expression of abscisic acid (ABA) biosynthesis genes (OsNCEDs) was higher than in those of control seeds, whereas that of ABA catabolism genes (OsABA8′OHs) was lower. In the aleurone layer, despite no change in GA signaling as evidenced by no effect of heat stress on OsGAMYB gene expression, the transcripts of α-amylase genes OsAmy1C, OsAmy3B, and OsAmy3E were significantly down-regulated in heat-stressed seeds in comparison with controls. Changes in promoter methylation levels were consistent with transcriptional changes of ABA catabolism-related and α-amylase genes. These data suggest that high temperature during grain filling results in DNA methylation of ABA catabolism-related and α-amylase gene promoters, delaying germination of heat-stressed seeds.
Major explosions and paroxysms at Stromboli (Italy): a new historical catalog and temporal models of occurrence with uncertainty quantification
Authors: Bevilacqua Andrea , Bertagnini Antonella , Pompilio Massimo , Landi Patrizia , Del Carlo Paola , Di Roberto Alessio , Aspinall Willy , Neri Augusto
Published: October 2020

Stromboli volcano (Italy), always active with low energy explosive activity, is a very attractive place for visitors, scientists, and inhabitants of the island. Nevertheless, occasional more intense eruptions can present a serious danger. This study focuses on the modeling and estimation of their inter-event time and temporal rate. With this aim we constructed a new historical catalog of major explosions and paroxysms through a detailed review of scientific literature of the last ca. 140 years. The catalog includes the calendar date and phenomena descriptions for 180 explosive events, of which 36 were paroxysms. We evaluated the impact of the main sources of uncertainty affecting the historical catalog. In particular, we categorized as uncertain 45 major explosions that reportedly occurred before 1985 and tested the effect of excluding these events from our analysis. Moreover, after analyzing the entire record in the period [1879, 2020], we separately considered, as sequences, events in [1879, 1960] and in [1985, 2020] because of possible under recording issues in the period [1960, 1985]. Our new models quantify the temporal rate of major explosions and paroxysms as a function of time passed since the last event occurred. Recurrence hazard levels are found to be significantly elevated in the weeks and months following a major explosion or paroxysm, and then gradually decrease over longer periods. Computed hazard functions are also used to illustrate a methodology for estimating order-of-magnitude individual risk of fatality under certain basis conditions. This study represents a first quantitatively formal advance in determining long-term hazard levels at Stromboli.
Hepatic stem cell Numb gene is a potential target of Huang Qi Decoction against cholestatic liver fibrosis
Authors: Xu Wen , Xu Yan-nan , Zhang Xu , Xu Ying , Jian Xun , Chen Jia-mei , Chen Gao-feng , Zhang Hua , Liu Ping , Mu Yong-ping
Published: October 2020

Numb is a negative regulator of Notch signal pathway. Previous study has demonstrated that Notch signal pathway activation is required for hepatic progenitor cell (HPC) differentiating into cholangiocytes in cholestatic liver fibrosis (CLF), and Huang Qi Decoction (HQD) could prevent CLF through inhibition of the Notch signal pathway. However, the role of Numb in HQD against CLF is yet unclear. Thus, CLF rats transplanted into rat bone marrow-derived mesenchymal stem cells with knocked down Numb gene (BMSCNumb-KD) were treated with HQD. Simultaneously, Numb gene knockdown was also performed in WB-F344 cell line and then treated with refined HQD in vitro. In vivo study revealed that liver fibrosis was inhibited by HQD plus BMSCNumb-KD treatment, while Hyp content in liver tissue, the gene and protein expression of α-SMA, gene expression of Col I, TNF-α, and TGF-β1 were increased compared to that in HQD group. Furthermore, Notch signal pathway was inhibited by HQD plus BMSCNumb-KD, while the protein expression of Numb was decreased and RBP-Jκ and Hes1 was increased compared to that in HQD group. In vitro, HQD reduced the differentiation of WB-F344 cells into cholangiocyte phenotype, while this effect was attenuated after Numb-knockdown. This study highlights that the absence of hepatic stem cell Numb gene decreases effect of HQD against CLF, which give rise the conclusion that Numb might be a potential target for HQD against CLF.
Effect of high fat diet and excessive compressive mechanical force on pathologic changes of temporomandibular joint
Authors: Du Jing , Jiang Qian , Mei Li , Yang Ren , Wen Juan , Lin Shuang , Li Huang
Published: October 2020

The aim of this study was to investigate the effect of high fat diet and excessive compressive mechanical force on temporomandibular joint. In vivo, a mouse model of temporomandibular joint compressive loading device was used. A high fat diet mouse model and a combined mouse model intraperitoneally treated with or without simvastatin were used in the study. The pathological changes of mandibular condylar cartilage were assessed by Safranin-O staining. The IL-1β, MMP-3, leptin expression changes in the cartilage were detected by immunohistochemistry. In vitro, the mandibular condylar chondrocytes were treated with or without L-1β and simvastatin. The mRNA expression level of matrix MMPs and leptin were assessed. Both excessive compressive mechanical force and high fat diet induced obesity caused TMJ osteoarthritis-like changes and increased expression of IL-1β, MMP-3, and leptin. These pathological changes were much more serious when the two interventions were exerted together, while simvastatin could obviously alleviate these changes. The mRNA expression of MMP-3, MMP-13, and leptin increased in the IL-1β treated chondrocytes treated with IL-1β, and decreased with simvastatin treatment. The development of temporomandibular joint pathological changes could be caused by the excessive compressive mechanical force and high fat diet induced obesity.
Crystal structure and site-directed mutagenesis of circular bacteriocin plantacyclin B21AG reveals cationic and aromatic residues important for antimicrobial activity
Authors: Gor Mian-Chee , Vezina Ben , McMahon Róisín M. , King Gordon J. , Panjikar Santosh , Rehm Bernd H. A. , Martin Jennifer L. , Smith Andrew T.
Published: October 2020

Plantacyclin B21AG is a circular bacteriocin produced by Lactiplantibacillus plantarum B21 which displays antimicrobial activity against various Gram-positive bacteria including foodborne pathogens, Listeria monocytogenes and Clostridium perfringens. It is a 58-amino acid cyclised antimicrobial peptide, with the N and C termini covalently linked together. The circular peptide backbone contributes to remarkable stability, conferring partial proteolytic resistance and structural integrity under a wide temperature and pH range. Here, we report the first crystal structure of a circular bacteriocin from a food grade Lactobacillus. The protein was crystallised using the hanging drop vapour diffusion method and the structure solved to a resolution of 1.8 Å. Sequence alignment against 18 previously characterised circular bacteriocins revealed the presence of conserved charged and aromatic residues. Alanine substitution mutagenesis validated the importance of these residues. Minimum inhibitory concentration analysis of these Ala mutants showed that Phe8Ala and Trp45Ala mutants displayed a 48- and 32-fold reduction in activity, compared to wild type. The Lys19Ala mutant displayed the weakest activity, with a 128-fold reduction. These experiments demonstrate the relative importance of aromatic and cationic residues for the antimicrobial activity of plantacyclin B21AG and by extension, other circular bacteriocins sharing these evolutionarily conserved residues.
Submesoscale modulation of deep water formation in the Labrador Sea
Authors: Tagklis Filippos , Bracco A. , Ito T. , Castelao R. M.
Published: October 2020

Submesoscale structures fill the ocean surface, and recent numerical simulations and indirect observations suggest that they may extend to the ocean interior. It remains unclear, however, how far-reaching their impact may be—in both space and time, from weather to climate scales. Here transport pathways and the ultimate fate of the Irminger Current water from the continental slope to Labrador Sea interior are investigated through regional ocean simulations. Submesoscale processes modulate this transport and in turn the stratification of the Labrador Sea interior, by controlling the characteristics of the coherent vortices formed along West Greenland. Submesoscale circulations modify and control the Labrador Sea contribution to the global meridional overturning, with a linear relationship between time-averaged near surface vorticity and/or frontogenetic tendency along the west coast of Greenland, and volume of convected water. This research puts into contest the lesser role of the Labrador Sea in the overall control of the state of the MOC argued through the analysis of recent OSNAP (Overturning in the Subpolar North Atlantic Program) data with respect to estimates from climate models. It also confirms that submesoscale turbulence scales-up to climate relevance, pointing to the urgency of including its advective contribution in Earth systems models.
New insights on human IRE1 tetramer structures based on molecular modeling
Authors: Carlesso Antonio , Hörberg Johanna , Reymer Anna , Eriksson Leif A.
Published: October 2020

Inositol-Requiring Enzyme 1α (IRE1α; hereafter IRE1) is a transmembrane kinase/ribonuclease protein related with the unfolded protein response (UPR) signaling. Experimental evidence suggests that IRE1 forms several three dimensional (3D) structural variants: dimers, tetramers and higher order oligomers, where each structural variant can contain different IRE1 conformers in different arrangements. For example, studies have shown that two sets of IRE1 dimers exist; a face-to-face dimer and a back-to-back dimer, with the latter considered the important unit for UPR signaling propagation. However, the structural configuration and mechanistic details of the biologically important IRE1 tetramers are limited. Here, we combine protein–protein docking with molecular dynamics simulations to derive human IRE1 tetramer models and identify a molecular mechanism of IRE1 activation. To validate the derived models of the human IRE1 tetramer, we compare the dynamic behavior of the models with the yeast IRE1 tetramer crystallographic structure. We show that IRE1 tetramer conformational changes could be linked to the initiation of the unconventional splicing of mRNA encoding X-box binding protein-1 (XBP1), which allows for the expression of the transcription factor XBP1s (XBP1 spliced). The derived IRE1 tetrameric models bring new mechanistic insights about the IRE1 molecular activation mechanism by describing the IRE1 tetramers as active protagonists accommodating the XBP1 substrate.
The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity
Authors: Gorchs Laia , Ahmed Sultan , Mayer Chanté , Knauf Alisa , Fernández Moro Carlos , Svensson Mattias , Heuchel Rainer , Rangelova Elena , Bergman Peter , Kaipe Helen
Published: October 2020

The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.
Prebiotic effects of yeast mannan, which selectively promotes Bacteroides thetaiotaomicron and Bacteroides ovatus in a human colonic microbiota model
Authors: Oba Shunsuke , Sunagawa Tadahiro , Tanihiro Reiko , Awashima Kyoko , Sugiyama Hiroshi , Odani Tetsuji , Nakamura Yasunori , Kondo Akihiko , Sasaki Daisuke , Sasaki Kengo
Published: October 2020

Yeast mannan (YM) is an indigestible water-soluble polysaccharide of the yeast cell wall, with a notable prebiotic effect on the intestinal microbiota. We previously reported that YM increased Bacteroides thetaiotaomicron abundance in in vitro rat faeces fermentation, concluding that its effects on human colonic microbiota should be investigated. In this study, we show the effects of YM on human colonic microbiota and its metabolites using an in vitro human faeces fermentation system. Bacterial 16S rRNA gene sequence analysis showed that YM administration did not change the microbial diversity or composition. Quantitative real-time PCR analysis revealed that YM administration significantly increased the relative abundance of Bacteroides ovatus and B. thetaiotaomicron. Moreover, a positive correlation was observed between the relative ratio (with or without YM administration) of B. thetaiotaomicron and B. ovatus (r = 0.92), suggesting that these bacteria utilise YM in a coordinated manner. In addition, YM administration increased the production of acetate, propionate, and total short-chain fatty acids. These results demonstrate the potential of YM as a novel prebiotic that selectively increases B. thetaiotaomicron and B. ovatus and improves the intestinal environment. The findings also provide insights that might be useful for the development of novel functional foods.
In vivo measurement of shear modulus of the human cornea using optical coherence elastography
Authors: Ramier Antoine , Eltony Amira M. , Chen YiTong , Clouser Fatima , Birkenfeld Judith S. , Watts Amy , Yun Seok-Hyun
Published: October 2020

Corneal stiffness plays a critical role in shaping the cornea with respect to intraocular pressure and physical interventions. However, it remains difficult to measure the mechanical properties noninvasively. Here, we report the first measurement of shear modulus in human corneas in vivo using optical coherence elastography (OCE) based on surface elastic waves. In a pilot study of 12 healthy subjects aged between 25 and 67, the Rayleigh-wave speed was 7.86 ± 0.75 m/s, corresponding to a shear modulus of 72 ± 14 kPa. Our data reveal two unexpected trends: no correlation was found between the wave speed and IOP between 13–18 mmHg, and shear modulus decreases with age (− 0.32 ± 0.17 m/s per decade). We propose that shear stiffness is governed by the interfibrillar matrix, whereas tensile strength is dominated by collagen fibrils. Rayleigh-wave OCE may prove useful for clinical diagnosis, refractive surgeries, and treatment monitoring.