bluuebunny/crossref_metadata_2025 huggingface dataset:
Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice
Authors: Zuo Bingfeng , Qi Han , Lu Zhen , Chen Lu , Sun Bo , Yang Rong , Zhang Yang , Liu Zhili , Gao Xianjun , You Abin , Wu Li , Jing Renwei , Zhou Qibing , Yin HaiFang
Published: April 2020

Treating large established tumors is challenging for dendritic cell (DC)-based immunotherapy. DC activation with tumor cell-derived exosomes (TEXs) carrying multiple tumor-associated antigen can enhance tumor recognition. Adding a potent adjuvant, high mobility group nucleosome-binding protein 1 (HMGN1), boosts DCs’ ability to activate T cells and improves vaccine efficiency. Here, we demonstrate that TEXs painted with the functional domain of HMGN1 (TEX-N1ND) via an exosomal anchor peptide potentiates DC immunogenicity. TEX-N1ND pulsed DCs (DCTEX-N1ND) elicit long-lasting antitumor immunity and tumor suppression in different syngeneic mouse models with large tumor burdens, most notably large, poorly immunogenic orthotopic hepatocellular carcinoma (HCC). DCTEX-N1NDshow increased homing to lymphoid tissues and contribute to augmented memory T cells. Importantly, N1ND-painted serum exosomes from cancer patients also promote DC activation. Our study demonstrates the potency of TEX-N1ND to strengthen DC immunogenicity and to suppress large established tumors, and thus provides an avenue to improve DC-based immunotherapy.
The Sox2 transcription factor binds RNA
Authors: Holmes Zachariah E. , Hamilton Desmond J. , Hwang Taeyoung , Parsonnet Nicholas V. , Rinn John L. , Wuttke Deborah S. , Batey Robert T.
Published: April 2020

Certain transcription factors are proposed to form functional interactions with RNA to facilitate proper regulation of gene expression. Sox2, a transcription factor critical for maintenance of pluripotency and neurogenesis, has been found associated with several lncRNAs, although it is unknown whether these interactions are direct or via other proteins. Here we demonstrate that human Sox2 interacts directly with one of these lncRNAs with high affinity through its HMG DNA-binding domain in vitro. These interactions are primarily with double-stranded RNA in a non-sequence specific fashion, mediated by a similar but not identical interaction surface. We further determined that Sox2 directly binds RNA in mouse embryonic stem cells by UV-cross-linked immunoprecipitation of Sox2 and more than a thousand Sox2-RNA interactions in vivo were identified using fRIP-seq. Together, these data reveal that Sox2 employs a high-affinity/low-specificity paradigm for RNA binding in vitro and in vivo.
Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics
Authors: Sadek Jouliana , Wuo Michael G. , Rooklin David , Hauenstein Arthur , Hong Seong Ho , Gautam Archana , Wu Hao , Zhang Yingkai , Cesarman Ethel , Arora Paramjit S.
Published: April 2020

Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topological complexity of this protein has limited inhibitor design. We undertook a comprehensive effort to block the interaction between vFLIP, a Kaposi’s sarcoma herpesviral oncoprotein, and NEMO using small molecule screening and rational design. Our efforts reveal that a tertiary protein structure mimic of NEMO is necessary for potent inhibition. The rationally designed mimic engages vFLIP directly causing complex disruption, protein degradation and suppression of NF-κB signaling in primary effusion lymphoma (PEL). NEMO mimic treatment induces cell death and delays tumor growth in a PEL xenograft model. Our studies with this inhibitor reveal the critical nexus of signaling complex stability in the regulation of NF-κB by a viral oncoprotein.
Sediment controls dynamic behavior of a Cordilleran Ice Stream at the Last Glacial Maximum
Authors: Cowan Ellen A. , Zellers Sarah D. , Müller Juliane , Walczak Maureen H. , Worthington Lindsay L. , Caissie Beth E. , Clary Wesley A. , Jaeger John M. , Gulick Sean P. S. , Pratt Jacob W. , Mix Alan C. , Fallon Stewart J.
Published: April 2020

The uncertain response of marine terminating outlet glaciers to climate change at time scales beyond short-term observation limits models of future sea level rise. At temperate tidewater margins, abundant subglacial meltwater forms morainal banks (marine shoals) or ice-contact deltas that reduce water depth, stabilizing grounding lines and slowing or reversing glacial retreat. Here we present a radiocarbon-dated record from Integrated Ocean Drilling Program (IODP) Site U1421 that tracks the terminus of the largest Alaskan Cordilleran Ice Sheet outlet glacier during Last Glacial Maximum climate transitions. Sedimentation rates, ice-rafted debris, and microfossil and biogeochemical proxies, show repeated abrupt collapses and slow advances typical of the tidewater glacier cycle observed in modern systems. When global sea level rise exceeded the local rate of bank building, the cycle of readvances stopped leading to irreversible retreat. These results support theory that suggests sediment dynamics can control tidewater terminus position on an open shelf under temperate conditions delaying climate-driven retreat.
Dynamic wrinkling pattern exhibiting tunable fluorescence for anticounterfeiting applications
Authors: Ma Tianjiao , Li Tiantian , Zhou Liangwei , Ma Xiaodong , Yin Jie , Jiang Xuesong
Published: April 2020

A dynamic surface pattern with a topography and fluorescence in response to environmental stimulus can enable information recording, hiding, and reading. Such patterns are therefore widely used in information security and anticounterfeiting. Here, we demonstrate a dynamic dual pattern using a supramolecular network comprising a copolymer containing pyridine (P4VP-nBA-S) and hydroxyl distyrylpyridine (DSP-OH) as the skin layer for bilayer wrinkling systems, in which both the wrinkle morphology and fluorescence color can be simultaneously regulated by visible light-triggered isomerization of DSP-OH, or acids. Acid-induced protonation of pyridines can dynamically regulate the cross-linking of the skin layer through hydrogen bonding, and the fluorescence of DSP-OH. On selective irradiation with 450 nm visible light or acid treatment, the resulting hierarchical patterned surface becomes smooth and wrinkled reversibly, and simultaneously its fluorescence changes dynamically from blue to orange-red. The smart surfaces with dynamic hierarchical wrinkles and fluorescence can find potential application in anticounterfeiting.
Glycolytic reprograming in Salmonella counters NOX2-mediated dissipation of ΔpH
Authors: Chakraborty Sangeeta , Liu Lin , Fitzsimmons Liam , Porwollik Steffen , Kim Ju-Sim , Desai Prerak , McClelland Michael , Vazquez-Torres Andres
Published: April 2020

The microbial adaptations to the respiratory burst remain poorly understood, and establishing how the NADPH oxidase (NOX2) kills microbes has proven elusive. Here we demonstrate that NOX2 collapses the ΔpH of intracellular Salmonella Typhimurium. The depolarization experienced by Salmonella undergoing oxidative stress impairs folding of periplasmic proteins. Depolarization in respiring Salmonella mediates intense bactericidal activity of reactive oxygen species (ROS). Salmonella adapts to the challenges oxidative stress imposes on membrane bioenergetics by shifting redox balance to glycolysis and fermentation, thereby diminishing electron flow through the membrane, meeting energetic requirements and anaplerotically generating tricarboxylic acid intermediates. By diverting electrons away from the respiratory chain, glycolysis also enables thiol/disulfide exchange-mediated folding of bacterial cell envelope proteins during periods of oxidative stress. Thus, primordial metabolic pathways, already present in bacteria before aerobic respiration evolved, offer a solution to the stress ROS exert on molecular targets at the bacterial cell envelope.
RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2
Authors: Alecki Célia , Chiwara Victoria , Sanz Lionel A. , Grau Daniel , Arias Pérez Osvaldo , Boulier Elodie L. , Armache Karim-Jean , Chédin Frédéric , Francis Nicole J.
Published: April 2020

Polycomb Group (PcG) proteins form memory of transient transcriptional repression that is necessary for development. InDrosophila, DNA elements termed Polycomb Response Elements (PREs) recruit PcG proteins. How PcG activities are targeted to PREs to maintain repressed states only in appropriate developmental contexts has been difficult to elucidate. PcG complexes modify chromatin, but also interact with both RNA and DNA, and RNA is implicated in PcG targeting and function. Here we show that R-loops form at many PREs inDrosophilaembryos, and correlate with repressive states. In vitro, both PRC1 and PRC2 can recognize R-loops and open DNA bubbles. Unexpectedly, we find that PRC2 drives formation of RNA-DNA hybrids, the key component of R-loops, from RNA and dsDNA. Our results identify R-loop formation as a feature ofDrosophilaPREs that can be recognized by PcG complexes, and RNA-DNA strand exchange as a PRC2 activity that could contribute to R-loop formation.
Structural dynamics in proteins induced by and probed with X-ray free-electron laser pulses
Authors: Nass Karol , Gorel Alexander , Abdullah Malik M. , V. Martin Andrew , Kloos Marco , Marinelli Agostino , Aquila Andrew , Barends Thomas R. M. , Decker Franz-Josef , Bruce Doak R. , Foucar Lutz , Hartmann Elisabeth , Hilpert Mario , Hunter Mark S. , Jurek Zoltan , Koglin Jason E. , Kozlov Alexander , Lutman Alberto A. , Kovacs Gabriela Nass , Roome Christopher M. , Shoeman Robert L. , Santra Robin , Quiney Harry M. , Ziaja Beata , Boutet Sébastien , Schlichting Ilme
Published: April 2020

X-ray free-electron lasers (XFELs) enable crystallographic structure determination beyond the limitations imposed upon synchrotron measurements by radiation damage. The need for very short XFEL pulses is relieved through gating of Bragg diffraction by loss of crystalline order as damage progresses, but not if ionization events are spatially non-uniform due to underlying elemental distributions, as in biological samples. Indeed, correlated movements of iron and sulfur ions were observed in XFEL-irradiated ferredoxin microcrystals using unusually long pulses of 80 fs. Here, we report a femtosecond time-resolved X-ray pump/X-ray probe experiment on protein nanocrystals. We observe changes in the protein backbone and aromatic residues as well as disulfide bridges. Simulations show that the latter’s correlated structural dynamics are much slower than expected for the predicted high atomic charge states due to significant impact of ion caging and plasma electron screening. This indicates that dense-environment effects can strongly affect local radiation damage-induced structural dynamics.
Phase-dependent amplification of working memory content and performance
Authors: ten Oever Sanne , De Weerd Peter , Sack Alexander T.
Published: April 2020

Successful working memory performance has been related to oscillatory mechanisms operating in low-frequency ranges. Yet, their mechanistic interaction with the distributed neural activity patterns representing the content of the memorized information remains unclear. Here, we record EEG during a working memory retention interval, while a task-irrelevant, high-intensity visual impulse stimulus is presented to boost the read-out of distributed neural activity related to the content held in working memory. Decoding of this activity with a linear classifier reveals significant modulations of classification accuracy by oscillatory phase in the theta/alpha ranges at the moment of impulse presentation. Additionally, behavioral accuracy is highest at the phases showing maximized decoding accuracy. At those phases, behavioral accuracy is higher in trials with the impulse compared to no-impulse trials. This constitutes the first evidence in humans that working memory information is maximized within limited phase ranges, and that phase-selective, sensory impulse stimulation can improve working memory.
Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection
Authors: Adland Emily , Millar Jane , Bengu Nomonde , Muenchhoff Maximilian , Fillis Rowena , Sprenger Kenneth , Ntlantsana Vuyokasi , Roider Julia , Vieira Vinicius , Govender Katya , Adamson John , Nxele Nelisiwe , Ochsenbauer Christina , Kappes John , Mori Luisa , van Lobenstein Jeroen , Graza Yeney , Chinniah Kogielambal , Kapongo Constant , Bhoola Roopesh , Krishna Malini , Matthews Philippa C. , Poderos Ruth Penya , Lluch Marta Colomer , Puertas Maria C. , Prado Julia G. , McKerrow Neil , Archary Moherndran , Ndung’u Thumbi , Groll Andreas , Jooste Pieter , Martinez-Picado Javier , Altfeld Marcus , Goulder Philip
Published: April 2020

Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of > 170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5–2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p = 0.0005) and are more type I interferon-resistant (p = 0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p = 0.01) and more susceptible to HIV infection in vitro (p = 0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p = 0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males.
Ribosome profiling at isoform level reveals evolutionary conserved impacts of differential splicing on the proteome
Authors: Reixachs-Solé Marina , Ruiz-Orera Jorge , Albà M. Mar , Eyras Eduardo
Published: April 2020

The differential production of transcript isoforms from gene loci is a key cellular mechanism. Yet, its impact in protein production remains an open question. Here, we describe ORQAS (ORF quantification pipeline for alternative splicing), a pipeline for the translation quantification of individual transcript isoforms using ribosome-protected mRNA fragments (ribosome profiling). We find evidence of translation for 40–50% of the expressed isoforms in human and mouse, with 53% of the expressed genes having more than one translated isoform in human, and 33% in mouse. Differential splicing analysis revealed that about 40% of the splicing changes at RNA level are concordant with changes in translation. Furthermore, orthologous cassette exons between human and mouse preserve the directionality of the change, and are enriched in microexons in a comparison between glia and glioma. ORQAS leverages ribosome profiling to uncover a widespread and evolutionarily conserved impact of differential splicing on translation, particularly of microexon-containing isoforms.
Glycogen metabolism regulates macrophage-mediated acute inflammatory responses
Authors: Ma Jingwei , Wei Keke , Liu Junwei , Tang Ke , Zhang Huafeng , Zhu Liyan , Chen Jie , Li Fei , Xu Pingwei , Chen Jie , Liu Jincheng , Fang Haiqing , Tang Liang , Wang Dianheng , Zeng Liping , Sun Weiwei , Xie Jing , Liu Yuying , Huang Bo
Published: April 2020

Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls macrophage-mediated inflammatory responses. IFN-γ/LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y14 in macrophages. The UDPG/P2Y14 signaling pathway not only upregulates the expression of STAT1 via activating RARβ but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases.
Quantifying the heterogeneity of macromolecular machines by mass photometry
Authors: Sonn-Segev Adar , Belacic Katarina , Bodrug Tatyana , Young Gavin , VanderLinden Ryan T. , Schulman Brenda A. , Schimpf Johannes , Friedrich Thorsten , Dip Phat Vinh , Schwartz Thomas U. , Bauer Benedikt , Peters Jan-Michael , Struwe Weston B. , Benesch Justin L. P. , Brown Nicholas G. , Haselbach David , Kukura Philipp
Published: April 2020

Sample purity is central to in vitro studies of protein function and regulation, and to the efficiency and success of structural studies using techniques such as x-ray crystallography and cryo-electron microscopy (cryo-EM). Here, we show that mass photometry (MP) can accurately characterize the heterogeneity of a sample using minimal material with high resolution within a matter of minutes. To benchmark our approach, we use negative stain electron microscopy (nsEM), a popular method for EM sample screening. We include typical workflows developed for structure determination that involve multi-step purification of a multi-subunit ubiquitin ligase and chemical cross-linking steps. When assessing the integrity and stability of large molecular complexes such as the proteasome, we detect and quantify assemblies invisible to nsEM. Our results illustrate the unique advantages of MP over current methods for rapid sample characterization, prioritization and workflow optimization.
Structural insights into the mechanism and inhibition of transglutaminase-induced ubiquitination by the Legionella effector MavC
Authors: Mu Yajuan , Wang Yue , Huang Yanfei , Li Dong , Han Youyou , Chang Min , Fu Jiaqi , Xie Yongchao , Ren Jie , Wang Hao , Zhang Yi , Luo Zhao-Qing , Feng Yue
Published: April 2020

Protein ubiquitination is one of the most prevalent post-translational modifications, controlling virtually every process in eukaryotic cells. Recently, the Legionella effector MavC was found to mediate a unique ubiquitination through transglutamination, linking ubiquitin (Ub) to UBE2N through UbGln40 in a process that can be inhibited by another Legionella effector, Lpg2149. Here, we report the structures of MavC/UBE2N/Ub ternary complex, MavC/UBE2N-Ub (product) binary complex, and MavC/Lpg2149 binary complex. During the ubiquitination, the loop containing the modification site K92 of UBE2N undergoes marked conformational change, and Lpg2149 inhibits this ubiquitination through competing with Ub to bind MavC. Moreover, we found that MavC itself also exhibits weak deubiquitinase activity towards this non-canonical ubiquitination. Together, our study not only provides insights into the mechanism and inhibition of this transglutaminase-induced ubiquitination by MavC, but also sheds light on the future studies into UBE2N inhibition by this modification and deubiquitinases of this unique ubiquitination.
Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease
Authors: Mayr Lisa , Grabherr Felix , Schwärzler Julian , Reitmeier Isabelle , Sommer Felix , Gehmacher Thomas , Niederreiter Lukas , He Gui-Wei , Ruder Barbara , Kunz Kai T. R. , Tymoszuk Piotr , Hilbe Richard , Haschka David , Feistritzer Clemens , Gerner Romana R. , Enrich Barbara , Przysiecki Nicole , Seifert Markus , Keller Markus A. , Oberhuber Georg , Sprung Susanne , Ran Qitao , Koch Robert , Effenberger Maria , Tancevski Ivan , Zoller Heinz , Moschen Alexander R. , Weiss Günter , Becker Christoph , Rosenstiel Philip , Kaser Arthur , Tilg Herbert , Adolph Timon E.
Published: April 2020

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.
The morphology, molecular development and ecological function of pseudonectaries on Nigella damascena (Ranunculaceae) petals
Authors: Liao Hong , Fu Xuehao , Zhao Huiqi , Cheng Jie , Zhang Rui , Yao Xu , Duan Xiaoshan , Shan Hongyan , Kong Hongzhi
Published: April 2020

Pseudonectaries, or false nectaries, the glistening structures that resemble nectaries or nectar droplets but do not secrete nectar, show considerable diversity and play important roles in plant-animal interactions. The morphological nature, optical features, molecular underpinnings and ecological functions of pseudonectaries, however, remain largely unclear. Here, we show that pseudonectaries ofNigella damascena(Ranunculaceae) are tiny, regional protrusions covered by tightly arranged, non-secretory polygonal epidermal cells with flat, smooth and reflective surface, and are clearly visible even under ultraviolet light and bee vision. We also show that genes associated with cell division, chloroplast development and wax formation are preferably expressed in pseudonectaries. Specifically,NidaYABBY5, an abaxial gene with ectopic expression in pseudonectaries, is indispensable for pseudonectary development: knockdown of it led to complete losses of pseudonectaries. Notably, when flowers without pseudonectaries were arrayed beside those with pseudonectaries, clear differences were observed in the visiting frequency, probing time and visiting behavior of pollinators (i.e., honey bees), suggesting that pseudonectaries serve as both visual attractants and nectar guides.
Capturing the primordial Kras mutation initiating urethane carcinogenesis
Authors: Li Siqi , MacAlpine David M. , Counter Christopher M.
Published: April 2020

The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras. Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to human cancers. To elucidate the principles underlying this RAS mutation tropism of urethane, we adapted an error-corrected, high-throughput sequencing approach to detect mutations in murine Ras genes at great sensitivity. This analysis not only captured the initiating Kras mutation days after urethane exposure, but revealed that the sequence specificity of urethane mutagenesis, coupled with transcription and isoform locus, to be major influences on the extreme tropism of this carcinogen.
The effects of contemporaneous peer punishment on cooperation with the future
Authors: Lohse Johannes , Waichman Israel
Published: April 2020

We use a laboratory version of the intergenerational goods game (IGG) to investigate whether peer punishment facilitates the successful provision of multigenerational public goods. In our experiment, groups (generations) decide sequentially about the provision of a multigenerational public good through the voluntary contributions of their members. Successful provision requires that contributions meet a threshold and exclusively benefits members of future generations. Provision costs are borne only by the current generation. We compare a baseline condition without a punishment institution to a treatment condition where peer punishment can be inflicted exclusively on members of the same generation but not on members of past or future generations. We find that without punishment the likelihood of reaching the contribution threshold is low and that making punishment available within a generation is partially successful in sustaining cooperation in a succession of multiple generations.
A nitrogen-doped nanotube molecule with atom vacancy defects
Authors: Ikemoto Koki , Yang Seungmin , Naito Hisashi , Kotani Motoko , Sato Sota , Isobe Hiroyuki
Published: April 2020

Nitrogen-doped carbon nanotubes have attracted attention in various fields, but lack of congeners with discrete molecular structures has hampered developments based on in-depth, chemical understandings. In this study, a nanotube molecule doped periodically with multiple nitrogen atoms has been synthesized by combining eight 2,4,6-trisubstituted pyridine units with thirty-two 1,3,5-trisubstituted benzene units. A synthetic strategy involving geodesic phenine frameworks is sufficiently versatile to tolerate pyridine units without requiring synthetic detours. Crystallographic analyses adopting aspherical multipole atom models reveal the presence of axially rotated structures as a minor disordered structure, which also provides detailed molecular and electronic structures. The nitrogen atoms on the nanotube serve as chemically distinct sites covered with negatively charged surfaces, and they increase the chance of electron injections by lowering the energy levels of the unoccupied orbitals that should serve as electron acceptors.
A superelastochromic crystal
Authors: Mutai Toshiki , Sasaki Toshiyuki , Sakamoto Shunichi , Yoshikawa Isao , Houjou Hirohiko , Takamizawa Satoshi
Published: April 2020

Chromism—color changes by external stimuli—has been intensively studied to develop smart materials because of easily detectability of the stimuli by eye or common spectroscopy as color changes. Luminescent chromism has particularly attracted research interest because of its high sensitivity. The color changes typically proceed in a one-way, two-state cycle, i.e. a stimulus-induced state will restore the initial state by another stimuli. Chromic systems showing instant, biphasic color switching and spontaneous reversibility will have wider practical applicability. Here we report luminescent chromism having such characteristics shown by mechanically controllable phase transitions in a luminescent organosuperelastic crystal. In mechanochromic luminescence, superelasticity—diffusion-less plastic deformation with spontaneous shape recoverability—enables real-time, reversible, and stepless control of the abundance ratio of biphasic color emissions via a single-crystal-to-single-crystal transformation by controlling a single stimulus, force stress. The unique chromic system, referred to as superelastochromism, holds potential for realizing informative molecule-based mechanical sensing.
Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation
Authors: Chen Minhui , Qiao Guanxi , Hylander Bonnie L. , Mohammadpour Hemn , Wang Xiang-Yang , Subjeck John R. , Singh Anurag K. , Repasky Elizabeth A.
Published: April 2020

The abscopal effect following ionizing radiation therapy (RT) is considered to be a rare event. This effect does occur more frequently when combined with other therapies, including immunotherapy. Here we demonstrate that the frequency of abscopal events following RT alone is highly dependent upon the degree of adrenergic stress in the tumor-bearing host. Using a combination of physiologic, pharmacologic and genetic strategies, we observe improvements in the control of both irradiated and non-irradiated distant tumors, including metastatic tumors, when adrenergic stress or signaling through β-adrenergic receptor is reduced. Further, we observe cellular and molecular evidence of improved, antigen-specific, anti-tumor immune responses which also depend upon T cell egress from draining lymph nodes. These data suggest that blockade of β2 adrenergic stress signaling could be a useful, safe, and feasible strategy to improve efficacy in cancer patients undergoing radiation therapy.
Kinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells
Authors: Belabed Meriem , Mauvais François-Xavier , Maschalidi Sophia , Kurowska Mathieu , Goudin Nicolas , Huang Jian-Dong , Fischer Alain , de Saint Basile Geneviève , van Endert Peter , Sepulveda Fernando E. , Ménasché Gaël
Published: April 2020

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1’s role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.
Machine-learning structural and electronic properties of metal halide perovskites using a hierarchical convolutional neural network
Authors: Saidi Wissam A. , Shadid Waseem , Castelli Ivano E.
Published: April 2020

The development of statistical tools based on machine learning (ML) and deep networks is actively sought for materials design problems. While structure-property relationships can be accurately determined using quantum mechanical methods, these first-principles calculations are computationally demanding, limiting their use in screening a large set of candidate structures. Herein, we use convolutional neural networks to develop a predictive model for the electronic properties of metal halide perovskites (MHPs) that have a billions-range materials design space. We show that a well-designed hierarchical ML approach has a higher fidelity in predicting properties of the MHPs compared to straight-forward methods. In this architecture, each neural network element has a designated role in the estimation process from predicting complex features of the perovskites such as lattice constant and octahedral till angle to narrowing down possible ranges for the values of interest. Using the hierarchical ML scheme, the obtained root-mean-square errors for the lattice constants, octahedral angle and bandgap for the MHPs are 0.01 Å, 5°, and 0.02 eV, respectively. Our study underscores the importance of a careful network design and a hierarchical approach to alleviate issues associated with imbalanced dataset distributions, which is invariably common in materials datasets.
Publisher Correction: An optimized workflow for single-cell transcriptomics and repertoire profiling of purified lymphocytes from clinical samples
Authors: Hanamsagar Richa , Reizis Timothy , Chamberlain Mathew , Marcus Robert , Nestle Frank O. , de Rinaldis Emanuele , Savova Virginia
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
The association between second to fourth digit ratio, reproductive and general health among women: findings from an Israeli pregnancy cohort
Authors: Tabachnik Maya , Sheiner Eyal , Wainstock Tamar
Published: April 2020

The ratio between the length of second and fourth digits (2D:4D) is a putative biomarker for prenatal testosterone and estrogen exposure. The aim of the study was to examine the association between 2D:4D and women’s general and reproductive health. This analysis was conducted within a prospective pregnancy cohort study. The study population included 187 women. 2D:4D was measured directly in both hands using a digital caliper. Multivariable linear and logistic models were used to study the associations between digit ratio and the studied health characteristics. Mean age of the participants was 30.7 ± 4.9 years. The mean age at menarche was 12.9 ± 1.4 years. Right hand 2D:4D mean ± SD was 0.965 ± 0.03. Left hand 2D:4D mean ± SD was 0.956 ± 0.03. An association was found between right 2D:4D and age at menarche, with older age in women with 2D:4D ≥ mean versus 2D:4D < mean (13.2 ± 1.5 and 12.8 ± 1.3 respectively, b = 0.48, 95%CI:0.06–0.91) while controlling for ethnicity. Higher 2D:4D was also associated with heavier menses bleeding and dysmenorrhea. There is an association between 2D:4D and sub optimal reproductive characteristics, including later age at menarche, heavier menses bleeding and dysmenorrhea. These findings support the association between the intrauterine period and reproductive characteristics. Further studies are required to support our findings.
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

Deep 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

The 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

Horses 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

Downy 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

Forskolin 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

Nutritional 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

The 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

R-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

The 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.