bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Treated like Chinamen’: United States immigration restriction and white British subjects
Authors: Rees Anne
Published: July 2019

In 1921, the United States introduced national immigration quotas. Although designed to curb the arrival of ‘undesirables’ from south-east Europe, this quota system also applied to Britain and its white Dominions. By 1929, Australia, New Zealand, and South Africa were each allocated 100 quota places per annum. The British quota was far greater, but still struggled to meet demand. Through a focus on the Australian example, this article investigates how an immigration regime intended to bolster America’s ‘Anglo-Saxon’ identity also exposed the limits of Anglospheric kinship by closing the gates to white Britons. Although the quotas had a comparatively minor impact on Britons, their exclusion held great significance in the context of Anglo-American relations, where the rhetoric of transnational white solidarity produced expectations of unqualified welcome in the United States. After 1921, as such welcome disappeared and then failed to rematerialize, the global community of white men’s countries was shaken and remade.
Pericarp-mediated chemical dormancy controls the fruit germination of the invasive hoary cress (Lepidium draba), but not of hairy whitetop (Lepidium appelianum)
Authors: Mohammed Said , Turečková Veronika , Tarkowská Danuše , Strnad Miroslav , Mummenhoff Klaus , Leubner-Metzger Gerhard
Published: July 2019

This study provides a comparative analysis of the dormancy and germination mechanisms of the indehiscent fruits of hoary cress (Lepidium drabaL.) and hairy whitetop (Lepidium appelianumAl-Shehbaz), two invasive weeds of the Brassicaceae. Germination assays comparing isolated seeds (manually removed from the fruits) and intact indehiscent fruits showed that the isolated seeds are nondormant and provided full germination for both species. In contrast to this, the species differed in the germination properties of their indehiscent fruits, in thatL. appelianumfruits were nondormant, while theL. drabafruit coat (pericarp) conferred a coat-imposed dormancy. The pericarp ofL. drabafresh fruit was water permeable, and neither mechanical scarification nor surface sterilization affected germination, supporting the concept that pericarp-mediated dormancy was not due to water impermeability or mechanical constraint. Washing ofL. drabafruits with water, afterripening (dry storage), and treatment with gibberellin (GA) stimulated the germination of this species, all of which are indicative of physiological dormancy. Analyses of endogenous abscisic acid (ABA) and GA levels combined with treatment experiments with wash water from fresh and afterripenedL. drabapericarps and with ABA dose–response quantification of germination revealed that ABA is a key component of a pericarp-mediated chemical dormancy in this species. Consistent with this, pericarp ABA levels decreased during afterripening and upon fruit washing, and isolated fresh or afterripened seeds did not differ in their ABA sensitivities. The possible roles of the ABA-mediated pericarp dormancy for the germination ecophysiology and weed management of these species are discussed.
Diets, Food Miles, and Environmental Sustainability of Urban Food Systems: Analysis of Nine Indian Cities
Authors: Boyer D. , Sarkar J. , Ramaswami A.
Published: July 2019

With ever‐growing populations, cities are increasingly interested in ensuring a well‐functioning food system. However, knowledge of variation between individual city food systems is limited. This is particularly true in countries such as India, experiencing significant issues related to food security and sustainability. This paper advances the understanding of urban food systems, by analyzing the unique food systems of nine cities within India, through the integration of multiple city‐specific data sources including demand of residents, visitors and industries, and commodity‐specific supply chains to assess nutrition, environmental impact, and supply risk. This work finds a large degree of intercity food system variability across multiple food system characteristics. Specifically, levels of undernutrition vary, with the percentage of city populations who are underconsuming protein ranging from 0% to 70%, and for calories 0% to 90%. Environmental impacts (consumptive water loss, land use, and greenhouse gas emissions) of urban food demand also show variation, largely influenced by differing composition of residential diet. Greenhouse gas emissions are also largely influenced by location of production and spatially informed energy intensity of irrigation. Supply chain distance (“food‐miles”) also vary by city, with the range of 196 (Pondicherry) to 1,137 (Chennai) km/Mg—shorter than more industrialized nations such as the United States. Evaluating supply chain risk in terms of water scarcity in food‐producing regions that serve city demand finds production locations, on average, to be less water‐scarce than the watersheds local to the urban environments. This suggests water‐intensive agriculture may at times be best located at a distance from urban centers and competing demands.
Effects of Sea Spray on Microphysics and Intensity of Deep Convective Clouds Under Strong Winds
Authors: Shpund J. , Khain A. , Rosenfeld D.
Published: July 2019

Deep convective clouds similar to those arising in the tropical cyclone eyewall are simulated using a parcel model and 2‐D slab symmetric cloud model with spectral bin microphysics (the Hebrew University Cloud Model). The size distribution of sea spray particles (SSPs) at cloud base is calculated using the Lagrangian‐Eulerian bin microphysics model. The model describes the SSP production, advection, and formation of the size distribution of SSP in the hurricane atmospheric boundary layer at different strong wind speeds. The SSP distributions calculated by the Lagrangian‐Eulerian bin microphysics model are used in the parcel model and the Hebrew University Cloud Model to investigate the microphysical and dynamical effects of SSP on clouds. The SSPs ascending in cloud updrafts dramatically increase the number concentration of cloud drops within a wide range of drop sizes. As a result, sea spray creates clouds with unique property combinations of both maritime and continental types. These clouds have droplet size distributions characterized by a high drop concentration and a low effective radius, as in continental clouds. At the same time, the presence of SSP of a few hundred microns in radii triggers intense rain just above the cloud base, which is typical of extreme maritime clouds. In the presence of large sea spray drops, the smallest cloud condensational nuclei, including the smallest SSP, are activated, giving rise to the permanent in‐cloud nucleation of small droplets, which produce a high concentration of small ice crystals above the level of homogeneous freezing. We showed that the SSP substantially increased the maximum vertical velocity, cloud water content, and mass contents of ice particles. The results are compared with available observed data.
Is Arctic Amplification Dominated by Regional Radiative Forcing and Feedbacks: Perspectives From the World‐Avoided Scenario
Authors: Virgin J. G. , Smith K. L.
Published: July 2019

Arctic amplification (AA) is typically associated with Planck, lapse rate, and ice albedo feedbacks. However, the relative importance of poleward energy transport on AA remains uncertain. Here, we analyze integrations from a Chemistry Climate Model to investigate the impact of the Montreal Protocol on forcing, feedback, and transport contributions to AA. Two ensembles of future integrations are considered—one projecting decreasing ozone‐depleting substance concentrations and stratospheric ozone recovery and another assuming that ozone‐depleting substances are not regulated (the “World Avoided”). We find similar degrees of AA in both ensembles, despite a negative radiative forcing over the Arctic in the “World Avoided” from massive ozone loss. That negative radiative forcing is primarily balanced from positive atmospheric energy flux convergence and long‐wave cloud feedbacks. Our results highlight the impact of inhomogeneous radiative forcing on regional differences in forcing and feedback strength and the importance of radiative forcing meridional structure on poleward energy transport.
Multi‐instrument Observation of Nonlinear EMIC‐Driven Electron Precipitation at sub–MeV Energies
Authors: Hendry A. T. , Santolik O. , Kletzing C. A. , Rodger C. J. , Shiokawa K. , Baishev D.
Published: July 2019

In recent years, experimental results have consistently shown evidence of electromagnetic ion cyclotron (EMIC) wave‐driven electron precipitation down to energies as low as hundreds of keV. However, this is at odds with the limits expected from quasi‐linear theory. Recent analysis using nonlinear theory has suggested energy limits as low as hundreds of keV, consistent with the experimental results, although to date this has not been experimentally verified. In this study, we present concurrent observations from Polar‐orbiting Operational Environmental Satellite, Radiation Belt Storm Probes, Global Positioning System, and ground‐based instruments, showing concurrent EMIC waves and sub–MeV electron precipitation, and a global dropout in electron flux. We show through test particle simulation that the observed waves are capable of scattering electrons as low as hundreds of keV into the loss cone through nonlinear trapping, consistent with the experimentally observed electron precipitation.
On How High‐Latitude Chorus Waves Tip the Balance Between Acceleration and Loss of Relativistic Electrons
Authors: Wang Dedong , Shprits Yuri Y.
Published: July 2019

Modeling and observations have shown that energy diffusion by chorus waves is an important source of acceleration of electrons to relativistic energies. By performing long‐term simulations using the three‐dimensional Versatile Electron Radiation Belt code, in this study, we test how the latitudinal dependence of chorus waves can affect the dynamics of the radiation belt electrons. Results show that the variability of chorus waves at high latitudes is critical for modeling of megaelectron volt (MeV) electrons. We show that, depending on the latitudinal distribution of chorus waves under different geomagnetic conditions, they cannot only produce a net acceleration but also a net loss of MeV electrons. Decrease in high‐latitude chorus waves can tip the balance between acceleration and loss toward acceleration, or alternatively, the increase in high‐latitude waves can result in a net loss of MeV electrons. Variations in high‐latitude chorus may account for some of the variability of MeV electrons.
Geodynamo Conductivity Limits
Authors: Driscoll Peter E. , Du Zhixue
Published: July 2019

In a metal, as in Earth's core, the thermal and electrical conductivities are assumed to be correlated. In a planetary dynamo this implies a contradiction: that both electrical conductivity, which makes it easier to induce current and magnetic field, and conductive heat transport, which hinders thermal convection, should increase simultaneously. Here we show that this contradiction implies that the magnetic induction rate peaks at a particular value of electrical and thermal conductivity and derive the low‐ and high‐conductivity limits for thermal dynamo action. A dynamo regime diagram is derived as a function of electrical conductivity and temperature for Earth's core that identifies four distinct dynamo regimes: no dynamo, thermal dynamo, compositional dynamo, and thermocompositional dynamo. Estimates for the temperature‐dependent electrical conductivity of the core imply that the geodynamo may have come close to its high‐conductivity “no dynamo” limit prior to inner core nucleation, consistent with recent paleomagnetic observations.
An Integrated Geophysical Approach to Track Magma Intrusion: The 2018 Christmas Eve Eruption at Mount Etna
Authors: Cannavo' F. , Sciotto M. , Cannata A. , Di Grazia G.
Published: July 2019

On 24 December 2018, a violent eruption started at Mount Etna from a fissure on the southeastern flank. The intrusive phenomenon, accompanied by intense Strombolian and lava fountain activity, an ash‐rich plume, and lava flows, was marked by significant ground deformation and seismicity. In this work, we show how an integrated investigation combining high‐rate GPS data, volcano‐tectonic earthquakes, volcanic tremor, infrasound tremor, and infrasound events allows tracking the magma intrusion phenomenon spatially and temporally with unprecedented resolution. Moreover, it enabled showing how the central magma column lowered as a response to the flank eruption and to constrain the zone of interaction between the dike and the central plumbing system at a depth of 2–4 km below sea level. This is important for understanding flank and summit interaction, suggesting that explosive summit activity may in some cases be driven by lateral dike intrusions.
Observed Interactions Between Black Carbon and Hydrometeor During Wet Scavenging in Mixed‐Phase Clouds
Authors: Ding Shuo , Zhao Delong , He Cenlin , Huang Mengyu , He Hui , Tian Ping , Liu Quan , Bi Kai , Yu Chenjie , Pitt Joseph , Chen Ying , Ma Xincheng , Chen Yunbo , Jia Xingcan , Kong Shaofei , Wu Jian , Hu Dawei , Hu Kang , Ding Deping , Liu Dantong
Published: July 2019

Wet scavenging of black carbon (BC) has been subject to large uncertainty, which importantly determines its atmospheric lifetime and indirect forcing impact on cloud microphysics. This study reveals the complex BC‐hydrometeor interactions in mixed‐phase clouds via single particle measurements in the real‐world environment, by capturing precipitation processes throughout cloud formation, cold rain/graupel, and subsequent snow events at a mountain site influenced by anthropogenic sources in wintertime. We found highly efficient BC wet scavenging during cloud formation, with large and thickly coated BC preferentially incorporated into droplets. During snow processes, BC core sizes in the interstitial phase steadily increased. A mechanism was proposed whereby the BC mass within each droplet was accumulated through droplet collision, leading to larger BC cores, which were then released back to the interstitial air through the Wegener‐Bergeron‐Findeisen processes when ice dominated. These results provide fundamental basis for constraining BC wet scavenging.
Increased Fall Precipitation in the Southeastern United States Driven by Higher‐Intensity, Frontal Precipitation
Authors: Bishop Daniel A. , Williams A. Park , Seager Richard
Published: July 2019

During 1895‐2018, fall precipitation increased by nearly 40% in the southeastern United States north of the Gulf of Mexico due to increased circulation around the western North Atlantic Subtropical High, which enhanced moisture transports into the region. We find here that these increases in southeastern U.S. fall precipitation manifested almost entirely as increases in precipitation intensity, not frequency. Further, the enhanced moisture transports increased precipitation totals far more on the highest‐intensity precipitation days than on the lower‐intensity days, leading to nearly all of the increase to be delivered on extreme (top‐5% intensity) precipitation days. Eighty‐seven percent of the fall precipitation increase was driven by non‐tropical storms (mostly frontal), not tropical cyclones, though the proportion of precipitation falling as either storm type did not change. Further research is needed to evaluate whether these observed precipitation increases are likely to continue, stabilize, or reverse.
High‐Speed Video Observations of Recoil Leaders Producing and Not Producing Return Strokes in a Canton‐Tower Upward Flash
Authors: Wu Bin , Lyu Weitao , Qi Qi , Ma Ying , Chen Lyuwen , Jiang Ruijiao , Zhu Yanan , Rakov Vladimir A.
Published: July 2019

High‐speed video and electric field change data have been used to examine the initiation and propagation of 21 recoil leaders, 7 of which evolved into dart (or dart‐stepped) leaders (DLs) initiating return strokes and 14 were attempted leaders (ALs), in a Canton‐Tower upward flash. Three DLs and two ALs clearly exhibited bidirectional extension. Each DL was preceded by one or more ALs and initiated near the extremity of the positive end of the preceding AL. The positive end of each bidirectional DL generally appeared to be inactive (stationary) or intermittently propagated along the positive part of the preceding AL channel and extended into the virgin air. A sequence of two floating channel segments was formed ahead of the approaching positive end of one DL, causing its abrupt elongation.
IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes
Authors: Bonelli Michael , Dalwigk Karolina , Platzer Alexander , Olmos Calvo Isabel , Hayer Silvia , Niederreiter Birgit , Holinka Johannes , Sevelda Florian , Pap Thomas , Steiner Günter , Superti-Furga Giulio , Smolen Josef S. , Kiener Hans P. , Karonitsch Thomas
Published: July 2019

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.
Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players
Authors: Yuan Xiaotian , Larsson Catharina , Xu Dawei
Published: July 2019

Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.
The role of GPCRs in bone diseases and dysfunctions
Authors: Luo Jian , Sun Peng , Siwko Stefan , Liu Mingyao , Xiao Jianru
Published: July 2019

The superfamily of G protein-coupled receptors (GPCRs) contains immense structural and functional diversity and mediates a myriad of biological processes upon activation by various extracellular signals. Critical roles of GPCRs have been established in bone development, remodeling, and disease. Multiple human GPCR mutations impair bone development or metabolism, resulting in osteopathologies. Here we summarize the disease phenotypes and dysfunctions caused by GPCR gene mutations in humans as well as by deletion in animals. To date, 92 receptors (5 glutamate family, 67 rhodopsin family, 5 adhesion, 4 frizzled/taste2 family, 5 secretin family, and 6 other 7TM receptors) have been associated with bone diseases and dysfunctions (36 in humans and 72 in animals). By analyzing data from these 92 GPCRs, we found that mutation or deletion of different individual GPCRs could induce similar bone diseases or dysfunctions, and the same individual GPCR mutation or deletion could induce different bone diseases or dysfunctions in different populations or animal models. Data from human diseases or dysfunctions identified 19 genes whose mutation was associated with human BMD: 9 genes each for human height and osteoporosis; 4 genes each for human osteoarthritis (OA) and fracture risk; and 2 genes each for adolescent idiopathic scoliosis (AIS), periodontitis, osteosarcoma growth, and tooth development. Reports from gene knockout animals found 40 GPCRs whose deficiency reduced bone mass, while deficiency of 22 GPCRs increased bone mass and BMD; deficiency of 8 GPCRs reduced body length, while 5 mice had reduced femur size upon GPCR deletion. Furthermore, deficiency in 6 GPCRs induced osteoporosis; 4 induced osteoarthritis; 3 delayed fracture healing; 3 reduced arthritis severity; and reduced bone strength, increased bone strength, and increased cortical thickness were each observed in 2 GPCR-deficiency models. The ever-expanding number of GPCR mutation-associated diseases warrants accelerated molecular analysis, population studies, and investigation of phenotype correlation with SNPs to elucidate GPCR function in human diseases.
C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress
Authors: Zhang Bing , Zhang Ping , Tan Yanzhen , Feng Pan , Zhang Zhengbin , Liang Hongliang , Duan Weixun , Jin Zhenxiao , Wang Xiaowu , Liu Jincheng , Gao Erhe , Yu Shiqiang , Yi Dinghua , Sun Yang , Yi Wei
Published: July 2019

C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, which exerts protective function in ischemic or diabetic heart injury. However, the role of CTRP3 in cardiac hypertrophy remains unclear. The aim of this study was to investigate the pharmacological effects of CTRP3 on pathological cardiac hypertrophy induced by hypertension. Male C57BL/6 J wild-type (WT) mice, Ctrp3 knockout mice, and mice infected with lentivirus overexpressing mouse Ctrp3 underwent sham surgery or transverse aortic constriction (TAC) surgery. After 4 weeks, cardiac hypertrophy, fibrosis, and cardiac function were examined. Compared with WT mice, Ctrp3 deficiency substantially impaired contractile dysfunction, exacerbated the enlargement of cardiomyocytes and myocardial fibrosis, and reprogramed the expression of pathological genes after TAC. Conversely, CTRP3 overexpression played a role in restoring the left ventricular cardiac contractile function, alleviating cardiac hypertrophy and fibrosis, and inhibiting the expression of hypertrophic and fibrotic signaling in mice after TAC. Furthermore, CTRP3 regulated the expression of the p38/CREB pathway and of the primary modulating factors of the endoplasmic reticulum stress, i.e., GRP78 and the downstream molecules eukaryotic translation inhibition factor 2 submit α, C/EBP homologous protein, and inositol-requiring enzyme-1. Further, inhibition of p38 MAPK by SB203580 blunted the ER stress intensified by Ctrp3 deficiency. In vitro, CTRP3 protected neonatal rat cardiac myocytes against phenylephrine-induced cardiomyocyte hypertrophy. We conclude that CTRP3 protects the host against pathological cardiac remodeling and left ventricular dysfunction induced by pressure overload largely by inhibiting the p38/CREB pathway and alleviating p38-induced ER stress.
EZH2, JMJD3, and UTX epigenetically regulate hepatic plasticity inducing retro-differentiation and proliferation of liver cells
Authors: Pediconi Natalia , Salerno Debora , Lupacchini Leonardo , Angrisani Annapaola , Peruzzi Giovanna , De Smaele Enrico , Levrero Massimo , Belloni Laura
Published: July 2019

Modification of histones by lysine methylation plays a role in many biological processes, and it is dynamically regulated by several histone methyltransferases and demethylases. The polycomb repressive complex contains the H3K27 methyltransferase EZH2 and controls dimethylation and trimethylation of H3K27 (H3K27me2/3), which trigger gene suppression. JMJD3 and UTX have been identified as H3K27 demethylases that catalyze the demethylation of H3K27me2/3, which in turns lead to gene transcriptional activation. EZH2, JMJD3 and UTX have been extensively studied for their involvement in development, immune system, neurodegenerative disease, and cancer. However, their role in molecular mechanisms underlying the differentiation process of hepatic cells is yet to be elucidated. Here, we show that EZH2 methyltransferase and JMJD3/UTX demethylases were deregulated during hepatic differentiation of human HepaRG cells resulting in a strong reduction of H3K27 methylation levels. Inhibition of JMJD3 and UTX H3K27 demethylase activity by GSK-J4 epi-drug reverted phenotype of HepaRG DMSO-differentiated cells and human primary hepatocytes, drastically decreasing expression of hepatic markers and inducing cell proliferation. In parallel, inhibition of EZH2 H3K27me3 activity by GSK-126 epi-drug induced upregulation of hepatic markers and downregulated the expression of cell cycle inhibitor genes. To conclude, we demonstrated that modulation of H3K27 methylation by inhibiting methyl-transferase and dimethyl-transferase activity influences the differentiation status of hepatic cells, identifying a possible new role of EZH2, JMJD3 and UTX epi-drugs to modulate hepatic cell plasticity.
4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway (PPP) flux mediated by LKB1-AMPK/HDAC10/G6PD axis
Authors: Shan Changliang , Lu Zhaoliang , Li Zhen , Sheng Hao , Fan Jun , Qi Qi , Liu Shuangping , Zhang Shuai
Published: July 2019

Abstract

4-hydroxyphenylpyruvate dioxygenase (HPD) is an important modifier of tyrosine metabolism. However, the precise contribution of HPD to cancer metabolism and tumorigenesis remains unclear. In this study, we found that HPD was highly expressed in lung cancer and its higher expression correlated with poor prognosis in lung cancer patients. Suppressed HPD expression was sufficient to decrease oxidative pentose phosphate pathway (PPP) flux, leading to reduced RNA biosynthesis and enhanced reactive oxygen species (ROS) level, attenuated cancer cell proliferation, and tumor growth. Mechanistically, HPD not only promotes tyrosine catabolism leading to increased acetyl-CoA levels, the source of histone acetylation, but also stimulates histone deacetylase 10 (HDAC10) translocation from the nucleus into the cytoplasm mediated by tumor suppressor liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) signaling. Both controlled histone acetylation modification, which enhanced transcription of the important PPP enzyme Glucose-6-Phosphate Dehydrogenase (G6PD). Thus, this study reveals HPD as a novel regulator of LKB1–AMPK signaling-mediated HDAC10 nuclear location, which contributes to G6PD expression in promoting tumor growth, which is a promising target for lung cancer treatment.
Apogossypol-mediated reorganisation of the endoplasmic reticulum antagonises mitochondrial fission and apoptosis
Authors: Yedida Govindaraju , Milani Mateus , Cohen Gerald M , Varadarajan Shankar
Published: July 2019

The endoplasmic reticulum (ER) with its elaborate network of highly curved tubules and flat sheets interacts with several other organelles, including mitochondria, peroxisomes and endosomes, to play vital roles in their membrane dynamics and functions. Previously, we identified structurally diverse chemicals from different pharmacological classes, which induce a reversible reorganisation of ER membranes. Using apogossypol as a prototypic tool compound, we now show that ER membrane reorganisation occurs at the level of ER tubules but does not involve ER sheets. Reorganisation of ER membranes prevents DRP-1-mediated mitochondrial fission, thereby antagonising the functions of several mitochondrial fission-inducing agents. Previous reports have suggested that ER membranes mark the constriction sites of mitochondria by localising DRP-1, as well as BAX on mitochondrial membranes to facilitate both mitochondrial fission and outer membrane permeabilisation. Following ER membrane reorganisation and subsequent exposure to an apoptotic stimulus (BH3 mimetics), DRP-1 still colocalises with the reorganised ER membranes but BAX translocation and activation, cytochrome c release and phosphatidylserine externalisation are all inhibited, thereby diminishing the ability of BH3 mimetics to induce the intrinsic apoptotic pathway. Strikingly, both ER membrane reorganisation and its resulting inhibition of apoptosis could be reversed by inhibitors of dihydroorotate dehydrogenase (DHODH), namely teriflunomide and its active metabolite, leflunomide. However, neither genetic inhibition of DHODH using RNA interference nor metabolic supplementation with orotate or uridine to circumvent the consequences of a loss of DHODH activity rescued the effects of DHODH inhibitors, suggesting that the effects of these inhibitors in preventing ER membrane reorganisation is most likely independent of their ability to antagonise DHODH activity. Our results strengthen the hypothesis that ER is fundamental for key mitochondrial functions, such as fusion-fission dynamics and apoptosis.
Paradoxical impact of memory on color appearance of faces
Authors: Hasantash Maryam , Lafer-Sousa Rosa , Afraz Arash , Conway Bevil R.
Published: July 2019

What is color vision for? Here we compared the extent to which memory modulates color appearance of objects and faces. Participants matched the colors of stimuli illuminated by low-pressure sodium light, which renders scenes monochromatic. Matches for fruit were not predicted by stimulus identity. In contrast, matches for faces were predictable, but surprising: faces appeared green and looked sick. The paradoxical face-color percept could be explained by a Bayesian observer model constrained by efficient coding. The color-matching data suggest that the face-color prior is established by visual signals arising from the recently evolved L-M cone system, not the older S-cone channel. Taken together, the results show that when retinal mechanisms of color vision are impaired, the impact of memory on color perception is greatest for face color, supporting the idea that trichromatic color plays an important role in social communication.
Adhesion of two-dimensional titanium carbides (MXenes) and graphene to silicon
Authors: Li Yanxiao , Huang Shuohan , Wei Congjie , Wu Chenglin , Mochalin Vadym N.
Published: July 2019

Two-dimensional transition metal carbides (MXenes) have attracted a great interest of the research community as a relatively recently discovered large class of materials with unique electronic and optical properties. Understanding of adhesion between MXenes and various substrates is critically important for MXene device fabrication and performance. We report results of direct atomic force microscopy (AFM) measurements of adhesion of two MXenes (Ti3C2Tx and Ti2CTx) with a SiO2 coated Si spherical tip. The Maugis-Dugdale theory was applied to convert the AFM measured adhesion force to adhesion energy, while taking into account surface roughness. The obtained adhesion energies were compared with those for mono-, bi-, and tri-layer graphene, as well as SiO2 substrates. The average adhesion energies for the MXenes are 0.90 ± 0.03 J m−2 and 0.40 ± 0.02 J m−2 for thicker Ti3C2Tx and thinner Ti2CTx, respectively, which is of the same order of magnitude as that between graphene and silica tip.
Interseismic strain build-up on the submarine North Anatolian Fault offshore Istanbul
Authors: Lange Dietrich , Kopp Heidrun , Royer Jean-Yves , Henry Pierre , Çakir Ziyadin , Petersen Florian , Sakic Pierre , Ballu Valerie , Bialas Jörg , Özeren Mehmet Sinan , Ergintav Semih , Géli Louis
Published: July 2019

Using offshore geodetic observations, we show that a segment of the North Anatolian Fault in the central Sea of Marmara is locked and therefore accumulating strain. The strain accumulation along this fault segment was previously extrapolated from onshore observations or inferred from the absence of seismicity, but both methods could not distinguish between fully locked or fully creeping fault behavior. A network of acoustic transponders measured crustal deformation with mm-precision on the seafloor for 2.5 years and did not detect any significant fault displacement. Absence of deformation together with sparse seismicity monitored by ocean bottom seismometers indicates complete fault locking to at least 3 km depth and presumably into the crystalline basement. The slip-deficit of at least 4 m since the last known rupture in 1766 is equivalent to an earthquake of magnitude 7.1 to 7.4 in the Sea of Marmara offshore metropolitan Istanbul.
Chemical genomics reveals histone deacetylases are required for core regulatory transcription
Authors: Gryder Berkley E. , Wu Lei , Woldemichael Girma M. , Pomella Silvia , Quinn Taylor R. , Park Paul M. C. , Cleveland Abigail , Stanton Benjamin Z. , Song Young , Rota Rossella , Wiest Olaf , Yohe Marielle E. , Shern Jack F. , Qi Jun , Khan Javed
Published: July 2019

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.
Dietary intervention of mice using an improved Multiple Artificial-gravity Research System (MARS) under artificial 1 g
Authors: Matsuda Chie , Kato Tamotsu , Inoue-Suzuki Sayo , Kikuchi Jun , Ohta Toshiko , Kagawa Masaharu , Hattori Masahira , Kobayashi Hiroe , Shiba Dai , Shirakawa Masaki , Mizuno Hiroyasu , Furukawa Satoshi , Mukai Chiaki , Ohno Hiroshi
Published: July 2019

Japan Aerospace Exploration Agency (JAXA) has developed mouse habitat cage units equipped with an artificial gravity-producing centrifuge, called the Multiple Artificial-gravity Research System (MARS), that enables single housing of a mouse under artificial gravity (AG) in orbit. This is a report on a hardware evaluation. The MARS underwent improvement in water leakage under microgravity (MG), and was used in the second JAXA mouse mission to evaluate the effect of AG and diet on mouse biological system simultaneously. Twelve mice were divided into four groups of three, with each group fed a diet either with or without fructo-oligosaccharide and housed singly either at 1 g AG or MG for 30 days on the International Space Station, then safely returned to the Earth. Body weight tended to increase in AG mice and decrease in MG mice after spaceflight, but these differences were not significant. This indicates that the improved MARS may be useful in evaluating AG and dietary intervention for space flown mice.
Microgravity disturbance analysis on Chinese space laboratory
Authors: Dong Wenbo , Duan Wenxiang , Liu Wei , Zhang Yongkang
Published: July 2019

Many scientific experiments are conducted in space; therefore, it is critical to understand the microgravity environment of a space laboratory. The first Chinese cargo ship, Tianzhou-1 (TZ-1), entered space on 20 April, 2017 and later joined with the Tiangong-2 (TG-2) Chinese space laboratory. TZ-1 carried a high-precision electrostatic suspension accelerometer system (ES-ACC) for measuring the microgravity acceleration on the spacecraft and a microgravity-active vibration system (MAIS), which contained flexible quartz accelerometers (Q-ACC). The ES-ACC was able to provide a reduced-disturbance environment for the MAIS. The purpose of these two instruments was to validate novel technologies and as an opportunity to record the microgravity acceleration of TZ-1 and TG-2 in detail during spacecraft operation in different flight modes, with or without vibration isolation. The acceleration data were analyzed comprehensively in a time–frequency–amplitude spectrogram. Some periodical disturbances with orbital period and irregular signals related to certain in-orbit events were observed. After reducing those disturbances, the microgravity levels on TZ-1 and TG-2 could be resolved to better than 10−6 m/s2 in the root mean square in the frequency of 0.01–10 Hz. These accurate measurements aboard the Chinese space laboratory will provide valuable information to optimize working conditions for scientific experiments.
AgBR1 antibodies delay lethal Aedes aegypti-borne West Nile virus infection in mice
Authors: Uraki Ryuta , Hastings Andrew K. , Brackney Doug E. , Armstrong Philip M. , Fikrig Erol
Published: July 2019

West Nile virus (WNV) is transmitted by mosquitoes and can cause severe disease, including meningoencephalitis. AgBR1 is a mosquito salivary protein that enhances Aedes aegypti mosquito-borne Zika virus pathogenesis in mice. Here, we show that AgBR1 antibodies reduce the initial West Nile viral load and delay lethal infection after feeding by an infected Aedes aegypti mosquito. Targeting AgBR1 may therefore be incorporated into strategies to prevent mosquito-transmitted West Nile virus infection.
RETRACTED ARTICLE: Nucleic acid sensing activates the innate cytosolic surveillance pathway and promotes parasite survival in visceral leishmaniasis
Authors: Das Sushmita , Kumar Ashish , Mandal Abhishek , Abhishek Kumar , Verma Sudha , Kumar Ajay , Das Pradeep
Published: July 2019

Microbial pattern recognition critically contributes to innate response, both at extracellular and intracellular cytosolic surveillance pathway (CSP) interface. However, the role of pattern recognition by host innate receptors in CSP is poorly understood in Leishmania donovani infection. Here, we have demonstrated that cytosolic targeting of L.donovani DNA (Ld-DNA) inhibits macrophage responsiveness to IFNɣ, through decreased MHC-II expression and lowered pSTAT1 (Y701) levels, involving host three-prime repair exonuclease-1 (TREX-1). The Ld-DNA potently induced type-1 IFNs, i.e. significant over-production of IFNβ through activation of the IRF pathway. Interestingly, knockdown of TRIF or MyD88 expression in macrophages had no effect on cytosolic Ld-DNA transfection-mediated IFN-β production, indicating involvement of a TLR independent pathway. Contrastingly, Ld-DNA failed to induce IFNβ in both TBK-1 and IRF3KO knockout macrophages. Although IFNβ was not induced by Ld-DNA in STING- knockout macrophages, STING alone was not enough for the induction. Evidently, besides STING, Ld-DNA recognition for induction of IFNβ critically required cytosolic cyclic GMP-AMP synthase (cGAS). Furthermore, the cGAS dependent targeting of Ld-DNA induced IFNβ over-production that contributed to antimony resistance in L.donovani infection. We provide the first evidence that enhanced cytosolic sensing of Ld-DNA in infection by antimony resistant (SBR-LD), but not antimony sensitive L.donovani strains (SBS-LD), was critically regulated by host MDRs, multi drug resistant associated protein 1 (MRP 1) and permeability glycoprotein (P-gp) in macrophages. Collectively, our results disclose Ld-DNA as a vital pathogen associated molecular pattern (PAMP) driving host Type-I IFN responses and antimony resistance. The findings may help in future development of policies for novel anti-leishmanial therapeutics.
BODIPY-cholesterol can be reliably used to monitor cholesterol efflux from capacitating mammalian spermatozoa
Authors: Bernecic N. C. , Zhang M. , Gadella B. M. , Brouwers J. F. H. M. , Jansen J. W. A. , Arkesteijn G. J. A. , de Graaf S. P. , Leahy T.
Published: July 2019

Capacitation is the final maturation step spermatozoa undergo prior to fertilisation. The efflux of cholesterol from the sperm membrane to the extracellular environment is a crucial step during capacitation but current methods to quantify this process are suboptimal. In this study, we validate the use of a BODIPY-cholesterol assay to quantify cholesterol efflux from spermatozoa during in vitro capacitation, using the boar as a model species. The novel flow cytometric BODIPY-cholesterol assay was validated with endogenous cholesterol loss as measured by mass spectrometry and compared to filipin labelling. Following exposure to a range of conditions, the BODIPY-cholesterol assay was able to detect and quantify cholesterol efflux akin to that measured with mass spectrometry. The ability to counterstain for viability is a unique feature of this assay that allowed us to highlight the importance of isolating viable cells only for a reliable measure of cholesterol efflux. Finally, the BODIPY-cholesterol assay proved to be the superior method to quantify cholesterol efflux relative to filipin labelling, though filipin remains useful for assessing cholesterol redistribution. Taken together, the BODIPY-cholesterol assay is a simple, inexpensive and reliable flow cytometric method for the measurement of cholesterol efflux from spermatozoa during in vitro capacitation.
A reliable Epstein-Barr Virus classification based on phylogenomic and population analyses
Authors: Zanella Louise , Riquelme Ismael , Buchegger Kurt , Abanto Michel , Ili Carmen , Brebi Priscilla
Published: July 2019

The Epstein-Barr virus (EBV) infects more than 90% of the human population, playing a key role in the origin and progression of malignant and non-malignant diseases. Many attempts have been made to classify EBV according to clinical or epidemiological information; however, these classifications show frequent incongruences. For instance, they use a small subset of genes for sorting strains but fail to consider the enormous genomic variability and abundant recombinant regions present in the EBV genome. These could lead to diversity overestimation, alter the tree topology and misinterpret viral types when classified, therefore, a reliable EBV phylogenetic classification is needed to minimize recombination signals. Recombination events occur 2.5-times more often than mutation events, suggesting that recombination has a much stronger impact than mutation in EBV genomic diversity, detected within common ancestral node positions. The Hierarchical Bayesian Analysis of Population Structure (hierBAPS) resulted in the differentiation of 12 EBV populations showed seven monophyletic and five paraphyletic. The populations identified were related to geographic location, of which three populations (EBV-p1/Asia/GC, EBV-p2/Asia II/Tumors and EBV-p4/China/NPC) were related to tumor development. Therefore, we proposed a new consistent and non-simplistic EBV classification, beneficial in minimizing the recombination signal in the phylogeny reconstruction, investigating geography relationship and even infer associations to human diseases. These EBV classifications could also be useful in developing diagnostic applications or defining which strains need epidemiological surveillance.
mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase
Authors: Wu Xianjin , Li Shenghua , Hu Xing , Xiang Xiaoliang , Halloran Megan , Yang Linlin , Williams Terence M. , Houghton Peter J. , Shen Changxian , He Zhengfu
Published: July 2019

mTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation.
The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury
Authors: Hoshino Yutaka , Nishide Kenji , Nagoshi Narihito , Shibata Shinsuke , Moritoki Nobuko , Kojima Kota , Tsuji Osahiko , Matsumoto Morio , Kohyama Jun , Nakamura Masaya , Okano Hideyuki
Published: July 2019

Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.