bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ephemeral Signature of Permafrost Carbon in an Arctic Fluvial Network
Authors: Drake Travis W. , Guillemette François , Hemingway Jordon D. , Chanton Jeffery P. , Podgorski David C. , Zimov Nikita S. , Spencer Robert G. M.
Published: April 2018

Arctic fluvial networks process, outgas, and transport significant quantities of terrestrial organic carbon (C), particularly dissolved organic carbon (DOC). The proportion of permafrost C in these fluxes, however, is poorly constrained. A primary obstacle to the quantification of permafrost‐derived DOC is that it is rapidly respired without leaving a unique tracer of its presence. In this study, we investigated the production of bacterial respiratory carbon dioxide (CO2; measured as dissolved inorganic carbon; DIC) during maximum late‐summer thaw in sites spanning a fluvial network (Kolyma Basin, Siberia) to assess whether the biodegradation of permafrost DOC could be detected by the presence of a persistent aged (14C‐depleted) signature on the DIC pool. Using Keeling plot interpretation of DIC produced in bioincubations of river water, we show that bacteria respire varying sources of DOC moving downstream through the fluvial network. Respiration of permafrost (production of aged CO2) was only detected in heavily permafrost thaw influenced sites. In nonpermafrost thaw impacted sites, ambient DIC was modern (14C‐enriched), but rather than precluding the respiration of permafrost OC upstream, we suggest that 14C‐depleted DIC is overwhelmed by modern DIC. Investigation of dissolved organic matter composition via Fourier transform ion cyclotron resonance mass spectrometry highlighted that elevated levels of aliphatic and nitrogen‐containing compounds were associated with the production of aged DIC, providing molecular‐level insight as to why permafrost‐derived dissolved organic matter is rapidly respired. Overall, results from this study demonstrate the difficulty of tracing inputs of a highly reactive substrate to systems with diverse organic matter sources.
Spatial and Temporal Robustness of Sr/Ca‐SST Calibrations in Red Sea Corals: Evidence for Influence of Mean Annual Temperature on Calibration Slopes
Authors: Murty S. A. , Bernstein W. N. , Ossolinski J. E. , Davis R. S. , Goodkin N. F. , Hughen K. A.
Published: April 2018

Sr/Ca ratios recorded in the aragonite skeleton of massive coral colonies are commonly used to reconstruct seasonal‐ to centennial‐scale variability in sea surface temperature (SST). While the Sr/Ca paleothermometer is robust in individual colonies, Sr/Ca‐SST relationships between colonies vary, leading to questions regarding the utility of the proxy. We present biweekly‐resolution calibrations of Sr/Ca from five Porites spp. corals to satellite SST across 10° of latitude in the Red Sea to evaluate the Sr/Ca proxy across both spatial and temporal scales. SST is significantly correlated with coral Sr/Ca at each site, accounting for 69–84% of Sr/Ca variability (P ≪ 0.01). Intercolony variability in Sr/Ca‐SST sensitivities reveals a latitudinal trend, where calibration slopes become shallower with increasing mean annual temperature. Mean annual temperature is strongly correlated with the biweekly‐resolution calibration slopes across five Red Sea sites (r2 = 0.88, P = 0.05), while also correlating significantly to Sr/Ca‐SST slopes for 33 Porites corals from across the entire Indo‐Pacific region (r2 = 0.26, P < 0.01). Although interannual summer, winter, and mean annual calibrations for individual Red Sea colonies are inconsistently robust, combined multicoral calibrations are significant at summer (r2 = 0.53, P ≪ 0.01), winter (r2 = 0.62, P ≪ 0.01), and mean annual time scales (r2 = 0.79, P ≪ 0.01). Our multicoral, multisite study indicates that the Sr/Ca paleothermometer is accurate across both temporal and spatial scales in the Red Sea and also potentially explains for the first time variability in Sr/Ca‐SST calibration slopes across the Indo‐Pacific region. Our study provides strong evidence supporting the robustness of the coral Sr/Ca proxy for examining seasonal to multicentury variability in global climate phenomena.
Deep Atlantic Carbonate Ion and CaCO3 Compensation During the Ice Ages
Authors: Sosdian S. M. , Rosenthal Y. , Toggweiler J. R.
Published: April 2018

Higher alkalinity compensates for reduced CaCO3 burial in the deep ocean in response to increased carbon sequestration. This process could account for about half of the reduction in glacial atmospheric CO2. To date, our understanding of this process comes from benthic carbon isotope and CaCO3 burial records. Here we present a 1.5 Myr orbitally resolved deep ocean calcite saturation record (ΔCO32−) derived from benthic foraminiferal B/Ca ratios in the North Atlantic. Glacial ΔCO32− declines across the mid‐Pleistocene transition suggesting increased sequestration of carbon in the deep Atlantic. The magnitude, timing, and structure of deep Atlantic Ocean ΔCO32− parallel changes in %CaCO3 and contrasts with the small amplitude, anti phased swings in Indo‐Pacific ΔCO32− and %CaCO3 during the mid‐to‐late Pleistocene questioning the classic view of CaCO3 compensatory mechanism. We propose that the increasing corrosivity of the deep Atlantic causes the locus of CaCO3 burial to shift into the equatorial Pacific where the flux of CaCO3 to the seafloor was sufficiently high to overcome low saturation and establish a new burial “hot spot.” Based on this mechanism, we propose that the persistently lowΔCO32− levels at marine isotope stage 12 set the stage for the high pCO2 levels at marine isotope stage 11 and subsequent interglacials via large swings in ocean alkalinity caused by shifts in CaCO3 burial. Similarly, the development of classic (“anticorrelated”) CaCO3 patterns was driven by enhanced ocean stratification and an increase in deep ocean corrosivity in response to mid‐Pleistocene transition cooling.
The Influence of Urban Development Patterns on Streamflow Characteristics in the Charlanta Megaregion
Authors: Debbage Neil , Shepherd J. M.
Published: April 2018

Although it is widely recognized that urbanization has a notable impact on streamflow characteristics, the relative influence of the extent, spatial configuration, and positioning of urban development on low, high, and peak flow regimes is still not fully understood. The overarching research objective of this study was to clarify these relationships by analyzing 119 watersheds throughout the Charlanta megaregion, which stretches from Charlotte, NC to Atlanta, GA. Spatial metrics were derived from land use/land cover data sets to quantify the urban development patterns of each watershed while the streamflow characteristics were evaluated using mean daily discharge and annual peak streamflow data. Analysis of variance tests, bivariate correlations, and multivariate regression models were used to identify intraregional variability and quantify the impact of urban development patterns on streamflow characteristics while controlling for the physical differences between watersheds. The statistical analysis revealed that increasing the extent of urban development enhanced high and low flow frequency as well as annual peak unit discharge. Therefore, urbanization within Charlanta generally produced a more extreme streamflow regime. In terms of the spatial configuration of urban development, the models indicated that more contiguous developed open space increased high and low flow frequency. Finally, the positional analysis suggested that clustering impervious surfaces in source areas distant from streams increased the frequency of high flows. The study highlights the overall importance of considering the extent, configuration, and positioning of urban development when devising land use policies aimed at minimizing streamflow alteration due to urbanization.
Mesoscale Variability of Conditions Favoring an Iron‐Induced Diatom Bloom Downstream of the Kerguelen Plateau
Authors: Della Penna Alice , Trull Thomas W. , Wotherspoon Simon , De Monte Silvia , Johnson Craig R. , d'Ovidio Francesco
Published: April 2018

Heterogeneity in phytoplankton distribution is related to spatial and temporal variations in biogeochemical and ecological processes. In the open ocean, the interaction of these processes with meso‐ and submeso‐scale dynamics (1‐100 km, few days to months) gives rise to complex spatio‐temporal patterns, whose characterization is difficult without extensive sampling efforts. In this study, we integrate pigment sampling and multisatellite data to assess the link between iron enrichment and diatom dominance in the open ocean region east of the Kerguelen Islands (Indian Sector of the Southern Ocean). In this region, the High Nutrient Low Chlorophyll conditions typical of the Southern Ocean are alleviated by the transport of iron off the Kerguelen Plateau, resulting in a plume of chlorophyll that extends 1,000 km downstream. We show that in situ concentrations of the diatom‐associated pigment fucoxanthin and ocean‐color‐derived estimates of diatom dominance correlate with the “water age”, i.e., the time since the respective water parcel departed the Kerguelen Plateau. We propose a “threshold model” linking diatom ecological success and iron availability of downstream‐advected water parcels. The pattern of diatom dominance generated by this model predicts the extent and spatial structure of satellite‐based estimates at the regional scale (∼100s of km) and describes the mesoscale distribution of diatom dominance in the proximity of the plateau. However, the complexity of diatom dominance patterns further away from the plateau indicates that other physical and ecological mechanisms may drive phytoplankton dominance downstream.
Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline
Authors: Lissemore Jennifer I. , Sookman Debbie , Gravel Paul , Berney Alexandre , Barsoum Amir , Diksic Mirko , Nordahl Thomas E. , Pinard Gilbert , Sibon Igor , Cottraux Jean , Leyton Marco , Benkelfat Chawki
Published: April 2018

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-l-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-l-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.
Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population
Authors: Liu Qiang , Han Haijun , Wang Maiqiu , Yao Yinghao , Wen Li , Jiang Keran , Ma Yunlong , Fan Rongli , Chen Jiali , Su Kunkai , Yang Zhongli , Cui Wenyan , Yuan Wenji , Jiang Xianzhong , Li Jingjing , Payne Thomas J. , Wang Jundong , Li Ming D.
Published: April 2018

Nicotine dependence (ND) is a worldwide health problem. Numerous genetic studies have demonstrated a significant association of variants in nicotinic acetylcholine receptors (nAChRs) with smoking behaviors. However, most of these studies enrolled only subjects of European or African ancestry. In addition, although an increasing body of evidence implies a causal connection of single-nucleotide polymorphisms (SNPs) and epigenetic regulation of gene expression, few studies of this issue have been reported. In this study, we performed both association and interaction analysis for 67 SNPs inCHRNA3-A5, CHRNA7, CHRNB2, andCHRNB4with ND in a Chinese Han population (N = 5055). We further analyzedcis-mQTL for the three most significant SNPs and 5580 potential methylation loci within these target gene regions. Our results indicated that the SNPs rs1948 and rs7178270 inCHRNB4and rs3743075 inCHRNA3were significantly associated with the Fagerström Test for Nicotine Dependence (FTND) score (p = 6.6 × 10−5;p = 2.0 × 10−4, andp = 7.0 × 10−4, respectively). Haplotype-based association analysis revealed that two major haplotypes, T-G and C-A, formed by rs3743075–rs3743074 inCHRNA3, and other two major haplotypes, A-G-C and G-C-C, formed by rs1948–rs7178270–rs17487223 inCHRNB4, were significantly associated with the FTND score (p ≤ 8.0 × 10−4). Further, we found evidence for the presence of significant interaction among variants withinCHRNA3/B4/A5, CHRNA4/B2/A5, andCHRNA7in affecting ND, with correspondingpvalues of 5.8 × 10−6, 8.0 × 10−5, and 0.012, respectively. Finally, we identified two CpG sites (CpG_2975 and CpG_3007) inCHRNA3that are significantly associated with threecis-mQTL SNPs (rs1948, rs7178270, rs3743075) in theCHRNA5/A3/B4cluster (p ≤ 1.9 × 10−6), which formed four significant CpG–SNP pairs in our sample. Together, we revealed at least three novel SNPs inCHRNA3andCHRNB4to be significantly associated with the FTND score. Further, we showed that these significant variants contribute to ND via two methylated sites, and we demonstrated significant interaction affecting ND among variants inCHRNA5/A3/B4,CHRNA7, andCHRNA4/B2/A5. In sum, these findings provide robust evidence that SNPs in nAChR genes convey a risk of ND in the Chinese Han population.
Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist
Authors: Gordillo-Salas Marta , Pilar-Cuéllar Fuencisla , Auberson Yves P. , Adell Albert
Published: April 2018

In a previous study we found that the preferring GluN2A receptor antagonist, NVP-AAM077, elicited rapid antidepressant-like effects in the forced swim test that was related to the release of glutamate and serotonin in the medial prefrontal cortex. In the present work we sought to examine the duration of this behavioral effect as well as the molecular readouts involved. Our results showed that NVP-AAM077 reduced the immobility in the forced swim test 30 min and 24 h after its administration. However, this effect waned 7 days later. The rapid antidepressant-like response seems to be associated with increases in the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, mammalian target of rapamycin (mTOR) signaling, glia markers such as glial fibrillary acidic protein (GFAP) and excitatory amino acid transporter 1 (EAAT1), and a rapid mobilization of intracellular stores of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex.
Altered function and maturation of primary cortical neurons from a 22q11.2 deletion mouse model of schizophrenia
Authors: Sun Ziyi , Williams Damian J. , Xu Bin , Gogos Joseph A.
Published: April 2018

Given its high penetrance, clearly delineated and evolutionary conserved genomic structure, mouse models of the 22q11.2 deletion provide an ideal organism-based and cell-based model of this well-established disease mutation for schizophrenia. In this study we examined the development of changes in intrinsic properties, action potential firing and synaptic transmission using whole-cell patch-clamp recordings of cultured embryonic cortical neurons fromDf(16)A+/−and WT mice at DIV7 and DIV14, respectively. Compared to neurons from the WT littermates, significantly increased input resistance and decreased rising rate of action potential was observed inDf(16)A+/−mice at DIV7 but not at DIV14 indicative of delayed neuronal maturation. Neurons fromDf(16)A+/−mice also showed significantly higher cellular excitability at both DIV7 and DIV14. Evaluation of Ca2+homeostasis perturbation caused by 22q11.2 deletion using calcium imaging revealed a significantly lower amplitude of calcium elevation and a smaller area under the curve after depolarization in neurons fromDf(16)A+/−mice at both DIV7 and DIV14. Furthermore, the properties of inhibitory synaptic events were significantly altered inDf(16)A+/−mice. We identified changes in mRNA expression profiles, especially in ion channels, receptors, and transporters that may underlie the neurophysiological effects of this mutation. Overall, we show a number of alterations in electrophysiological and calcium homeostatic properties of embryonic cortical neurons from a 22q11.2 deletion mouse model at different culture times and provide valuable insights towards revealing disease mechanisms and discovery of new therapeutic compounds.
Heterogeneous Fe3 single-cluster catalyst for ammonia synthesis via an associative mechanism
Authors: Liu Jin-Cheng , Ma Xue-Lu , Li Yong , Wang Yang-Gang , Xiao Hai , Li Jun
Published: April 2018

The current industrial ammonia synthesis relies on Haber–Bosch process that is initiated by the dissociative mechanism, in which the adsorbed N2dissociates directly, and thus is limited by Brønsted–Evans–Polanyi (BEP) relation. Here we propose a new strategy that an anchored Fe3cluster on the θ-Al2O3(010) surface as a heterogeneous catalyst for ammonia synthesis from first-principles theoretical study and microkinetic analysis. We have studied the whole catalytic mechanism for conversion of N2to NH3on Fe3/θ-Al2O3(010), and find that an associative mechanism, in which the adsorbed N2is first hydrogenated to NNH, dominates over the dissociative mechanism, which we attribute to the large spin polarization, low oxidation state of iron, and multi-step redox capability of Fe3cluster. The associative mechanism liberates the turnover frequency (TOF) for ammonia production from the limitation due to the BEP relation, and the calculated TOF on Fe3/θ-Al2O3(010) is comparable to Ru B5 site.
Gauging force by tapping tendons
Authors: Martin Jack A. , Brandon Scott C. E. , Keuler Emily M. , Hermus James R. , Ehlers Alexander C. , Segalman Daniel J. , Allen Matthew S. , Thelen Darryl G.
Published: April 2018

Muscles are the actuators that drive human movement. However, despite many decades of work, we still cannot readily assess the forces that muscles transmit during human movement. Direct measurements of muscle–tendon loads are invasive and modeling approaches require many assumptions. Here, we introduce a non-invasive approach to assess tendon loads by tracking vibrational behavior. We first show that the speed of shear wave propagation in tendon increases with the square root of axial stress. We then introduce a remarkably simple shear wave tensiometer that uses micron-scale taps and skin-mounted accelerometers to track tendon wave speeds in vivo. Tendon wave speeds are shown to modulate in phase with active joint torques during isometric exertions, walking, and running. The capacity to non-invasively assess muscle–tendon loading can provide new insights into the motor control and biomechanics underlying movement, and could lead to enhanced clinical treatment of musculoskeletal injuries and diseases.
Placental miR-340 mediates vulnerability to activity based anorexia in mice
Authors: Schroeder Mariana , Jakovcevski Mira , Polacheck Tamar , Drori Yonat , Luoni Alessia , Röh Simone , Zaugg Jonas , Ben-Dor Shifra , Albrecht Christiane , Chen Alon
Published: April 2018

Anorexia nervosa (AN) is a devastating eating disorder characterized by self-starvation that mainly affects women. Its etiology is unknown, which impedes successful treatment options leading to a limited chance of full recovery. Here, we show that gestation is a vulnerable window that can influence the predisposition to AN. By screening placental microRNA expression of naive and prenatally stressed (PNS) fetuses and assessing vulnerability to activity-based anorexia (ABA), we identify miR-340 as a sexually dimorphic regulator involved in prenatal programming of ABA. PNS caused gene-body hypermethylation of placental miR-340, which is associated with reduced miR-340 expression and increased protein levels of several target transcripts, GR, Cry2 and H3F3b. MiR-340 is linked to the expression of several nutrient transporters both in mice and human placentas. Using placenta-specific lentiviral transgenes and embryo transfer, we demonstrate the key role miR-340 plays in the mechanism involved in early life programming of ABA.
Multi-faceted immunomodulatory and tissue-tropic clinical bacterial isolate potentiates prostate cancer immunotherapy
Authors: Anker Jonathan F. , Naseem Anum F. , Mok Hanlin , Schaeffer Anthony J. , Abdulkadir Sarki A. , Thumbikat Praveen
Published: April 2018

Immune checkpoint inhibitors have not been effective for immunologically “cold” tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increases survival and decreases tumor burden in orthotopic MYC- and PTEN-mutant prostate cancer models. CP1 administered intra-urethrally specifically homes to and colonizes tumors without causing any systemic toxicities. CP1 increases immunogenic cell death of cancer cells, T cell cytotoxicity, and tumor infiltration by activated CD8 T cells, Th17 T cells, mature dendritic cells, M1 macrophages, and NK cells. CP1 also decreases intra-tumoral regulatory T cells and VEGF. Mechanistically, blocking CP1-recruited T cells from infiltrating the tumor inhibits its therapeutic efficacy. CP1 is an immunotherapeutic tool demonstrating how a tissue-specific microbe can increase tumor immunogenicity and sensitize an otherwise resistant cancer type to immunotherapy.
True equilibrium measurement of transcription factor-DNA binding affinities using automated polarization microscopy
Authors: Jung Christophe , Bandilla Peter , von Reutern Marc , Schnepf Max , Rieder Susanne , Unnerstall Ulrich , Gaul Ulrike
Published: April 2018

The complex patterns of gene expression in metazoans are controlled by selective binding of transcription factors (TFs) to regulatory DNA. To improve the quantitative understanding of this process, we have developed a novel method that uses fluorescence anisotropy measurements in a controlled delivery system to determine TF-DNA binding energies in solution with high sensitivity and throughput. Owing to its large dynamic range, the method, named high performance fluorescence anisotropy (HiP-FA), allows for reliable quantification of both weak and strong binding; binding specificities are calculated on the basis of equilibrium constant measurements for mutational DNA variants. We determine the binding preference landscapes for 26 TFs and measure high absolute affinities, but mostly lower binding specificities than reported by other methods. The revised binding preferences give rise to improved predictions of in vivo TF occupancy and enhancer expression. Our approach provides a powerful new tool for the systems-biological analysis of gene regulation.
Anthropogenic combustion iron as a complex climate forcer
Authors: Matsui Hitoshi , Mahowald Natalie M. , Moteki Nobuhiro , Hamilton Douglas S. , Ohata Sho , Yoshida Atsushi , Koike Makoto , Scanza Rachel A. , Flanner Mark G.
Published: April 2018

Atmospheric iron affects the global carbon cycle by modulating ocean biogeochemistry through the deposition of soluble iron to the ocean. Iron emitted by anthropogenic (fossil fuel) combustion is a source of soluble iron that is currently considered less important than other soluble iron sources, such as mineral dust and biomass burning. Here we show that the atmospheric burden of anthropogenic combustion iron is 8 times greater than previous estimates by incorporating recent measurements of anthropogenic magnetite into a global aerosol model. This new estimation increases the total deposition flux of soluble iron to southern oceans (30–90 °S) by 52%, with a larger contribution of anthropogenic combustion iron than dust and biomass burning sources. The direct radiative forcing of anthropogenic magnetite is estimated to be 0.021 W m−2 globally and 0.22 W m−2 over East Asia. Our results demonstrate that anthropogenic combustion iron is a larger and more complex climate forcer than previously thought, and therefore plays a key role in the Earth system.
Evolution of high-level resistance during low-level antibiotic exposure
Authors: Wistrand-Yuen Erik , Knopp Michael , Hjort Karin , Koskiniemi Sanna , Berg Otto G. , Andersson Dan I.
Published: April 2018

It has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target (gidB mutations), (ii) reduction in aminoglycoside uptake (cyoB, nuoG, and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA (znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance.
Vibrio vulnificus quorum-sensing molecule cyclo(Phe-Pro) inhibits RIG-I-mediated antiviral innate immunity
Authors: Lee Wooseong , Lee Seung-Hoon , Kim Minwoo , Moon Jae-Su , Kim Geon-Woo , Jung Hae-Gwang , Kim In Hwang , Oh Ji Eun , Jung Hi Eun , Lee Heung Kyu , Ku Keun Bon , Ahn Dae-Gyun , Kim Seong-Jun , Kim Kun-Soo , Oh Jong-Won
Published: April 2018

The recognition of pathogen-derived ligands by pattern recognition receptors activates the innate immune response, but the potential interaction of quorum-sensing (QS) signaling molecules with host anti-viral defenses remains largely unknown. Here we show that the Vibrio vulnificus QS molecule cyclo(Phe-Pro) (cFP) inhibits interferon (IFN)-β production by interfering with retinoic-acid-inducible gene-I (RIG-I) activation. Binding of cFP to the RIG-I 2CARD domain induces a conformational change in RIG-I, preventing the TRIM25-mediated ubiquitination to abrogate IFN production. cFP enhances susceptibility to hepatitis C virus (HCV), as well as Sendai and influenza viruses, each known to be sensed by RIG-I but did not affect the melanoma-differentiation-associated gene 5 (MDA5)-recognition of norovirus. Our results reveal an inter-kingdom network between bacteria, viruses and host that dysregulates host innate responses via a microbial quorum-sensing molecule modulating the response to viral infection.
A mobile endocytic network connects clathrin-independent receptor endocytosis to recycling and promotes T cell activation
Authors: Compeer Ewoud B. , Kraus Felix , Ecker Manuela , Redpath Gregory , Amiezer Mayan , Rother Nils , Nicovich Philip R. , Kapoor-Kaushik Natasha , Deng Qiji , Samson Guerric P. B. , Yang Zhengmin , Lou Jieqiong , Carnell Michael , Vartoukian Haig , Gaus Katharina , Rossy Jérémie
Published: April 2018

Endocytosis of surface receptors and their polarized recycling back to the plasma membrane are central to many cellular processes, such as cell migration, cytokinesis, basolateral polarity of epithelial cells and T cell activation. Little is known about the mechanisms that control the organization of recycling endosomes and how they connect to receptor endocytosis. Here, we follow the endocytic journey of the T cell receptor (TCR), from internalization at the plasma membrane to recycling back to the immunological synapse. We show that TCR triggering leads to its rapid uptake through a clathrin-independent pathway. Immediately after internalization, TCR is incorporated into a mobile and long-lived endocytic network demarked by the membrane-organizing proteins flotillins. Although flotillins are not required for TCR internalization, they are necessary for its recycling to the immunological synapse. We further show that flotillins are essential for T cell activation, supporting TCR nanoscale organization and signaling.
Curcumin interacts directly with the Cysteine 259 residue of STAT3 and induces apoptosis in H-Ras transformed human mammary epithelial cells
Authors: Hahn Young-Il , Kim Su-Jung , Choi Bu-Young , Cho Kyung-Cho , Bandu Raju , Kim Kwang Pyo , Kim Do-Hee , Kim Wonki , Park Joon Sung , Han Byung Woo , Lee Jeewoo , Na Hye-Kyung , Cha Young-Nam , Surh Young-Joon
Published: April 2018

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longaL., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Rastransformed breast epithelial cells (H-RasMCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-RasMCF10A cells. The α,β-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-RasMCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.
Quantitative optical mapping of two-dimensional materials
Authors: Jessen Bjarke S. , Whelan Patrick R. , Mackenzie David M. A. , Luo Birong , Thomsen Joachim D. , Gammelgaard Lene , Booth Timothy J. , Bøggild Peter
Published: April 2018

The pace of two-dimensional materials (2DM) research has been greatly accelerated by the ability to identify exfoliated thicknesses down to a monolayer from their optical contrast. Since this process requires time-consuming and error-prone manual assignment to avoid false-positives from image features with similar contrast, efforts towards fast and reliable automated assignments schemes is essential. We show that by modelling the expected 2DM contrast in digitally captured images, we can automatically identify candidate regions of 2DM. More importantly, we show a computationally-light machine vision strategy for eliminating false-positives from this set of 2DM candidates through the combined use of binary thresholding, opening and closing filters, and shape-analysis from edge detection. Calculation of data pyramids for arbitrarily high-resolution optical coverage maps of two-dimensional materials produced in this way allows the real-time presentation and processing of this image data in a zoomable interface, enabling large datasets to be explored and analysed with ease. The result is that a standard optical microscope with CCD camera can be used as an analysis tool able to accurately determine the coverage, residue/contamination concentration, and layer number for a wide range of presented 2DMs.
A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model
Authors: Shah Parth N. , Shah Kush N. , Smolen Justin A. , Tagaev Jasur A. , Torrealba Jose , Zhou Lan , Zhang Shiyi , Zhang Fuwu , Wagers Patrick O. , Panzner Matthew J. , Youngs Wiley J. , Wooley Karen L. , Cannon Carolyn L.
Published: April 2018

To address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the “drug efficacy metric” (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using an on-target human bronchial epithelial cell-line correlates well (R2 > 0.99) with in vivo efficacy, as measured by median survival hours in a Pseudomonas aeruginosa pneumonia mouse model following aerosolized antimicrobial treatment. In contrast, DEMs derived using off-target primary human dermal fibroblasts correlate poorly (R2 = 0.0595), which confirms our hypothesis. SCC1 and SCC22 have been identified as promising drug candidates through these studies, and SCC22 demonstrates a dose-dependent survival advantage compared to sham treatment. Finally, silver-bearing biodegradable nanoparticles were predicted to exhibit excellent in vivo efficacy based on its in vitro DEM value, which was confirmed in our mouse pneumonia model. Thus, the DEM successfully predicted the efficacy of various silver-based antimicrobials, and may serve as an excellent tool for the rapid screening of potential antimicrobial candidates without the need for extensive animal experimentation.
Generalized conditions of spherical carbonate concretion formation around decaying organic matter in early diagenesis
Authors: Yoshida Hidekazu , Yamamoto Koshi , Minami Masayo , Katsuta Nagayoshi , Sin-ichi Sirono , Metcalfe Richard
Published: April 2018

Isolated spherical carbonate concretions observed in marine sediments are fascinating natural objet trouve because of their rounded shapes and distinct sharp boundaries. They occur in varied matrices and often contain well preserved fossils. The formation process of such concretions has been explained by diffusion and rapid syn-depositional reactions with organic solutes and other pore water constituents. However, the rates, conditions and formation process of syngenetic spherical concretions are still not fully clear. Based on the examination of different kinds of spherical concretions from several locations in Japan, a diffusion based growth diagram was applied to define the generalized growth conditions of spherical concretions formed around decaying organic matter. All analytical data imply that the spherical concretions formed very rapidly, at least three to four orders of magnitude faster than previously estimated timescales. The values indicate that spherical concretions are preferentially grown within clay- to silt-grade marine sediments deposited in relatively deep (a few tens of metres) environments dominated by diffusive solute transport, very early in diagenesis.
Extreme air pollution events in Hokkaido, Japan, traced back to early snowmelt and large-scale wildfires over East Eurasia: Case studies
Authors: Yasunari Teppei J. , Kim Kyu-Myong , da Silva Arlindo M. , Hayasaki Masamitsu , Akiyama Masayuki , Murao Naoto
Published: April 2018

To identify the unusual climate conditions and their connections to air pollutions in a remote area due to wildfires, we examine three anomalous large-scale wildfires in May 2003, April 2008, and July 2014 over East Eurasia, as well as how products of those wildfires reached an urban city, Sapporo, in the northern part of Japan (Hokkaido), significantly affecting the air quality. NASA’s MERRA-2 (the Modern-Era Retrospective analysis for Research and Applications, Version 2) aerosol re-analysis data closely reproduced the PM2.5 variations in Sapporo for the case of smoke arrival in July 2014. Results show that all three cases featured unusually early snowmelt in East Eurasia, accompanied by warmer and drier surface conditions in the months leading to the fires, inducing long-lasting soil dryness and producing climate and environmental conditions conducive to active wildfires. Due to prevailing anomalous synoptic-scale atmospheric motions, smoke from those fires eventually reached a remote area, Hokkaido, and worsened the air quality in Sapporo. In future studies, continuous monitoring of the timing of Eurasian snowmelt and the air quality from the source regions to remote regions, coupled with the analysis of atmospheric and surface conditions, may be essential in more accurately predicting the effects of wildfires on air quality.
Multifunctional activities of ERF109 as affected by salt stress in Arabidopsis
Authors: Bahieldin Ahmed , Atef Ahmed , Edris Sherif , Gadalla Nour O. , Ramadan Ahmed M. , Hassan Sabah M. , Al Attas Sanaa G. , Al-Kordy Magdy A. , Al-Hajar Abdulrahman S. M. , Sabir Jamal S. M. , Nasr Mahmoud E. , Osman Gamal H. , El-Domyati Fotouh M.
Published: April 2018

Transcriptomic analysis was conducted in leaves of Arabidopsis T-DNA insertion ERF109-knocked out (KO) mutant or plants overexpressing (OE) the gene to detect its role in driving expression of programmed cell death- (PCD-) or growth-related genes under high salt (200 mM NaCl) stress. The analysis yielded ~22–24 million reads, of which 90% mapped to the Arabidopsis reference nuclear genome. Hierarchical cluster analysis of gene expression and principal component analysis (PCA) successfully separated transcriptomes of the two stress time points. Analysis indicated the occurrence of 65 clusters of gene expression with transcripts of four clusters differed at the genotype (e.g., WT (wild type), KO
ERF109
or OE
ERF109
) level. Regulated transcripts involved DIAP1-like gene encoding a death-associated inhibitor of reactive oxygen species (ROS). Other ERF109-regulated transcripts belong to gene families encoding ROS scavenging enzymes and a large number of genes participating in three consecutive pathways, e.g., phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan metabolism and plant hormone signal transduction. We investigated the possibility that ERF109 acts as a “master switch” mediator of a cascade of consecutive events across these three pathways initially by driving expression of ASA1 and YUC2 genes and possibly driving GST, IGPS and LAX2 genes. Action of downstream auxin-regulator, auxin-responsive as well as auxin carrier genes promotes plant cell growth under adverse conditions.
Presence and User Experience in a Virtual Environment under the Influence of Ethanol: An Explorative Study
Authors: Lorenz Mario , Brade Jennifer , Diamond Lisa , Sjölie Daniel , Busch Marc , Tscheligi Manfred , Klimant Philipp , Heyde Christoph-E. , Hammer Niels
Published: April 2018

Virtual Reality (VR) is used for a variety of applications ranging from entertainment to psychological medicine. VR has been demonstrated to influence higher order cognitive functions and cortical plasticity, with implications on phobia and stroke treatment. An integral part for successful VR is a high sense of presence – a feeling of ‘being there’ in the virtual scenario. The underlying cognitive and perceptive functions causing presence in VR scenarios are however not completely known. It is evident that the brain function is influenced by drugs, such as ethanol, potentially confounding cortical plasticity, also in VR. As ethanol is ubiquitous and forms part of daily life, understanding the effects of ethanol on presence and user experience, the attitudes and emotions about using VR applications, is important. This exploratory study aims at contributing towards an understanding of how low-dose ethanol intake influences presence, user experience and their relationship in a validated VR context. It was found that low-level ethanol consumption did influence presence and user experience, but on a minimal level. In contrast, correlations between presence and user experience were strongly influenced by low-dose ethanol. Ethanol consumption may consequently alter cognitive and perceptive functions related to the connections between presence and user experience.
Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β
Authors: Arndt Joseph W. , Qian Fang , Smith Benjamin A. , Quan Chao , Kilambi Krishna Praneeth , Bush Martin W. , Walz Thomas , Pepinsky R. Blake , Bussière Thierry , Hamann Stefan , Cameron Thomas O. , Weinreb Paul H.
Published: April 2018

Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer’s disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3–7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies. The crystal structure of the Fab fragment of aducanumab bound to its epitope peptide reveals that aducanumab binds to the N terminus of Aβ in an extended conformation, distinct from those seen in structures with other antibodies that target this immunodominant epitope. Aducanumab recognizes a compact epitope that sits in a shallow pocket on the antibody surface.In silicoanalyses suggest that aducanumab interacts weakly with the Aβ monomer and may accommodate a variety of peptide conformations, further supporting its selectivity for Aβ aggregates. Our studies provide a structural rationale for the low affinity of aducanumab for non-pathogenic monomers and its greater selectivity for aggregated forms than is seen for other Aβ-targeting antibodies.
Author Correction: Hybrid organic-inorganic polariton laser
Authors: Paschos G. G. , Somaschi N. , Tsintzos S. I. , Coles D. , Bricks J. L. , Hatzopoulos Z. , Lidzey D. G. , Lagoudakis P. G. , Savvidis P. G.
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers
Authors: Hoshina Azusa , Kawamoto Tatsuya , Sueta Shin-Ichi , Mae Shin-Ichi , Araoka Toshikazu , Tanaka Hiromi , Sato Yasunori , Yamagishi Yukiko , Osafune Kenji
Published: April 2018

Cell therapy using renal progenitors differentiated from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) has the potential to significantly reduce the number of patients receiving dialysis therapy. However, the differentiation cultures may contain undifferentiated or undesired cell types that cause unwanted side effects, such as neoplastic formation, when transplanted into a body. Moreover, the hESCs/iPSCs are often genetically modified in order to isolate the derived renal progenitors, hampering clinical applications. To establish an isolation method for renal progenitors induced from hESCs/iPSCs without genetic modifications, we screened antibodies against cell surface markers. We identified the combination of four markers, CD9−CD140a+CD140b+CD271+, which could enrich OSR1+SIX2+ renal progenitors. Furthermore, these isolated cells ameliorated renal injury in an acute kidney injury (AKI) mouse model when used for cell therapy. These cells could contribute to the development of hiPSC-based cell therapy and disease modeling against kidney diseases.
Finite-time quantum entanglement in propagating squeezed microwaves
Authors: Fedorov K. G. , Pogorzalek S. , Las Heras U. , Sanz M. , Yard P. , Eder P. , Fischer M. , Goetz J. , Xie E. , Inomata K. , Nakamura Y. , Di Candia R. , Solano E. , Marx A. , Deppe F. , Gross R.
Published: April 2018

Two-mode squeezing is a fascinating example of quantum entanglement manifested in cross-correlations of non-commuting observables between two subsystems. At the same time, these subsystems themselves may contain no quantum signatures in their self-correlations. These properties make two-mode squeezed (TMS) states an ideal resource for applications in quantum communication. Here, we generate propagating microwave TMS states by a beam splitter distributing single mode squeezing emitted from distinct Josephson parametric amplifiers along two output paths. We experimentally study the fundamental dephasing process of quantum cross-correlations in continuous-variable propagating TMS microwave states and accurately describe it with a theory model. In this way, we gain the insight into finite-time entanglement limits and predict high fidelities for benchmark quantum communication protocols such as remote state preparation and quantum teleportation.
SRC-like adaptor protein 2 (SLAP2) is a negative regulator of KIT-D816V-mediated oncogenic transformation
Authors: Rupar Kaja , Moharram Sausan A. , Kazi Julhash U. , Rönnstrand Lars
Published: April 2018

KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitment of proteins that mediate downstream signaling and also modulate receptor signaling. Here we show that the SRC-like adaptor protein 2 (SLAP2) binds to wild-type KIT in a ligand-dependent manner and is furthermore found constitutively associated with the oncogenic mutant KIT-D816V. Peptide fishing analysis mapped pY568 and pY570 as potential SLAP2 association sites in KIT, which overlaps with the SRC binding sites in KIT. Expression of SLAP2 in cells expressing the transforming mutant KIT-D816V led to reduced cell viability and reduced colony formation. SLAP2 also partially blocked phosphorylation of several signal transduction molecules downstream of KIT such as AKT, ERK, p38 and STAT3. Finally, SLAP2 expression enhanced ubiquitination of KIT and its subsequent degradation. Taken together, our data demonstrate that SLAP2 negatively modulates KIT-D816V-mediated transformation by enhancing degradation of the receptor.
Analysis of dynamically stable patterns in a maze-like corridor using the Wasserstein metric
Authors: Ishiwata Ryosuke , Kinukawa Ryota , Sugiyama Yuki
Published: April 2018

The two-dimensional optimal velocity (2d-OV) model represents a dissipative system with asymmetric interactions, thus being suitable to reproduce behaviours such as pedestrian dynamics and the collective motion of living organisms. In this study, we found that particles in the 2d-OV model form optimal patterns in a maze-like corridor. Then, we estimated the stability of such patterns using the Wasserstein metric. Furthermore, we mapped these patterns into the Wasserstein metric space and represented them as points in a plane. As a result, we discovered that the stability of the dynamical patterns is strongly affected by the model sensitivity, which controls the motion of each particle. In addition, we verified the existence of two stable macroscopic patterns which were cohesive, stable, and appeared regularly over the time evolution of the model.
Author Correction: Laparoscopic Versus Open Liver Resection for Colorectal Liver Metastases: A Comprehensive Systematic Review and Meta-analysis
Authors: Xie Si-Ming , Xiong Jun-Jie , Liu Xue-Ting , Chen Hong-Yu , Iglesia-García Daniel , Altaf Kiran , Bharucha Shameena , Huang Wei , Nunes Quentin M. , Szatmary Peter , Liu Xu-Bao
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.