bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical Study on Multispacecraft Widespread Solar Energetic Particle Events During Solar Cycle 24
Authors: Xie H. , St. Cyr O. C. , Mäkelä P. , Gopalswamy N.
Published: July 2019

We conduct a statistical study on the large three‐spacecraft widespread solar energetic particle (SEP) events. Longitudinal distributions of the peak intensities, onset delays, and relation between the SEP intensity, coronal mass ejection (CME) shock speed, width, and the kinetic energy of the CME have been investigated. We apply a Gaussian fit to obtain the SEP intensity I0 and distribution width σ and a forward‐modeling fit to determine the true shock speed and true CME width. We found a good correlation between σ and connection angle to the flare site and I0 and the kinetic energy of the CME. By including the true shock speed and true CME widths, we reduce root‐mean‐square errors on the predicted SEP intensity by ∼41% for protons compared to Richardson et al.'s (2014, https://doi.org/10.1007/s11207-014-0524-8) prediction. The improved correlation between the CME kinetic energy and SEP intensity provides strong evidence for the CME‐shock acceleration theory of SEPs. In addition, we found that electron and proton release time delays (DTs) relative to Type II radio bursts increase with connection angles. The average electron (proton) DT is ∼14 (32) min for strongly anisotropic events and ∼2.5 (4.4) hr for weakly anisotropic events. Poor magnetic connectivity and large scattering effects are two main reasons to cause large delays.
Impact of Atmospheric Retrievals on Hurricane Florence/Michael Forecasts in a Regional NWP Model
Authors: Shao Min , Smith William L.
Published: July 2019

Atmospheric temperature and water vapor profiles from the Infrared Atmospheric Sounding Interferometer and the Cross‐track Infrared Sounder with acceptable qualities under clear condition and above clouds are derived using the Dual‐Regression algorithm based on the Principle Component‐based Radiative Transfer Model. The application of the derived atmospheric retrievals with high temporal and spatial resolutions in a regional weather model is studied for two hurricane cases by assimilating the retrievals in an hourly update cycle. Improvements on hurricane forecast are obtained by assimilating satellite retrievals as compared to both conventional operational data and radiance assimilation. Position of the predicted hurricane center, which is especially critical for landfall position, is corrected with a maximum improvement of 45 km compared to conventional assimilation. Predictions of heavy precipitation produced by hurricanes are improved with smaller bias and standard deviation. Precipitation scores used for the validation of predictions also show great improvements in heavy precipitation forecast against conventional data and radiance assimilation. Hurricane structure representation is substantially improved. Specifically, more symmetric structures, stronger warm cores, deeper convections, and more accurate winds lead to the improvements in precipitation forecasts. Potential applications of such approaches can be applied to assimilating the retrieved information from the geostationary satellite instruments by adding higher temporal and horizontal resolutions to the polar satellite hyperspectral sounding data.
Scale‐Dependent Patterning of Wetland Depressions in a Low‐Relief Karst Landscape
Authors: Quintero Carlos J. , Cohen Matthew J.
Published: July 2019

Thousands of small wetland depression features (cypress domes) dot the low‐relief karst of Big Cypress National Preserve (BICY) in South Florida, USA. We hypothesized that these wetland depressions are organized in a regular pattern, which is atypical of wetlandscapes elsewhere. Regular patterning implies the existence of coupled feedbacks operating at different spatial scales, with local wetland depression expansion (facilitation via karst dissolution) limited by competition among adjacent depressions for finite water resources (inhibition). We sought to test the hypothesis that wetlands in BICY exhibit regular patterning, and to quantify pattern properties to evaluate competing genesis mechanisms. We tested four predictions about landscape structure and geometry using high‐resolution Light Detection and Ranging elevation data from six 2.25‐km2 domains across BICY. Specifically, we predicted (1) feature overdispersion resulting from competition between adjacent basins; (2) truncated wetland area distributions due to growth inhibition feedbacks; (3) periodicity in surface elevation indicating a characteristic pattern wavelength; and (4) elevation bimodality indicating distinct upland and wetland states. All four predictions were strongly supported. Depressions were significantly overdispersed and efficiently fill the landscape, generating hexagonal patterning. Wetland areas followed truncated power law scaling, indicating incremental constraints on basin expansion, in contrast to depression areas elsewhere. Variogram and radial spectrum analyses revealed clear periodicity (~150‐ to 250‐m wavelength) in surface elevations. Finally, surface elevations were consistently bimodal with elevation divergence of 10 to 40 cm. Regular patterning of wetland depressions across BICY is clear, implying long‐term biogeomorphic control on landform structure in this karst landscape.
LncRNA TTN-AS1 promotes migration, invasion, and epithelial mesenchymal transition of lung adenocarcinoma via sponging miR-142-5p to regulate CDK5
Authors: Jia Yunlong , Duan Yuqing , Liu Tianxu , Wang Xuexiao , Lv Wei , Wang Mengjie , Wang Jiali , Liu Lihua
Published: July 2019

Emerging evidence suggests that long noncoding RNA (lncRNA) plays pivotal roles in regulating various biological process in human cancers. Titin-antisense RNA1 (TTN-AS1) has been regarded as a tumor promoting lncRNA in numerous cancers. However, the clinical significance and biological function of TTN-AS1 in lung adenocarcinoma (LUAD) remain unclear. In the present study, we revealed that the expression of TTN-AS1 was upregulated in LUAD tissues and cell lines. High TTN-AS1 expression was associated with TNM stage and lymph node metastasis of LUAD patients. In addition, high expression of TTN-AS1 was correlated with poor postoperative prognosis of LUAD patients. Knockdown of TTN-AS1 significantly inhibited the growth, proliferation, migration, and invasion ability of LUAD cells in vitro. Then, by using bioinformation analysis and luciferase reporter experiment, we identified that TTN-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-142-5p to regulate the expression of cyclin-dependent kinase 5 (CDK5) in LUAD. Since CDK5 is a key regulator in the process of epithelial mesenchymal transition (EMT), we detected the expression of EMT-related proteins, consequently, EMT was suppressed by knockdown of TTN-AS1 while this phenomenon was rescued by miR-142-5p inhibitor. Taken above, our study revealed that TTN-AS1 played an important role in LUAD progression. TTN-AS1/miR-142-5p/CDK5 regulatory axis may serve as a novel therapeutic target in the treatment of LUAD.
IL-29 promoted obesity-induced inflammation and insulin resistance
Authors: Lin Tian-Yu , Chiu Chiao-Juno , Kuan Chen-Hsiang , Chen Fang-Hsu , Shen Yin-Chen , Wu Chih-Hsing , Hsu Yu-Hsiang
Published: July 2019

Adipocyte-macrophage crosstalk plays a critical role to regulate adipose tissue microenvironment and cause chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes, however, little is known about its role in metabolic disorders. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. In addition, IL-29 promoted monocyte/macrophage migration. Inhibition of IL-29 could reduce inflammatory cytokine production in macrophage-adipocyte coculture system, which mimic an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for treating obesity and insulin resistance in patients with metabolic disorders.
A stomatal safety-efficiency trade-off constrains responses to leaf dehydration
Authors: Henry Christian , John Grace P. , Pan Ruihua , Bartlett Megan K. , Fletcher Leila R. , Scoffoni Christine , Sack Lawren
Published: July 2019

Stomata, the microvalves on leaf surfaces, exert major influences across scales, from plant growth and productivity to global carbon and water cycling. Stomatal opening enables leaf photosynthesis, and plant growth and water use, whereas plant survival of drought depends on stomatal closure. Here we report that stomatal function is constrained by a safety-efficiency trade-off, such that species with greater stomatal conductance under high water availability (gmax) show greater sensitivity to closure during leaf dehydration, i.e., a higher leaf water potential at which stomatal conductance is reduced by 50% (Ψgs50). The gmax - Ψgs50 trade-off and its mechanistic basis is supported by experiments on leaves of California woody species, and in analyses of previous studies of the responses of diverse flowering plant species around the world. Linking the two fundamental key roles of stomata—the enabling of gas exchange, and the first defense against drought—this trade-off constrains the rates of water use and the drought sensitivity of leaves, with potential impacts on ecosystems.
Stimulation of CRISPR-mediated homology-directed repair by an engineered RAD18 variant
Authors: Nambiar Tarun S. , Billon Pierre , Diedenhofen Giacomo , Hayward Samuel B. , Taglialatela Angelo , Cai Kunheng , Huang Jen-Wei , Leuzzi Giuseppe , Cuella-Martin Raquel , Palacios Andrew , Gupta Anuj , Egli Dieter , Ciccia Alberto
Published: July 2019

Precise editing of genomic DNA can be achieved upon repair of CRISPR-induced DNA double-stranded breaks (DSBs) by homology-directed repair (HDR). However, the efficiency of this process is limited by DSB repair pathways competing with HDR, such as non-homologous end joining (NHEJ). Here we individually express in human cells 204 open reading frames involved in the DNA damage response (DDR) and determine their impact on CRISPR-mediated HDR. From these studies, we identify RAD18 as a stimulator of CRISPR-mediated HDR. By defining the RAD18 domains required to promote HDR, we derive an enhanced RAD18 variant (e18) that stimulates CRISPR-mediated HDR in multiple human cell types, including embryonic stem cells. Mechanistically, e18 induces HDR by suppressing the localization of the NHEJ-promoting factor 53BP1 to DSBs. Altogether, this study identifies e18 as an enhancer of CRISPR-mediated HDR and highlights the promise of engineering DDR factors to augment the efficiency of precision genome editing.
MAPCap allows high-resolution detection and differential expression analysis of transcription start sites
Authors: Bhardwaj Vivek , Semplicio Giuseppe , Erdogdu Niyazi Umut , Manke Thomas , Akhtar Asifa
Published: July 2019

The position, shape and number of transcription start sites (TSS) are critical determinants of gene regulation. Most methods developed to detect TSSs and study promoter usage are, however, of limited use in studies that demand quantification of expression changes between two or more groups. In this study, we combine high-resolution detection of transcription start sites and differential expression analysis using a simplified TSS quantification protocol, MAPCap (Multiplexed Affinity Purification of Capped RNA) along with the software icetea. Applying MAPCap on developing Drosophila melanogaster embryos and larvae, we detected stage and sex-specific promoter and enhancer activity and quantify the effect of mutants of maleless (MLE) helicase at X-chromosomal promoters. We observe that MLE mutation leads to a median 1.9 fold drop in expression of X-chromosome promoters and affects the expression of several TSSs with a sexually dimorphic expression on autosomes. Our results provide quantitative insights into promoter activity during dosage compensation.
The role of energy storage in deep decarbonization of electricity production
Authors: Arbabzadeh Maryam , Sioshansi Ramteen , Johnson Jeremiah X. , Keoleian Gregory A.
Published: July 2019

Deep decarbonization of electricity production is a societal challenge that can be achieved with high penetrations of variable renewable energy. We investigate the potential of energy storage technologies to reduce renewable curtailment and CO2 emissions in California and Texas under varying emissions taxes. We show that without energy storage, adding 60 GW of renewables to California achieves 72% CO2 reductions (relative to a zero-renewables case) with close to one third of renewables being curtailed. Some energy storage technologies, on the other hand, allow 90% CO2 reductions from the same renewable penetrations with as little as 9% renewable curtailment. In Texas, the same renewable-deployment level leads to 54% emissions reductions with close to 3% renewable curtailment. Energy storage can allow 57% emissions reductions with as little as 0.3% renewable curtailment. We also find that generator flexibility can reduce curtailment and the amount of energy storage that is needed for renewable integration.
The late stage of COPI vesicle fission requires shorter forms of phosphatidic acid and diacylglycerol
Authors: Park Seung-Yeol , Yang Jia-Shu , Li Zhen , Deng Pan , Zhu Xiaohong , Young David , Ericsson Maria , Andringa Ruben L. H. , Minnaard Adriaan J. , Zhu Chunmei , Sun Fei , Moody D. Branch , Morris Andrew J. , Fan Jun , Hsu Victor W.
Published: July 2019

Studies on vesicle formation by the Coat Protein I (COPI) complex have contributed to a basic understanding of how vesicular transport is initiated. Phosphatidic acid (PA) and diacylglycerol (DAG) have been found previously to be required for the fission stage of COPI vesicle formation. Here, we find that PA with varying lipid geometry can all promote early fission, but only PA with shortened acyl chains promotes late fission. Moreover, diacylglycerol (DAG) acts after PA in late fission, with this role of DAG also requiring shorter acyl chains. Further highlighting the importance of the short-chain lipid geometry for late fission, we find that shorter forms of PA and DAG promote the vesiculation ability of COPI fission factors. These findings advance a general understanding of how lipid geometry contributes to membrane deformation for vesicle fission, and also how proteins and lipids coordinate their actions in driving this process.
Continuous plate subduction marked by the rise of alkali magmatism 2.1 billion years ago
Authors: Liu He , Sun Wei-dong , Zartman Robert , Tang Ming
Published: July 2019

Over the Earth’s evolutionary history, the style of plate subduction has evolved through time due to the secular cooling of the mantle. While continuous subduction is a typical feature of modern plate tectonics, a stagnant-lid tectonic regime with localized episodic subduction likely characterized the early Earth. The timing of the transition between these two subduction styles bears important insights into Earth’s cooling history. Here we apply a statistical analysis to a large geochemical dataset of mafic rocks spanning the last 3.5 Ga, which shows an increasing magnitude of alkali basaltic magmatism beginning at ca. 2.1 Ga. We propose that the rapid rise of continental alkali basalts correlates with an abruptly decreasing degree of mantle melting resulting from the enhanced cooling of the mantle at ca. 2.1 Ga. This might be a consequence of the initiation of continuous subduction, which recycled increasing volumes of cold oceanic crust into the mantle.
A high-speed search engine pLink 2 with systematic evaluation for proteome-scale identification of cross-linked peptides
Authors: Chen Zhen-Lin , Meng Jia-Ming , Cao Yong , Yin Ji-Li , Fang Run-Qian , Fan Sheng-Bo , Liu Chao , Zeng Wen-Feng , Ding Yue-He , Tan Dan , Wu Long , Zhou Wen-Jing , Chi Hao , Sun Rui-Xiang , Dong Meng-Qiu , He Si-Min
Published: July 2019

We describe pLink 2, a search engine with higher speed and reliability for proteome-scale identification of cross-linked peptides. With a two-stage open search strategy facilitated by fragment indexing, pLink 2 is ~40 times faster than pLink 1 and 3~10 times faster than Kojak. Furthermore, using simulated datasets, synthetic datasets, 15N metabolically labeled datasets, and entrapment databases, four analysis methods were designed to evaluate the credibility of ten state-of-the-art search engines. This systematic evaluation shows that pLink 2 outperforms these methods in precision and sensitivity, especially at proteome scales. Lastly, re-analysis of four published proteome-scale cross-linking datasets with pLink 2 required only a fraction of the time used by pLink 1, with up to 27% more cross-linked residue pairs identified. pLink 2 is therefore an efficient and reliable tool for cross-linking mass spectrometry analysis, and the systematic evaluation methods described here will be useful for future software development.
Catalytic enantioselective addition of organometallics to unprotected carboxylic acids
Authors: Yan Xingchen , Harutyunyan Syuzanna R.
Published: July 2019

Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,β-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of β-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.
Modification of messenger RNA by 2′-O-methylation regulates gene expression in vivo
Authors: Elliott Brittany A. , Ho Hsiang-Ting , Ranganathan Srivathsan V. , Vangaveti Sweta , Ilkayeva Olga , Abou Assi Hala , Choi Alex K. , Agris Paul F. , Holley Christopher L.
Published: July 2019

Epitranscriptomic modifications of mRNA are important regulators of gene expression. While internal 2′-O-methylation (Nm) has been discovered on mRNA, questions remain about its origin and function in cells and organisms. Here, we show that internal Nm modification can be guided by small nucleolar RNAs (snoRNAs), and that these Nm sites can regulate mRNA and protein expression. Specifically, two box C/D snoRNAs (SNORDs) and the 2′-O-methyltransferase fibrillarin lead to Nm modification in the protein-coding region of peroxidasin (Pxdn). The presence of Nm modification increases Pxdn mRNA expression but inhibits its translation, regulating PXDN protein expression and enzyme activity both in vitro and in vivo. Our findings support a model in which snoRNA-guided Nm modifications of mRNA can regulate physiologic gene expression by altering mRNA levels and tuning protein translation.
Profiling host ANP32A splicing landscapes to predict influenza A virus polymerase adaptation
Authors: Domingues Patricia , Eletto Davide , Magnus Carsten , Turkington Hannah L. , Schmutz Stefan , Zagordi Osvaldo , Lenk Matthias , Beer Martin , Stertz Silke , Hale Benjamin G.
Published: July 2019

Species’ differences in cellular factors limit avian influenza A virus (IAV) zoonoses and human pandemics. The IAV polymerase, vPol, harbors evolutionary sites to overcome restriction and determines virulence. Here, we establish host ANP32A as a critical driver of selection, and identify host-specific ANP32A splicing landscapes that predict viral evolution. We find that avian species differentially express three ANP32A isoforms diverging in a vPol-promoting insert. ANP32As with shorter inserts interact poorly with vPol, are compromised in supporting avian-like IAV replication, and drive selection of mammalian-adaptive vPol sequences with distinct kinetics. By integrating selection data with multi-species ANP32A splice variant profiling, we develop a mathematical model to predict avian species potentially driving (swallow, magpie) or maintaining (goose, swan) mammalian-adaptive vPol signatures. Supporting these predictions, surveillance data confirm enrichment of several mammalian-adaptive vPol substitutions in magpie IAVs. Profiling host ANP32A splicing could enhance surveillance and eradication efforts against IAVs with pandemic potential.
Genetically diverse Pseudomonas aeruginosa populations display similar transcriptomic profiles in a cystic fibrosis explanted lung
Authors: Kordes Adrian , Preusse Matthias , Willger Sven D. , Braubach Peter , Jonigk Danny , Haverich Axel , Warnecke Gregor , Häussler Susanne
Published: July 2019

Previous studies have demonstrated substantial genetic diversification ofPseudomonas aeruginosaacross sub-compartments in cystic fibrosis (CF) lungs. Here, we isolateP. aeruginosafrom five different sampling areas in the upper and lower airways of an explanted CF lung, analyze ex vivo transcriptional profiles by RNA-seq, and use colony re-sequencing and deep population sequencing to determine the genetic diversity within and across the various sub-compartments. We find that, despite genetic variation, the ex vivo transcriptional profiles ofP. aeruginosapopulations inhabiting different regions of the CF lung are similar. Although we cannot estimate the extent to which the transcriptional response recorded here actually reflects the in vivo transcriptomes, our results indicate that there may be a common in vivo transcriptional profile in the CF lung environment.
Facile access to nitroarenes and nitroheteroarenes using N-nitrosaccharin
Authors: Calvo Roxan , Zhang Kun , Passera Alessandro , Katayev Dmitry
Published: July 2019

Nitroaromatics and nitroheteroaromatics serve as key building blocks and intermediates in synthesis, and form the core scaffold of a vast number of materials, dyes, explosives, agrochemicals and pharmaceuticals. However, their synthesis relies on harsh methodologies involving excess mineral acids, which present a number of critical drawbacks in terms of functional group compatibility and environmental impact. Modern, alternative strategies still suffer from significant limitations in terms of practicality, and a general protocol amenable to the direct C-H functionalization of a broad range of aromatics has remained elusive. Herein we introduce a bench-stable, inexpensive, easy to synthesize and recyclable nitrating reagent based on saccharin. This reagent acts as a controllable source of the nitronium ion, allowing mild and practical nitration of both arenes and heteroarenes displaying an exceptional functional group tolerance.
Impacts of air pollutants from rural Chinese households under the rapid residential energy transition
Authors: Shen Guofeng , Ru Muye , Du Wei , Zhu Xi , Zhong Qirui , Chen Yilin , Shen Huizhong , Yun Xiao , Meng Wenjun , Liu Junfeng , Cheng Hefa , Hu Jianying , Guan Dabo , Tao Shu
Published: July 2019

Rural residential energy consumption in China is experiencing a rapid transition towards clean energy, nevertheless, solid fuel combustion remains an important emission source. Here we quantitatively evaluate the contribution of rural residential emissions to PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 μm) and the impacts on health and climate. The clean energy transitions result in remarkable reductions in the contributions to ambient PM2.5, avoiding 130,000 (90,000–160,000) premature deaths associated with PM2.5 exposure. The climate forcing associated with this sector declines from 0.057 ± 0.016 W/m2 in 1992 to 0.031 ± 0.008 W/m2 in 2012. Despite this, the large remaining quantities of solid fuels still contributed 14 ± 10 μg/m3 to population-weighted PM2.5 in 2012, which comprises 21 ± 14% of the overall population-weighted PM2.5 from all sources. Rural residential emissions affect not only rural but urban air quality, and the impacts are highly seasonal and location dependent.
Genomic Features of High-Priority Salmonella enterica Serovars Circulating in the Food Production Chain, Brazil, 2000–2016
Authors: Monte Daniel F. , Lincopan Nilton , Berman Hanna , Cerdeira Louise , Keelara Shivaramu , Thakur Siddhartha , Fedorka-Cray Paula J. , Landgraf Mariza
Published: July 2019

Multidrug-resistant (MDR) Salmonella enterica has been deemed a high-priority pathogen by the World Health Organization. Two hundred and sixty-four Salmonella enterica isolates recovered over a 16-year period (2000 to 2016) from the poultry and swine production chains, in Brazil, were investigated by whole-genome sequencing (WGS). Most international lineages belonging to 28 serovars, including, S. enterica serovars S. Schwarzengrund ST96, S. Typhimurium ST19, S. Minnesota ST548, S. Infantis ST32, S. Heidelberg ST15, S. Newport ST45, S. Brandenburg ST65 and S. Kentucky ST198 displayed MDR and virulent genetic backgrounds. In this regard, resistome analysis revealed presence of qnrE1 (identified for the first time in S. Typhimurium from food chain), qnrB19, qnrS1, blaCTX-M-8, blaCTX-M-2 and blaCMY-2 genes, as well as gyrA mutations; whereas ColpVC, IncHI2A, IncHI2, IncFIA, Incl1, IncA/C2, IncR, IncX1 and po111 plasmids were detected. In addition, phylogenetic analysis revealed multiple independent lineages such as S. enterica serovars S. Infantis, S. Schwarzengrund, S. Minnesota, S. Kentucky and S. Brandenburg. In brief, ocurrence and persistence of international lineages of S. enterica serovars in food production chain is supported by conserved genomes and wide virulome and resistome.
Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide
Authors: Ehlting Christian , Rex Julia , Albrecht Ute , Deenen René , Tiedje Christopher , Köhrer Karl , Sawodny Oliver , Gaestel Matthias , Häussinger Dieter , Bode Johannes Georg
Published: July 2019

The p38MAPK downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2−/− or MK2/3−/− animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)α subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-β. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-β. In the absence of MK2, MK3 also delayed the nuclear translocation of NFκB by delaying the ubiquitination and subsequent degradation of IκBβ, reflecting the substantial plasticity of the response of BMDM to LPS.
Fast long-term denudation rate of steep alpine headwalls inferred from cosmogenic 36Cl depth profiles
Authors: Mair David , Lechmann Alessandro , Yesilyurt Serdar , Tikhomirov Dmitry , Delunel Romain , Vockenhuber Christof , Akçar Naki , Schlunegger Fritz
Published: July 2019

Quantifications of in-situ denudation rates on vertical headwalls, averaged over millennia, have been thwarted because of inaccessibility. Here, we benefit from a tunnel crossing a large and vertical headwall in the European Alps (Eiger), where we measured concentrations of in-situ cosmogenic 36Cl along five depth profiles linking the tunnel with the headwall surface. Isotopic concentrations of 36Cl are low in surface samples, but high at depth relative to expectance for their position. The results of Monte-Carlo modelling attribute this pattern to inherited nuclides, young minimum exposure ages and to fast average denudation rates during the last exposure. These rates are consistently high across the Eiger and range from 45 ± 9 cm kyr−1 to 356 ± 137 cm kyr−1 (1σ) for the last centuries to millennia. These high rates together with the large inheritance point to a mechanism where denudation has been accomplished by frequent, cm-scale rock fall paired with chemical dissolution of limestone.
Systemic arterial hypertension leads to decreased semen quality and alterations in the testicular microcirculation in rats
Authors: Colli Lucas Giglio , Belardin Larissa Berloffa , Echem Cinthya , Akamine Eliana Hiromi , Antoniassi Mariana Pereira , Andretta Rhayza Roberta , Mathias Lucas Solla , Rodrigues Stephen Fernandes de Paula , Bertolla Ricardo Pimenta , de Carvalho Maria Helena Catelli
Published: July 2019

Arterial hypertension is a cardiovascular disease that leads to important systemic alterations and drastically impairs normal organ function over time. Hypertension affects around 700 million men of reproductive age and hypertensive men present increased risk for reproductive disorders, such as erectile dysfunction. However, the link between arterial hypertension and male reproductive disorders is associative at best. Moreover, many studies have reported associations between decreased male fertility and/or semen quality and alterations to general male health. In this study we aim to investigate the effect of systemic high blood pressure in sperm quality, sperm functional characteristics and testicular physiology in a rat model. Hypertensive rats presented altered testicular morphology – mainly vascular alterations and impaired testicular vasomotion. Hypertensive rats also presented decrease in sperm concentration, DNA integrity and increased percentages of sperm with dysfunctional mitochondria, intracellular superoxide anion activity and abnormal morphology. This study provides mechanistic insights by which arterial hypertension affects the testes, evidencing the testes as another target organ for hypertension as well as its impact on sperm quality.
Thermodynamic Stability and Structural Insights for CH3NH3Pb1−xSixI3, CH3NH3Pb1−xGexI3, and CH3NH3Pb1−xSnxI3 Hybrid Perovskite Alloys: A Statistical Approach from First Principles Calculations
Authors: Guedes-Sobrinho Diego , Guilhon Ivan , Marques Marcelo , Teles Lara K.
Published: July 2019

The recent reaching of 20% of conversion efficiency by solar cells based on metal hybrid perovskites (MHP), e.g., the methylammonium (MA) lead iodide, CH3NH3PbI3(MAPbI3), has excited the scientific community devoted to the photovoltaic materials. However, the toxicity of Pb is a hindrance for large scale commercial of MHP and motivates the search of another congener eco-friendly metal. Here, we employed first-principles calculations via density functional theory combined with the generalized quasichemical approximation to investigate the structural, thermodynamic, and ordering properties of MAPb1−xSixI3, MAPb1−xGexI3, and MAPb1−xSnxI3alloys as pseudo-cubic structures. The inclusion of a smaller second metal, as Si and Ge, strongly affects the structural properties, reducing the cavity volume occupied by the organic cation and limitating the free orientation under high temperature effects. Unstable and metaestable phases are observed at room temperature for MAPb1−xSixI3, whereas MAPb1−xGexI3is energetically favored for Pb-rich in ordered phases even at very low temperatures. Conversely, the high miscibility of Pb and Sn into MAPb1−xSnxI3yields an alloy energetically favored as a pseudo-cubic random alloy with tunable properties at room temperature.
Evidence of different climatic adaptation strategies in humans and non-human primates
Authors: Buck L. T. , De Groote I. , Hamada Y. , Hassett B. R. , Ito T. , Stock J. T.
Published: July 2019

To understand human evolution it is critical to clarify which adaptations enabled our colonisation of novel ecological niches. For any species climate is a fundamental source of environmental stress during range expansion. Mammalian climatic adaptations include changes in size and shape reflected in skeletal dimensions and humans fit general primate ecogeographic patterns. It remains unclear however, whether there are also comparable amounts of adaptation in humans, which has implications for understanding the relative importance of biological/behavioural mechanisms in human evolution. We compare cranial variation between prehistoric human populations from throughout Japan and ecologically comparable groups of macaques. We compare amounts of intraspecific variation and covariation between cranial shape and ecological variables. Given equal rates and sufficient time for adaptation for both groups, human conservation of non-human primate adaptation should result in comparable variation and patterns of covariation in both species. In fact, we find similar amounts of intraspecific variation in both species, but no covariation between shape and climate in humans, contrasting with strong covariation in macaques. The lack of covariation in humans may suggest a disconnect in climatic adaptation strategies from other primates. We suggest this is due to the importance of human behavioural adaptations, which act as a buffer from climatic stress and were likely key to our evolutionary success.
Identifying Archaeological Bone via Non-Destructive ZooMS and the Materiality of Symbolic Expression: Examples from Iroquoian Bone Points
Authors: McGrath Krista , Rowsell Keri , Gates St-Pierre Christian , Tedder Andrew , Foody George , Roberts Carolynne , Speller Camilla , Collins Matthew
Published: July 2019

Today, practical, functional and symbolic choices inform the selection of raw materials for worked objects. In cases where we can discern the origin of worked bone, tooth, ivory and antler objects in the past, we assume that similar choices are being made. However, morphological species identification of worked objects is often impossible due to the loss of identifying characteristics during manufacture. Here, we describe a novel non-destructive ZooMS (Zooarchaeology by Mass Spectrometry) method which was applied to bone points from Pre-Contact St. Lawrence Iroquoian village sites in southern Quebec, Canada. The traditional ZooMS technique requires destructive analysis of a sample, which can be problematic when dealing with artefacts. Here we instead extracted proteins from the plastic bags in which the points had been stored. ZooMS analysis revealed hitherto unexpected species, notably black bear (Ursus americanus) and human (Homo sapiens sapiens), used in point manufacture. These surprising results (confirmed through genomic sequencing) highlight the importance of advancing biomolecular research in artefact studies. Furthermore, they unexpectedly and exceptionally allow us to identify and explore the tangible, material traces of the symbolic relationship between bears and humans, central to past and present Iroquoian cosmology and mythology.
Bruton’s tyrosine kinase is at the crossroads of metabolic adaptation in primary malignant human lymphocytes
Authors: Sharif-Askari Bahram , Doyon Daniel , Paliouras Miltiadis , Aloyz Raquel
Published: July 2019

In this work we explored metabolic aspects of human primary leukemic lymphocytes that hold a potential impact on the treatment of Bruton tyrosine kinase (BTK)-driven diseases. Our results suggest that there is crosstalk between Bruton tyrosine kinase (BTK) signaling and bioenergetic stress responses. In primary chronic lymphocytic leukemia (CLL) lymphocytes, pharmacological interference with mitochondrial ATP synthesis or glucose metabolism affects BTK activity. Conversely, an inhibitor of BTK used clinically (ibrutinib) induces bioenergetic stress responses that in turn affect ibrutinib resistance. Although the detailed molecular mechanisms are still to be defined, our work shows for the first time that in primary B cells, metabolic stressors enhance BTK signaling and suggest that metabolic rewiring to hyperglycemia affects ibrutinib resistance in TP53 deficient chronic lymphocytic leukemia (CLL) lymphocytes.
The effect of labor and delivery mode on electrocortical and brainstem autonomic function during neonatal transition
Authors: Mulkey Sarah B. , Kota Srinivas , Govindan Rathinaswamy B. , Al-Shargabi Tareq , Swisher Christopher B. , Eze Augustine , Hitchings Laura , Russo Stephanie , Herrera Nicole , McCarter Robert , Maxwell G. Larry , Baker Robin , du Plessis Adre J.
Published: July 2019

Delivery of the newborn occurs either vaginally or via caesarean section. It is not known whether the mode of delivery and exposure to labor affects early autonomic nervous system (ANS) function, as measured by heart rate variability (HRV), or cortical electroencephalogram (EEG) activity. The objective of the study was to determine if autonomic function in newborns differs by mode of delivery. Simultaneous recording of EEG and electrocardiogram were collected in low-risk term newborns at <72 hours of age to measure HRV, the asymmetry index, and EEG power. Newborns were compared by delivery type: vaginal delivery (VD), cesarean section (CS) after labor (L-CS), or elective CS (E-CS). Quantile Regression controlled for gestational age, postnatal age, and percent active states. One hundred and eighteen newborns were studied at 25.2 (11.4) hours of age. Sixty-two (52.5%) were born by VD, 22 by L-CS (18.6%), and 34 by E-CS (28.8%). HRV metrics didn’t differ by delivery mode. Asymmetry index was higher in L-CS compared to VD and E-CS (P = 0.03). On EEG, L-CS newborns showed lower relative gamma power compared to VD and E-CS (P = 0.005). The study found that overall ANS tone is not altered by mode of delivery in low-risk term newborns.
A bioinformatic analysis identifies circadian expression of splicing factors and time-dependent alternative splicing events in the HD-MY-Z cell line
Authors: Genov Nikolai , Basti Alireza , Abreu Mónica , Astaburuaga Rosario , Relógio Angela
Published: July 2019

The circadian clock regulates key cellular processes and its dysregulation is associated to several pathologies including cancer. Although the transcriptional regulation of gene expression by the clock machinery is well described, the role of the clock in the regulation of post-transcriptional processes, including splicing, remains poorly understood. In the present work, we investigated the putative interplay between the circadian clock and splicing in a cancer context. For this, we applied a computational pipeline to identify oscillating genes and alternatively spliced transcripts in time-course high-throughput data sets from normal cells and tissues, and cancer cell lines. We investigated the temporal phenotype of clock-controlled genes and splicing factors, and evaluated their impact in alternative splice patterns in the Hodgkin Lymphoma cell line HD-MY-Z. Our data points to a connection between clock-controlled genes and splicing factors, which correlates with temporal alternative splicing in several genes in the HD-MY-Z cell line. These include the genes DPYD, SS18, VIPR1 and IRF4, involved in metabolism, cell cycle, apoptosis and proliferation. Our results highlight a role for the clock as a temporal regulator of alternative splicing, which may impact malignancy in this cellular model.
Multicentre evaluation of Xpert MTB/RIF assay in detecting urinary tract tuberculosis with urine samples
Authors: Chen Yu , Wu Peng , Fu Liang , Liu Yu-hong , Zhang Yao , Zhao Yanping
Published: July 2019

Genitourinary tuberculosis (GUTB) accounts for up to 40% of extrapulmonary tuberculosis cases. Rapid tests for GUTB are urgently needed because it is often associated with delayed health-care seeking, leading to serious consequences. This study evaluated the performance of the Xpert MTB/RIF assay in the rapid diagnosis of urinary tract tuberculosis (UTB) and rifampicin-resistant tuberculosis with urine specimens. In all, 302 patients were included from four hospitals in China. Suspected UTB patients were tested with Xpert, smear, and MGIT 960 culture. Drug susceptibility testing (DST) was conducted for culture-positive cases. The performance of the assays was evaluated against MGIT 960 culture and a composite reference standard (CRS). Among all participants, 150 (49.7%) had CRS-positive UTB, of whom 36 (24.0%) were culture-confirmed. Against culture, Xpert and smear achieved a sensitivity of 94.4% (95% CI: 81.3–99.3%) and 22.2% (95% CI: 10.1–39.2%), respectively. Against CRS, the sensitivity of Xpert, smear and culture was 41.3% (95% CI: 33.4–49.7%), 7.3% (95% CI: 3.7–12.7%), and 24.0% (95% CI: 17.4–31.6%). Xpert had better performance than smear and culture in detecting UTB from urine samples and could be considered for the diagnosis of UTB. Moreover, Xpert showed better performance than MGIT 960-based DST using urine culture.
Resistance of in natura and torrefied wood chips to xylophage fungi
Authors: Castro Vinícius Resende de , de Castro Freitas Matheus Perdigão , Zanuncio Antônio José Vinha , Zanuncio José Cola , Surdi Paula Gabriella , Carneiro Angélica de Cássia Oliveira , Vital Benedito Rocha
Published: July 2019

The diversity of fungi allows for their colonisation in different environments, including wood destined for power generation, with an ability to degrade or hinder its use. Torrefaction or pre-carbonisation, a low oxygenation heat treatment with temperatures between 200 and 300 °C, accumulates carbon and lignin, decreases hygroscopicity, increases energy efficiency and reduces the wood attractiveness to xylophagous microorganisms. This work aimed to study the resistance of Eucalyptus urophylla wood chips, submitted to torrefaction temperatures of 180, 220 and 260 °C for 20 minutes, to xylophagous fungi, according to the ASTM D-2017 method (2005). The white rot fungi Phanerochaete chrysosporium, Pleurotus ostreatus and Trametes versicolor and the brown rot fungus Gloeophyllum trabeum were used. After 12 weeks of exposure, the mass losses of wood samples in natura and torrified at 180 °C attacked by Pleurotus ostreatus and Trametes versicolor was higher. Torrefaction increased the resistance to fungi; the treatment at 260 °C was the most efficient with lower mass losses caused by fungi attacks and, consequently, greater resistance to the fungi tested.
Deregulation of TLR4 signaling pathway characterizes Bicuspid Aortic valve syndrome
Authors: Balistreri Carmela R. , Marullo Antonino G. M. , Madonna Michele , Cavarretta Elena , Allegra Alberto , Cesarini Valeriana , Iaccarino Alessandra , Schiavon Sonia , Peruzzi Mariangela , Greco Ernesto , Sciarretta Sebastiano , Pisano Calogera , Ruvolo Giovanni , Torella Michele , Frati Giacomo
Published: July 2019

Bicuspid aortic valve (BAV) disease is recognized to be a syndrome with a complex and multifaceted pathophysiology. Its progression is modulated by diverse evolutionary conserved pathways, such as Notch-1 pathway. Emerging evidence is also highlighting the key role of TLR4 signaling pathway in the aortic valve pathologies and their related complications, such as sporadic ascending aorta aneurysms (AAA). Consistent with these observations, we aimed to evaluate the role of TLR4 pathway in both BAV disease and its common complication, such as AAA. To this aim, 70 subjects with BAV (M/F 50/20; mean age: 58.8 ± 14.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M/F 35/35; mean age: 69.1 ± 12.8 years), with and without AAA were enrolled. Plasma assessment, tissue and gene expression evaluations were performed. Consistent with data obtained in the previous study on immune clonotypic T and B altered responses, we found reduced levels of systemic TNF-α, IL-1, IL-6, IL-17 cytokines in BAV cases, either in the presence or absence of AAA, than TAV cases (p < 0.0001 by ANOVA test). Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p < 0.0001 by ANOVA test). These results may suggest a deregulation in the activity or in the expression of TLR4 signaling pathway in all BAV cases. Portrait of these data is, indeed, the significantly decreased gene expression of inflammatory cytokines and TLR4, in both normal and aneurysmatic tissue samples, from BAV with AAA than TAV with AAA. In conclusion, our study demonstrates that subjects with BAV display a significant deregulation of TLR4 signaling pathway paralleled by a deregulation of Notch-1 pathway, as previously showed. This data suggests that the crosstalk between the Notch-1 and TLR4 signaling pathways may play a crucial role in both physiological embryological development, and homeostasis and functionality of aortic valve in adult life.
Functionalization of Brain Region-specific Spheroids with Isogenic Microglia-like Cells
Authors: Song Liqing , Yuan Xuegang , Jones Zachary , Vied Cynthia , Miao Yu , Marzano Mark , Hua Thien , Sang Qing-Xiang Amy , Guan Jingjiao , Ma Teng , Zhou Yi , Li Yan
Published: July 2019

Current brain spheroids or organoids derived from human induced pluripotent stem cells (hiPSCs) still lack a microglia component, the resident immune cells in the brain. The objective of this study is to engineer brain region-specific organoids from hiPSCs incorporated with isogenic microglia-like cells in order to enhance immune function. In this study, microglia-like cells were derived from hiPSCs using a simplified protocol with stage-wise growth factor induction, which expressed several phenotypic markers, including CD11b, IBA-1, CX3CR1, and P2RY12, and phagocytosed micron-size super-paramagnetic iron oxides. The derived cells were able to upregulate pro-inflammatory gene (TNF-α) and secrete anti-inflammatory cytokines (i.e., VEGF, TGF-β1, and PGE2) when stimulated with amyloid β42 oligomers, lipopolysaccharides, or dexamethasone. The derived isogenic dorsal cortical (higher expression of TBR1 and PAX6) and ventral (higher expression of NKX2.1 and PROX1) spheroids/organoids displayed action potentials and synaptic activities. Co-culturing the microglia-like cells (MG) with the dorsal (D) or ventral (V) organoids showed differential migration ability, intracellular Ca2+signaling, and the response to pro-inflammatory stimuli (V-MG group had higher TNF-α and TREM2 expression). Transcriptome analysis exhibited 37 microglia-related genes that were differentially expressed in MG and D-MG groups. In addition, the hybrid D-MG spheroids exhibited higher levels of immunoreceptor genes in activating members, but the MG group contained higher levels for most of genes in inhibitory members (except SIGLEC5 and CD200). This study should advance our understanding of the microglia function in brain-like tissue and establish a transformative approach to modulate cellular microenvironment toward the goal of treating various neurological disorders.