bluuebunny/crossref_metadata_2025 huggingface dataset:
Confocal Analysis of the Distribution and Persistence of Sindbis Virus (TaV-GFP) Infection in Midguts ofAedes aegyptiMosquitoes
Authors: Saredy Jason J. , Chim Florence Y. , Lyski Zoë L. , Ahearn Yani P. , Bowers Doria F.
Published: March 2020

Biological transmission of arthropod-borne viruses (arboviruses) to vertebrate hosts by hematophagous insects poses a global threat because such arboviruses can result in a range of serious public health infectious diseases. Sindbis virus (SINV), the prototypeAlphavirus, was used to track infections in the posterior midgut (PMG) ofAedes aegyptiadult mosquitoes. Females were fed viremic blood containing a virus reporter, SINV [Thosea asignavirus-green fluorescent protein (TaV-GFP)], that leaves a fluorescent signal in infected cells. We assessed whole-mount PMGs to identify primary foci, secondary target tissues, distribution, and virus persistence. Following a viremic blood meal, PMGs were dissected and analyzed at various days of post blood-feeding. We report that virus foci indicated by GFP in midgut epithelial cells resulted in a 9.8% PMG infection and a 10.8% dissemination from these infected guts. The number of virus foci ranged from 1 to 3 per individual PMG and was more prevalent in the PMG-middle > PMG-frontal > PMG-caudal regions. SINV TaV-GFP was first observed in the PMG (primary target tissue) at 3 days post blood-feeding, was sequestered in circumscribed foci, replicated in PMG peristaltic muscles (secondary target tissue) following dissemination, and GFP was observed to persist in PMGs for 30 days postinfection.
The attitudinal gender gap across generations: support for redistribution and government spending in contexts of high and low welfare provision
Authors: Shorrocks Rosalind , Grasso Maria T.
Published: March 2020

We compare gender gaps in attitudes towards redistribution and social spending across generations in the USA and Britain. We show that the US context, characterized by lower welfare provision, results in consistent or even widening gender gaps for generations born post-1925. On the other hand, the British context, characterized by higher welfare provision relative to the USA, exhibits a narrowing and closing of the gender gap for younger generations, for two out of three indicators of spending preferences. These findings provide some, albeit mixed, evidence that women are more consistently in favour of social spending and redistribution than men in contexts characterized by low welfare provision such as the USA. Where there are higher levels of social support, we argue women could become increasingly more likely to express a preference for levels of spending and redistribution that is similar to men's, narrowing the gender gap among younger generations.
Shear Wave Splitting and Mantle Flow Beneath Alaska
Authors: McPherson A. M. , Christensen D. H. , Abers G. A. , Tape C.
Published: March 2020

Shear wave splitting is often assumed to be caused by mantle flow or preexisting lithospheric fabrics. We present 2,389 new SKS shear wave splitting observations from 384 broadband stations deployed in Alaska from January 2010 to August 2017. In Alaska, splitting appears to be controlled by the absolute plate motion (APM) of the North American and Pacific plates, the interaction between the two plates, and the geometry of the subducting Pacific‐Yakutat plate. Outside of the subduction zone's influence, the fast directions in northern Alaska parallel the North American APM direction. Fast directions near the Queen Charlotte‐Fairweather transform margin are parallel to the faults and are likely caused by the strike‐slip deformation extending throughout the lithosphere. In the mantle wedge, fast directions are oriented along the strike of the slab with large splitting times and are caused by along‐strike flow in the mantle wedge as the slab provides a barrier to flow. South of the Alaska Peninsula, the fast directions are parallel to the trench regardless of sea floor fabric, indicating along strike flow under the Pacific plate. Under the Kenai Peninsula, the complex flat slab geometry may cause subslab flow to be parallel to Pacific APM direction or to the North America‐Pacific relative motion.
Seismic Event Coda‐Correlation: Toward Global Coda‐Correlation Tomography
Authors: Wang Sheng , Tkalčić Hrvoje
Published: March 2020

Seismic event coda‐correlation is a mathematical manifestation of the seismic wavefield, and it is characterized by many prominent features that are formed due to the similarity between multiple pairs of seismic phases. This new paradigm sets a stage for extracting valuable information about Earth structure. However, earthquake coda‐correlation has a fundamentally different physical mechanism from ambient‐noise correlation and thus cannot be utilized in the same way as the ambient‐noise correlation tomography that has been rigorously studied both in terms of theory and applications. Therefore, we are motivated to devise a new framework for the coda‐correlation tomography, in which relevant features in coda‐correlation are decomposed and separate constituents are individually related to Earth structure to build sensitivity kernels for tomography. Our theoretical framework is verified via a toy‐problem experiment, and we compare the newly proposed method here with the one based on the assumption that an interreceiver response (Green's function) can be obtained. We illustrate that significant differences can arise in the interpretation of results if the Green's function is used instead of the newly proposed framework based on the understanding of the formation of coda‐correlation. The proposed framework paves the way for further detailed and application‐oriented method improvements and exploitation of the coda‐correlation tomography in global and planetary seismology.
The Roles of Elastic Properties, Magmatic Pressure, and Tectonic Stress in Saucer‐Shaped Sill Growth
Authors: Gill S. P. A. , Walker R. J.
Published: March 2020

Near‐surface igneous sills commonly exhibit saucer‐like shapes, formed due to interaction with the Earth's surface once some critical sill length is reached relative to its depth. Sill geometry has been strongly linked to the host material conditions, particularly in terms of the elastic properties and shear cohesion of the host rock, operating as primary controls on sill geometry. Here we conduct dynamic numerical simulations for sill growth in the near surface, in which we vary the host rock properties, magma pressure profile internal to the sill ∆P, and the externally applied tectonic stress σr, to consider their contributions to sill geometry. We find that elastic properties alone have little impact on sill geometry. Saucer shapes reflect the additive stress components of the magma overpressure within the sill, and the tectonic stress, controlled by the locus of the maximum energy release rate Gmax. Initially, Gmax is in‐plane with the sill but deflects to ~25° at a critical base length rc relative to depth, due to interaction between the sill and the free surface. Increasing σr decreases this angle and increases rc of the sill. ∆P controls sill growth rate but has little effect on overall geometry. Host rock cohesion and elastic properties control the absolute magnitudes of σr required to effect a change in sill geometry.
The Venusian Atmospheric Oxygen Ion Escape: Extrapolation to the Early Solar System
Authors: Persson M. , Futaana Y. , Ramstad R. , Masunaga K. , Nilsson H. , Hamrin M. , Fedorov A. , Barabash S.
Published: March 2020

The present atmosphere of Venus contains almost no water, but recent measurements indicate that in its early history, Venus had an Earth‐like ocean. Understanding how the Venusian atmosphere evolved is important not only for Venus itself but also for understanding the evolution of other planetary atmospheres. In this study, we quantify the escape rates of oxygen ions from the present Venus to infer the past of the Venusian atmosphere. We show that an extrapolation of the current escape rates back in time leads to the total escape of 0.02–0.6 m of a global equivalent layer of water. This implies that the loss of ions to space, inferred from the present state, cannot account for the loss of an historical Earth‐like ocean. We find that the O+ escape rate increases with solar wind energy flux, where more energy available leads to a higher escape rate. Oppositely, the escape rate decreases slightly with increased extreme ultraviolet radiation (EUV) flux, though the small variation of EUV flux over the measured solar cycle may explain the weak dependency. These results indicate that there is not enough energy transferred from the solar wind to Venus' upper atmosphere that can lead to the escape of the atmosphere over the past 3.9 billion years. This means that the Venusian atmosphere did not have as much water in its atmosphere as previously assumed or the present‐day escape rates do not represent the historical escape rates at Venus. Otherwise, some other mechanisms have acted to more effectively remove the water from the Venusian atmosphere.
Coupled Nitrate and Phosphate Availability Facilitated the Expansion of Eukaryotic Life at Circa 1.56 Ga
Authors: Wang Zhipeng , Wang Xinqiang , Shi Xiaoying , Tang Dongjie , Stüeken Eva E. , Song Huyue
Published: March 2020

Recent geochemical and paleontological studies have revealed a significant ocean oxygenation episode and an evolutionary leap of eukaryotes at the onset of the Mesoproterozoic. However, the potential role of nitrogen availability and its interaction with other nutrients in these environmental and biological events have not been investigated. Here we present an integrated study of nitrogen isotopes (δ15N), organic carbon isotopes (δ13Corg), and major and trace element concentrations from Member III of the Gaoyuzhuang Formation in the central North China Craton where the earliest macroscopic multicellular eukaryotic fossils were reported. The enrichments of redox‐sensitive elements (Mo, U, and V), coupled with Mo‐U covariations, δ13Corg, and I/(Ca + Mg), indicate that the Gaoyuzhuang Member III in the study area was deposited in largely suboxic‐anoxic environments with ephemeral occurrences of euxinia. These data reinforce previous inferences of a strongly redox stratified ocean during the early Mesoproterozoic, but a pulsed oxygenation event may have resulted in deepening of the chemocline. The high δ15N values from the study section are interpreted as a result of aerobic N cycling and the presence of a fairly stable nitrate pool in the surface oxic layer, possibly due to the combined effects of oxygenation and low primary productivity. Increased availability of nitrate could have contributed to the expansion of eukaryotic life at this time. However, our data also suggest that nitrate alone was not the only trigger. Instead, this evolutionary leap was likely facilitated by multiple environmental factors, including a rise in O2 levels and increasing supplies of phosphorus and other bio‐essential trace elements.
A Non‐steady State Model Based on Dual Nitrogen and Oxygen Isotopes to Constrain Moss Nitrate Uptake and Reduction
Authors: Liu Xue‐Yan , Wu Di , Song Xin , Dong Yu‐Ping , Chen Chong‐Juan , Song Wei , Liu Cong‐Qiang , Koba Keisuke
Published: March 2020

Epilithic mosses are early colonizers of the terrestrial biosphere, which constitute a special ecosystem regulating rock‐atmosphere interactions. Terrestrial mosses can take up nitrate (NO3−), a major form of bioavailable N, from soil substrates. However, the importance of substrate NO3− relative to atmospheric NO3− remains unclear in moss NO3− utilization. This has prevented the understanding of moss NO3− dynamics and their responses to environmental N loadings. This study investigated monthly concentrations, δ15N, and δ18O of NO3− in four epilithic moss species from August 2006 to August 2007 in Guiyang, southwestern China. We developed a non‐steady state isotope mass‐balance model to evaluate fractional contributions of atmospheric NO3− (Фatm) and soil NO3− (Фsoil), moss NO3− uptake flux (Finflux), moss NO3− reduction flux (Freduction), and the percentage of NO3− reduction in moss NO3− uptake (freduced). The monthly Фsoil values averaged 53 ± 13% and the monthly freduced values averaged 50 ± 35%. Both the monthly Freduction and freduced increased as the monthly Finflux increased, particularly when the Фsoil values were higher than Фatm values. However, the amount of annual NO3− reduction (219.7 ± 30.5 μg‐N/g, dw) accounted for only 1.0 ± 0.2% of the bulk N of the mosses. We conclude that half of the NO3− in epilithic mosses is derived from the soil NO3− and that NO3− uptake from the soil induces moss NO3− reduction, but the total NO3− assimilation contributed a low fraction of the total N in the studied mosses. These findings are important for understanding N sources and N dynamics in terrestrial mosses.
Tajik Basin and Southwestern Tian Shan, Northwestern India‐Asia Collision Zone: 1. Structure, Kinematics, and Salt Tectonics in the Tajik Fold‐and‐Thrust Belt of the Western Foreland of the Pamir
Authors: Gągała Łukasz , Ratschbacher Lothar , Ringenbach Jean‐Claude , Kufner Sofia‐Katarina , Schurr Bernd , Dedow Ralf , Abdulhameed Sanaa , Le Garzic Edouard , Gadoev Mustafo , Oimahmadov Ilhomjon
Published: March 2020

Surface, seismic, and borehole data characterize the Neogene‐Recent Tajik fold‐and‐thrust belt of the Tajik basin. The basin experienced little sub‐detachment basement deformation, acting as a rigid foreland plate during the Pamir orogeny. The Tajik fold‐and‐thrust belt contains variable thin‐skinned structural styles, changing along and across strike as a function of the thickness and facies of Upper Jurassic evaporites, which constitute the basal detachment, and the influence of the surrounding thick‐skinned belts. The southern Tajik fold‐and‐thrust belt shows regularly spaced, salt‐cored, thrusted detachment anticlines that transition northward into imbricated thrust sheets grouped in oppositely verging stacks facing each other across a common footwall syncline. The width of the fold‐and‐thrust belt decreases northeastward accommodated by the Ilyak fault, a lateral ramp developed over a seismically active dextral basement fault. The southeastern Tajik fold‐and‐thrust belt contains massive subaerial salt sheets, formed by squeezing of preexisting salt diapirs. The salt‐tectonic domain originates from a local depocenter within the Late Jurassic Amu Darya‐Tajik evaporitic basin. Serial cross sections, integrating the structural geometries, yielded minimum thin‐skinned shortening oriented at ~90° to the India‐Asia convergence direction, increasing from ~93 km in the south to ~148 km in the center, and dropping to ~22 km in the northeast; total shortening—including the foreland buttress—is ≥170 km. Most of the shortening in the central‐southern Tajik fold‐and‐thrust belt occurred by hinterland‐vergent, high‐displacement back thrusts. The Pamir played a dominant role in the transfer of shortening to the sedimentary infill of the Tajik basin with the Tian Shan acting as a semi‐passive buttress.
Reformulation of Bayesian Geostatistical Approach on Principal Components
Authors: Zhao Yue , Luo Jian
Published: March 2020

In this note, we reformulate Bayesian geostatistical inverse approach based on principal component analysis of the spatially correlated parameter field to be estimated. The unknown parameter field is described by a latent‐variable model as a realization of projections on its principal component axes. The reformulated geostatistical approach (RGA) achieves substantial dimensionality reduction by estimating the latent variable of projections on truncated principal components instead of directly estimating the parameter field. We provide solutions for best estimates and posterior variances for linear and quasi‐linear inverse problems. The number of normal equations to be solved is reduced to k+p, where k is the number of retained principal components and p is the number of drifts, both independent of the number of observations. To determine the Jacobian matrix for quasi‐linear problems, the number of forward model runs in each iteration is reduced to k+p+1. There is no need to evaluate the Jacobian matrix in terms of the unknown parameter field. RGA unifies the problem setup and computational techniques for large‐dimensional inverse problems introduced previously, which are now naturally built in the reformulated framework. RGA is more efficient and scalable for both large‐dimensional inverse problems and problems with a massive volume of observations. Moreover, conditional realizations of the parameter field can be conveniently generated by generating conditional realizations of latent variables on truncated principal component axes. We also relate the new approach to the classical geostatistical approach formulas. Large‐dimensional hydraulic tomography problems are used to demonstrate the application of the reformulated approach.
Machine‐Learning‐Based Analysis of the Guy‐Greenbrier, Arkansas Earthquakes: A Tale of Two Sequences
Authors: Park Yongsoo , Mousavi S. Mostafa , Zhu Weiqiang , Ellsworth William L. , Beroza Gregory C.
Published: March 2020

We revisited the June 2010 to October 2011 Guy‐Greenbrier earthquake sequence in central Arkansas using PhaseNet, a deep neural network trained to pick P and S arrival times. We applied PhaseNet to continuous waveform data and used phase association and hypocenter relocation to locate nearly 90,000 events. Our catalog suggests that the sequence consists of two adjacent earthquake sequences on the same fault and that the second sequence may be associated with the wastewater disposal well to the west of the Guy‐Greenbrier Fault, rather than the wells to the north and the east that were previously implicated. We find that each sequence is composed of many small clusters that exhibit diffusion along the fault at shorter timescales. Our study demonstrates that machine‐learning‐based earthquake catalog development is now feasible and will yield new insights into earthquake behavior.
Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells
Authors: Chen Chih-Ta , Liao Li-Zhu , Lu Ching-Hui , Huang Yung-Hsuan , Lin Yu-Kie , Lin Jung-Hsin , Chow Lu-Ping
Published: March 2020

Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of ~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7Rcells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma.
The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance
Authors: Suchý Tomáš , Zieschang Christian , Popkova Yulia , Kaczmarek Isabell , Weiner Juliane , Liebing Aenne-Dorothea , Çakir Mehmet Volkan , Landgraf Kathrin , Gericke Martin , Pospisilik John Andrew , Körner Antje , Heiker John T. , Dannenberger Dirk , Schiller Jürgen , Schöneberg Torsten , Liebscher Ines , Thor Doreen
Published: March 2020

Background

G protein-coupled receptors (GPCR) are well-characterized regulators of a plethora of physiological functions among them the modulation of adipogenesis and adipocyte function. The class of Adhesion GPCR (aGPCR) and their role in adipose tissue, however, is poorly studied. With respect to the demand for novel targets in obesity treatment, we present a comprehensive study on the expression and function of this enigmatic GPCR class during adipogenesis and in mature adipocytes.

Methods

The expression of all aGPCR representatives was determined by reanalyzing RNA-Seq data and by performing qPCR in different mouse and human adipose tissues under low- and high-fat conditions. The impact of aGPCR expression on adipocyte differentiation and lipid accumulation was studied by siRNA-mediated knockdown of all expressed members of this receptor class. The biological characteristics and function of mature adipocytes lacking selected aGPCR were analyzed by mass spectrometry and biochemical methods (lipolysis, glucose uptake, adiponectin secretion).

Results

More than ten aGPCR are significantly expressed in visceral and subcutaneous adipose tissues and several aGPCR are differentially regulated under high-caloric conditions in human and mouse. Receptor knockdown of six receptors resulted in an impaired adipogenesis indicating their expression is essential for proper adipogenesis. The altered lipid composition was studied in more detail for two representatives, ADGRG2/GPR64 and ADGRG6/GPR126. While GPR126 is mainly involved in adipocyte differentiation, GPR64 has an additional role in mature adipocytes by regulating metabolic processes.

Conclusions

Adhesion GPCR are significantly involved in qualitative and quantitative adipocyte lipid accumulation and can control lipolysis. Factors driving adipocyte formation and function are governed by signaling pathways induced by aGPCR yielding these receptors potential targets for treating obesity.
Drp1 modulates mitochondrial stress responses to mitotic arrest
Authors: Peña-Blanco Aida , Haschka Manuel D. , Jenner Andreas , Zuleger Theresia , Proikas-Cezanne Tassula , Villunger Andreas , García-Sáez Ana J.
Published: March 2020

Antimitotic drugs are extensively used in the clinics to treat different types of cancer. They can retain cells in a prolonged mitotic arrest imposing two major fates, mitotic slippage, or mitotic cell death. While the former is molecularly well characterized, the mechanisms that control mitotic cell death remain poorly understood. Here, we performed quantitative proteomics of HeLa cells under mitotic arrest induced with paclitaxel, a microtubule-stabilizer drug, to identify regulators of such cell fate decision. We identified alterations in several apoptosis-related proteins, among which the mitochondrial fission protein Drp1 presented increased levels. We found that Drp1 depletion during prolonged mitotic arrest led to strong mitochondrial depolarization and faster mitotic cell death as well as enhanced mitophagy, a mechanism to remove damaged mitochondria. Our findings support a new role of Drp1 in orchestrating the cellular stress responses during mitosis, where mitochondrial function and distribution into the daughter cells need to be coordinated with cell fate. This novel function of Drp1 in the cell cycle becomes best visible under conditions of prolonged mitotic arrest.
Correction: Comparison of methods for transcriptome imputation through application to two common complex diseases
Authors: Fryett James J. , Inshaw Jamie , Morris Andrew P. , Cordell Heather J.
Published: March 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Visible-light promoted regioselective amination and alkylation of remote C(sp3)-H bonds
Authors: Guo Quanping , Peng Qiang , Chai Hongli , Huo Yumei , Wang Shan , Xu Zhaoqing
Published: March 2020

The C-N cross coupling reaction has always been a fundamental task in organic synthesis. However, the direct use of N-H group of aryl amines to generate N-centered radicals which would couple with alkyl radicals to construct C-N bonds is still rare. Here we report a visible light-promoted C-N radical cross coupling for regioselective amination of remote C(sp3)-H bonds. Under visible light irradiation, the N-H groups of aryl amines are converted to N-centered radicals, and are then trapped by alkyl radicals, which are generated from Hofmann-Löffler-Freytag (HLF) type 1,5-hydrogen atom transfer (1,5-HAT). With the same strategy, the regioselective C(sp3)-C(sp3) cross coupling is also realized by using alkyl Hantzsch esters (or nitrile) as radical alkylation reagents. Notably, the α-C(sp3)-H of tertiary amines can be directly alkylated to form the C(sp3)-C(sp3) bonds via C(sp3)-H − C(sp3)-H cross coupling through the same photoredox pathway.
Transcription factor p73 regulates Th1 differentiation
Authors: Ren Min , Kazemian Majid , Zheng Ming , He JianPing , Li Peng , Oh Jangsuk , Liao Wei , Li Jessica , Rajaseelan Jonathan , Kelsall Brian L. , Peltz Gary , Leonard Warren J.
Published: March 2020

Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4+ T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.
Bringing biocatalytic deuteration into the toolbox of asymmetric isotopic labelling techniques
Authors: Rowbotham J. S. , Ramirez M. A. , Lenz O. , Reeve H. A. , Vincent K. A.
Published: March 2020

Enzymes dependent on nicotinamide cofactors are important components of the expanding range of asymmetric synthetic techniques. New challenges in asymmetric catalysis are arising in the field of deuterium labelling, where compounds bearing deuterium (2H) atoms at chiral centres are becoming increasingly desirable targets for pharmaceutical and analytical chemists. However, utilisation of NADH-dependent enzymes for2H-labelling is not straightforward, owing to difficulties in supplying a suitably isotopically-labelled cofactor ([4-2H]-NADH). Here we report on a strategy that combines a clean reductant (H2) with a cheap source of2H-atoms (2H2O) to generate and recycle [4-2H]-NADH. By coupling [4-2H]-NADH-recycling to an array of C=O, C=N, and C=C bond reductases, we demonstrate asymmetric deuteration across a range of organic molecules under ambient conditions with near-perfect chemo-, stereo- and isotopic selectivity. We demonstrate the synthetic utility of the system by applying it in the isolation of the heavy drug (1S,3’R)-[2’,2’,3’-2H3]-solifenacin fumarate on a preparative scale.
Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
Authors: Färkkilä Anniina , Gulhan Doga C. , Casado Julia , Jacobson Connor A. , Nguyen Huy , Kochupurakkal Bose , Maliga Zoltan , Yapp Clarence , Chen Yu-An , Schapiro Denis , Zhou Yinghui , Graham Julie R. , Dezube Bruce J. , Munster Pamela , Santagata Sandro , Garcia Elizabeth , Rodig Scott , Lako Ana , Chowdhury Dipanjan , Shapiro Geoffrey I. , Matulonis Ursula A. , Park Peter J. , Hautaniemi Sampsa , Sorger Peter K. , Swisher Elizabeth M. , D’Andrea Alan D. , Konstantinopoulos Panagiotis A.
Published: March 2020

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
Identification and characterization of N9-methyltransferase involved in converting caffeine into non-stimulatory theacrine in tea
Authors: Zhang Yue-Hong , Li Yi-Fang , Wang Yongjin , Tan Li , Cao Zhi-Qin , Xie Chao , Xie Guo , Gong Hai-Biao , Sun Wan-Yang , Ouyang Shu-Hua , Duan Wen-Jun , Lu Xiaoyun , Ding Ke , Kurihara Hiroshi , Hu Dan , Zhang Zhi-Min , Abe Ikuro , He Rong-Rong
Published: March 2020

Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.
Multiscale computational understanding and growth of 2D materials: a review
Authors: Momeni Kasra , Ji Yanzhou , Wang Yuanxi , Paul Shiddartha , Neshani Sara , Yilmaz Dundar E. , Shin Yun Kyung , Zhang Difan , Jiang Jin-Wu , Park Harold S. , Sinnott Susan , van Duin Adri , Crespi Vincent , Chen Long-Qing
Published: March 2020

The successful discovery and isolation of graphene in 2004, and the subsequent synthesis of layered semiconductors and heterostructures beyond graphene have led to the exploding field of two-dimensional (2D) materials that explore their growth, new atomic-scale physics, and potential device applications. This review aims to provide an overview of theoretical, computational, and machine learning methods and tools at multiple length and time scales, and discuss how they can be utilized to assist/guide the design and synthesis of 2D materials beyond graphene. We focus on three methods at different length and time scales as follows: (i) nanoscale atomistic simulations including density functional theory (DFT) calculations and molecular dynamics simulations employing empirical and reactive interatomic potentials; (ii) mesoscale methods such as phase-field method; and (iii) macroscale continuum approaches by coupling thermal and chemical transport equations. We discuss how machine learning can be combined with computation and experiments to understand the correlations between structures and properties of 2D materials, and to guide the discovery of new 2D materials. We will also provide an outlook for the applications of computational approaches to 2D materials synthesis and growth in general.
Imaging mechanism for hyperspectral scanning probe microscopy via Gaussian process modelling
Authors: Ziatdinov Maxim , Kim Dohyung , Neumayer Sabine , Vasudevan Rama K. , Collins Liam , Jesse Stephen , Ahmadi Mahshid , Kalinin Sergei V.
Published: March 2020

We investigate the ability to reconstruct and derive spatial structure from sparsely sampled 3D piezoresponse force microcopy data, captured using the band-excitation (BE) technique, via Gaussian Process (GP) methods. Even for weakly informative priors, GP methods allow unambiguous determination of the characteristic length scales of the imaging process both in spatial and frequency domains. We further show that BE data set tends to be oversampled in the spatial domains, with ~30% of original data set sufficient for high-quality reconstruction, potentially enabling faster BE imaging. At the same time, reliable reconstruction along the frequency domain requires the resonance peak to be within the measured band. This behavior suggests the optimal strategy for the BE imaging on unknown samples. Finally, we discuss how GP can be used for automated experimentation in SPM, by combining GP regression with non-rectangular scans.
Author Correction: Topological electronic states in HfRuP family superconductors
Authors: Qian Yuting , Nie Simin , Yi Changjiang , Kong Lingyuan , Fang Chen , Qian Tian , Ding Hong , Shi Youguo , Wang Zhijun , Weng Hongming , Fang Zhong
Published: March 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Impact of UV irradiation at full scale on bacterial communities in drinking water
Authors: Pullerits Kristjan , Ahlinder Jon , Holmer Linda , Salomonsson Emelie , Öhrman Caroline , Jacobsson Karin , Dryselius Rikard , Forsman Mats , Paul Catherine J. , Rådström Peter
Published: March 2020

Water in a full-scale drinking water treatment plant was irradiated with ultraviolet (UV) doses of 250, 400, and 600 J/m2, and the effect on bacterial communities investigated using 16s rRNA gene amplicon sequencing, heterotrophic plate counts (HPCs), coliform, andEscherichia colicounts. The bacteria in the irradiated water were also analyzed following storage for 6 days at 7 °C, to approximate the conditions in the distribution system. The log10reduction of HPCs at 400 J/m2was 0.43 ± 0.12. Phylogenetic examination, including DESeq2 analysis, showed thatActinobacteriawas more resistant to UV irradiation, whereasBacteroideteswas sensitive to UV. PhylumProteobacteriacontained monophyletic groups that were either sensitive or resistant to UV exposure. The amplicon sequence variants (ASVs) resistant to UV irradiation had a greater average GC content than the ASVs sensitive to UV, at 55% ± 1.7 (n = 19) and 49% ± 2.5 (n = 16), respectively. FamiliesChitinophagaceae,Pelagibacteraceae,Holophagaceae,Methylophilaceae, andCytophagaceaedecreased linearly in relative abundance, with increasing UV dose (P < 0.05, Pearson’s correlation). When irradiated water was stored,Chitinophagaceae,Comamonadaceae, andFlavobacteriaceaefamilies decreased in relative abundance, whereasACK-M1,Mycobacteriaceae, andNitrosomonadaceaewere increasing in relative abundance. This suggests that the impact of UV irradiation cannot only be considered directly after application but that this treatment step likely continues to influence microbial dynamics throughout the distribution system.
Multidisciplinary database of permeability of fault zones and surrounding protolith rocks at world-wide sites
Authors: Scibek Jacek
Published: March 2020

Brittle faults and fault zones are important fluid flow conduits through the upper part of Earth’s crust that are involved in many well-known phenomena (e.g. earthquakes, thermal water and gas transport, or water leakage to underground tunnels). The permeability property, or the ability of porous materials to conduct water and gas, is one of the key parameters required in understanding and predicting fluid flow. Although close to a thousand studies have been done, and permeability tested in parts of fault zones, a sytematic summary and database is lacking. This data descriptor is for a multi-disciplinary world-wide compilation and review of bulk and matrix permeability of fault zones: 410 datasets, 521 reviewed sites, 379 locations, >10000 publications searched. The review covers studies of faulting processes, geothermal engineering, radioactive waste repositories, groundwater resources, petroleum reservoirs, and underground engineering projects. The objectives are to stimulate the cross-disciplinary data sharing and communication about fault zone hydrogeology, document the biases and strategies for testing of fault zones, and provide the basic statistics of permeability values for models that require these parameters.
A database of freshwater fish species of the Amazon Basin
Authors: Jézéquel Céline , Tedesco Pablo A. , Bigorne Rémy , Maldonado-Ocampo Javier A. , Ortega Hernan , Hidalgo Max , Martens Koen , Torrente-Vilara Gislene , Zuanon Jansen , Acosta Astrid , Agudelo Edwin , Barrera Maure Soraya , Bastos Douglas A. , Bogotá Gregory Juan , Cabeceira Fernando G. , Canto André L. C. , Carvajal-Vallejos Fernando M. , Carvalho Lucélia N. , Cella-Ribeiro Ariana , Covain Raphaël , Donascimiento Carlos , Dória Carolina R. C. , Duarte Cleber , Ferreira Efrem J. G. , Galuch André V. , Giarrizzo Tommaso , Leitão Rafael P. , Lundberg John G. , Maldonado Mabel , Mojica José I. , Montag Luciano F. A. , Ohara Willian M. , Pires Tiago H. S. , Pouilly Marc , Prada-Pedreros Saúl , de Queiroz Luiz J. , Rapp Py-Daniel Lucia , Ribeiro Frank R. V. , Ríos Herrera Raúl , Sarmiento Jaime , Sousa Leandro M. , Stegmann Lis F. , Valdiviezo-Rivera Jonathan , Villa Francisco , Yunoki Takayuki , Oberdorff Thierry
Published: March 2020

The Amazon Basin is an unquestionable biodiversity hotspot, containing the highest freshwater biodiversity on earth and facing off a recent increase in anthropogenic threats. The current knowledge on the spatial distribution of the freshwater fish species is greatly deficient in this basin, preventing a comprehensive understanding of this hyper-diverse ecosystem as a whole. Filling this gap was the priority of a transnational collaborative project, i.e. the AmazonFish project - https://www.amazon-fish.com/. Relying on the outputs of this project, we provide the most complete fish species distribution records covering the whole Amazon drainage. The database, including 2,406 validated freshwater native fish species, 232,936 georeferenced records, results from an extensive survey of species distribution including 590 different sources (e.g. published articles, grey literature, online biodiversity databases and scientific collections from museums and universities worldwide) and field expeditions conducted during the project. This database, delivered at both georeferenced localities (21,500 localities) and sub-drainages grains (144 units), represents a highly valuable source of information for further studies on freshwater fish biodiversity, biogeography and conservation.
Mechanics of near-field deformation during co- and post-seismic shallow fault slip
Authors: Nevitt Johanna M. , Brooks Benjamin A. , Catchings Rufus D. , Goldman Mark R. , Ericksen Todd L. , Glennie Craig L.
Published: March 2020

Poor knowledge of how faults slip and distribute deformation in the shallow crust hinders efforts to mitigate hazards where faults increasingly intersect with the expanding global population at Earth’s surface. Here we analyze two study sites along the 2014M6.0 South Napa, California, earthquake rupture, each dominated by either co- or post-seismic shallow fault slip. We combine mobile laser scanning (MLS), active-source seismic tomography, and finite element modeling to investigate how deformation rate and mechanical properties of the shallow crust affect fault behavior. Despite four orders-of-magnitude difference in the rupture velocities, MLS-derived shear strain fields are remarkably similar at the two sites and suggest deceleration of the co-seismic rupture near Earth’s surface. Constrained by the MLS and seismic data, finite element models indicate shallow faulting is more sensitive to lithologic layering and plastic yielding than to the presence of fault compliant zones (i.e., regions surrounding faults with reduced stiffness). Although both elastic and elastoplastic models can reproduce the observed surface displacement fields within the uncertainty of MLS data, elastoplastic models likely provide the most reliable representations of subsurface fault behavior, as they produce geologically reasonable stress states and are consistent with field, geodetic, and seismological observations.
Specific functions for Mediator complex subunits from different modules in the transcriptional response of Arabidopsis thaliana to abiotic stress
Authors: Crawford Tim , Karamat Fazeelat , Lehotai Nóra , Rentoft Matilda , Blomberg Jeanette , Strand Åsa , Björklund Stefan
Published: March 2020

Adverse environmental conditions are detrimental to plant growth and development. Acclimation to abiotic stress conditions involves activation of signaling pathways which often results in changes in gene expression via networks of transcription factors (TFs). Mediator is a highly conserved co-regulator complex and an essential component of the transcriptional machinery in eukaryotes. Some Mediator subunits have been implicated in stress-responsive signaling pathways; however, much remains unknown regarding the role of plant Mediator in abiotic stress responses. Here, we use RNA-seq to analyze the transcriptional response of Arabidopsis thaliana to heat, cold and salt stress conditions. We identify a set of common abiotic stress regulons and describe the sequential and combinatorial nature of TFs involved in their transcriptional regulation. Furthermore, we identify stress-specific roles for the Mediator subunits MED9, MED16, MED18 and CDK8, and putative TFs connecting them to different stress signaling pathways. Our data also indicate different modes of action for subunits or modules of Mediator at the same gene loci, including a co-repressor function for MED16 prior to stress. These results illuminate a poorly understood but important player in the transcriptional response of plants to abiotic stress and identify target genes and mechanisms as a prelude to further biochemical characterization.
Nuclear receptor CAR-ERα signaling regulates the estrogen sulfotransferase gene in the liver
Authors: Yi MyeongJin , Fashe Muluneh , Arakawa Shingo , Moore Rick , Sueyoshi Tatsuya , Negishi Masahiko
Published: March 2020

Estrogen sulfotransferase (SULT1E1) inactivates estrogen and regulates its metabolic homeostats. Whereas SULT1E1 is expressed low in the liver of adult mice, it is induced by phenobarbital (PB) treatment or spontaneously in diabetic livers via nuclear receptors. Utilizing constitutive active/androstane receptor (CAR) KO, estrogen receptor α (ERα KO, phosphorylation-blocked ERα S216A KI mice, it is now demonstrated that, after being activated by PB, CAR binds and recruits ERα onto the Sulte1 promoter for subsequent phosphorylation at Ser216. This phosphorylation tightens CAR interacting with ERα and to activates the promoter. Hepatic SULT1E1 mRNA levels are constitutively up-regulated in type 1 diabetic Akita mice; CAR spontaneously accumulates in the nucleus and activates the Sult1e1 promoter by recruiting phosphorylated ERα in the liver as observed with PB-induced livers. Thus, this CAR-phosphorylated ERα signaling enables these two nuclear receptors to communicate, activating the Sult1e1 gene in response to either PB or diabetes in mice. ERα phosphorylation may integrate CAR into estrogen actions, providing insights into understanding drug-hormone interactions in clinical therapy.
Improving detection of protein-ligand binding sites with 3D segmentation
Authors: Stepniewska-Dziubinska Marta M. , Zielenkiewicz Piotr , Siedlecki Pawel
Published: March 2020

In recent years machine learning (ML) took bio- and cheminformatics fields by storm, providing new solutions for a vast repertoire of problems related to protein sequence, structure, and interactions analysis. ML techniques, deep neural networks especially, were proven more effective than classical models for tasks like predicting binding affinity for molecular complex. In this work we investigated the earlier stage of drug discovery process – finding druggable pockets on protein surface, that can be later used to design active molecules. For this purpose we developed a 3D fully convolutional neural network capable of binding site segmentation. Our solution has high prediction accuracy and provides intuitive representations of the results, which makes it easy to incorporate into drug discovery projects. The model’s source code, together with scripts for most common use-cases is freely available at http://gitlab.com/cheminfIBB/kalasanty.
Spin-photon module for scalable network architecture in quantum dots
Authors: Zhu Xing-Yu , Tu Tao , Guo Ao-Lin , Zhou Zong-Quan , Guo Guang-Can , Li Chuan-Feng
Published: March 2020

Reliable information transmission between spatially separated nodes is fundamental to a network architecture for scalable quantum technology. Spin qubit in semiconductor quantum dots is a promising candidate for quantum information processing. However, there remains a challenge to design a practical path from the existing experiments to scalable quantum processor. Here we propose a module consisting of spin singlet-triplet qubits and single microwave photons. We show a high degree of control over interactions between the spin qubit and the quantum light field can be achieved. Furthermore, we propose preparation of a shaped single photons with an efficiency of 98%, and deterministic quantum state transfer and entanglement generation between remote nodes with a high fidelity of 90%. This spin-photon module has met the threshold of particular designed error-correction protocols, thus provides a feasible approach towards scalable quantum network architecture.