bluuebunny/crossref_metadata_2025 huggingface dataset:
A Warm Layer in the Nightside Mesosphere of Mars
Authors: Nakagawa Hiromu , Jain Sonal K. , Schneider Nicholas M. , Montmessin Franck , Yelle Roger V. , Jiang Fayu , Verdier Loic , Kuroda Takeshi , Yoshida Nao , Fujiwara Hitoshi , Imamura Takeshi , Terada Naoki , Terada Kaori , Seki Kanako , Gröller Hannes , Deighan Justin I.
Published: February 2020

We report a new set of stellar occultation measurements for nightside temperature profiles made by the Mars Atmosphere and Volatile EvolutioN/Imaging Ultraviolet Spectrograph that provide evidence for a recurring layer of warm air between 70 and 90 km altitudes in the nightside mesosphere of Mars during Ls = 0–180° in Martian Year 33–34. The nightside profiles reveal a recurring peak of atmospheric temperature around 80 km over the equator to the middle latitudes in the northern hemisphere. The predictions of the Mars Climate Database have a warm layer with much smaller amplitudes. The observed peak amplitudes are larger than those predicted by the model by up to 90 K. Wavenumber‐3 structures are seen in the warm layer that are potentially signatures of thermal tides or stationary planetary waves, with amplitudes two times larger than predicted.
A Preindustrial Sea‐Level Rise Hotspot Along the Atlantic Coast of North America
Authors: Gehrels W. R. , Dangendorf S. , Barlow N. L. M. , Saher M. H. , Long A. J. , Woodworth P. L. , Piecuch C. G. , Berk K.
Published: February 2020

The Atlantic coast of North America north of Cape Hatteras has been proposed as a “hotspot” of late 20th century sea‐level rise. Here we test, using salt‐marsh proxy sea‐level records, if this coast experienced enhanced sea‐level rise over earlier multidecadal‐centennial periods. While we find in agreement with previous studies that 20th century rates of sea‐level change were higher compared to rates during preceding centuries, rates of 18th century sea‐level rise were only slightly lower, suggesting that the “hotspot” is a reoccurring feature for at least three centuries. Proxy sea‐level records from North America (Iceland) are negatively (positively) correlated with centennial changes in the North Atlantic Oscillation. They are consistent with sea‐level “fingerprints” of Arctic ice melt, and we therefore hypothesize that sea‐level fluctuations are related to changes in Arctic land‐ice mass. Predictions of future sea‐level rise should take into account these long‐term fluctuating rates of natural sea‐level change.
Chorus Acceleration of Relativistic Electrons in Extremely Low L‐Shell During Geomagnetic Storm of August 2018
Authors: Zhang Zhenxia , Chen Lunjin , Liu Si , Xiong Ying , Li Xinqiao , Wang Yongfu , Chu Wei , Zeren Zhima , Shen Xuhui
Published: February 2020

Based on data from the Van Allen Probes and ZH‐1 satellites, relativistic electron enhancements in extremely low L‐shell regions (reaching
) were observed during August 2018 major geomagnetic storm (minimum
nT). Contrary to what occurs in the outer belt, such an intense and deep electron penetration event is rare and more interesting. Strong whistler‐mode (chorus and hiss) waves, with amplitudes 81–126 pT, were also observed in the extremely low L‐shell simultaneously (reaching
) where the plasmapause was suppressed. The bounce‐averaged diffusion coefficient calculations support that the chorus waves can play a significantly important role in diffusing and accelerating the 1–3 MeV electrons even in such low L‐shells during storms. This is the first time that the electron acceleration induced by chorus waves in the extremely low L‐shell region is reported. This new finding will help to deeply understand the electron acceleration process in radiation belt physics.
The Relation of N‐S Auroral Streamers to Auroral Expansion
Authors: McPherron R. L. , El‐Alaoui M. , Walker R. J. , Nishimura Y. , Weygand J. M.
Published: February 2020

We investigate the relation of fast flows at the inner edge of the plasma sheet to the onset of auroral expansion. Recent work suggests that nearly all expansions are an instability triggered by an auroral streamer from far out in the magnetotail. We investigate an 8‐hr interval of activity on 14 March 2008 using ground magnetometer and all‐sky camera data to determine the onset times of six substorm expansions. We compare these times with Time History of Events and Macroscale Interactions during Substorms observations of plasma flow and magnetic field. We show that every expansion followed the arrival of a fast flow and dipolarization event at the inner edge of the plasma sheet. To relate the aurora to flows, we develop procedures for removing fixed lights, the moving Moon and its reflection, and contamination due to scattered moonlight. We scan movies of enhanced images for auroral streamers. Three onsets were tentatively associated with streamers. For two, the apparent source was very close to the growth phase arc mapping close to Earth. For one, an onset occurred in the recovery phase of an earlier substorm after a double oval had formed. For this one, the end of an N‐S streamer stopped about 2° north of the breakup arc. For the remaining three expansions, no streamers were associated with the onsets. Most substorms exhibit N‐S streamers in the recovery phase. These usually cannot be associated with fast flows. Either fast flows in the growth phase do not produce streamers or they make streamers that require significant image enhancement.
Subsolar Electron Temperatures in the Lower Martian Ionosphere
Authors: Peterson W.K. , Andersson L. , Ergun R. , Thiemann Ed , Pilinski Marcin , Thaller S. , Fowler C. , Mitchell D. , Benna M. , Yelle R. , Stone Shane
Published: February 2020

Martian subsolar electron temperatures obtained below 250 km are examined using data obtained by instruments on the Mars Atmosphere Evolution Mission (MAVEN) during the three subsolar deep dip campaigns and a one‐dimensional fluid model. This analysis was done because of the uncertainty in MAVEN low electron temperature observations at low altitudes and the fact that the Level 2 temperatures reported from the MAVEN Langmuir Probe and Waves instrument are more than 400 K above the neutral temperatures at the lowest altitudes sampled (~120 km). These electron temperatures are well above those expected before MAVEN was launched. We find that an empirical normalization parameter, neutral pressure divided by local electron heating rate, organized the electron temperature data and identified a similar altitude (~160 km) and time scale (~2,000 s) for all three deep dips. We show that MAVEN data are not consistent with a plasma characterized by electrons in thermal equilibrium with the neutral population above 100 km. Because of the lack data below 120 km and the uncertainties of the data and the cross sections used in the one‐dimensional fluid model above 120 km, we cannot use MAVEN observations to prove that the electron temperature converges to the neutral temperature below 100 km. However, the uncertainty of the electron temperature altitude profile below 120 km does not impact our understanding of the role of electron temperature in determining ion escape rates because ion escape is determined by electron temperatures above 180 km.
Array‐Based Iterative Measurements of Travel Times and Their Constraints on Outermost Core Structure
Authors: Wu Wenbo , Irving Jessica C. E.
Published: February 2020

Vigorous convection in Earth's outer core led to the suggestion that it is chemically homogeneous. However, there is increasing seismic evidence for structural complexities close to the outer core's upper and lower boundaries. Both body waves and normal mode data have been used to estimate a
wave velocity,
, at the top of the outer core (the
layer), which is lower than that in the Preliminary Reference Earth Model. However, these low
models do not agree on the form of this velocity anomaly. One reason for this is the difficulty in retrieving and measuring
arrival times. To address this issue, we propose a novel approach using data from seismic arrays to iteratively measure
‐
differential travel times. This approach extracts individual
signal from mixed waveforms of the
series, allowing us to reliably measure differential travel times. We successfully use this method to measure
time delays from earthquakes in the Fiji‐Tonga and Vanuatu subduction zones.
time delays are measured by waveform cross correlation between
and
, and the cross‐correlation coefficient allows us to access measurement quality. We also apply this iterative scheme to synthetic
seismograms to investigate the 3‐D mantle structure's effects. The mantle structure corrections are not negligible for our data, and neglecting them could bias the
estimation of uppermost outer core. After mantle structure corrections, we can still see substantial time delays of
,
, and
, supporting a low
at the top of Earth's outer core.
Global‐Scale Full‐Waveform Ambient Noise Inversion
Authors: Sager Korbinian , Boehm Christian , Ermert Laura , Krischer Lion , Fichtner Andreas
Published: February 2020

We present the first application of full‐waveform ambient noise inversion to observed correlation functions that jointly constrains 3‐D Earth structure and heterogeneous noise sources. For this, we model and interpret ambient noise correlations as recordings of correlation wavefields, which completely eliminates the limiting assumptions of Green's function retrieval, such as equipartitioning and homogeneous random noise sources. Our method accounts for seismic wave propagation physics in 3‐D heterogeneous and attenuating media and also for the heterogeneous and nonstationary nature of the ambient noise field. Designed as a proof of concept, the study considers long periods from 100 to 300 s, thus focusing on the Earth's hum. Treating correlations as self‐consistent observables allows us to make separate measurements on the causal and acausal branches of correlation functions, without any need to choose one of them or form the average. We validate our approach by assessing the quality of the obtained models and by comparing them to previous studies. This work is a step toward the establishment of full‐waveform ambient noise inversion as a tomographic technique with the goal to go beyond ambient noise tomography based on Green's function retrieval.
Individual Particle Characteristics, Optical Properties and Evolution of an Extreme Long‐Range Transported Biomass Burning Event in the European Arctic (Ny‐Ålesund, Svalbard Islands)
Authors: Moroni B. , Ritter C. , Crocchianti S. , Markowicz K. , Mazzola M. , Becagli S. , Traversi R. , Krejci R. , Tunved P. , Cappelletti D.
Published: February 2020

This paper reports an exceptional biomass burning (BB) advection event from Alaska registered at Ny‐Ålesund from 10 to 17 July 2015 with particular interest on the influence of the airborne particle characteristics on the optical properties of the aerosol during the event. To this purpose we considered two DEKATI 12‐stage aerosol samples spanning the entire advection and analyzed them by scanning electron microscopy techniques. Aerosol chemical data and microphysical properties were also evaluated in order to correlate any change of individual particle characteristics with the bulk properties of the aerosol. The results of individual particle analysis depict a complex event characterized by a first phase (P1) of massive input of BB carbonaceous particles (i.e., tar balls, popcorn refractory particles, and organic particles), and by a second phase (P2) dominated by inorganic salts. The peculiar feature of this BB event is the exceptionally large grain size of the subspherical organic particles at the beginning of the event with respect to the background. At these conditions a significant increase of the scattering efficiency may occur even for a small increase of the size parameter. Results of the simulation of the complex refractive indices (n‐ik) confirm this evaluation. Aerosol evolution during the event resulted from the combination of three distinct occurrences: (a) progressive rotation of air mass circulation toward non‐BB source areas, (b) development of a thick fog layer in the planetary boundary layer, and (c) sea salt spray direct advection of local/regional provenance.
Compositions of Dust and Sea Salts in the Dome C and Dome Fuji Ice Cores From Last Glacial Maximum to Early Holocene Based on Ice‐Sublimation and Single‐Particle Measurements
Authors: Oyabu I. , Iizuka Y. , Kawamura K. , Wolff E. , Severi M. , Ohgaito R. , Abe‐Ouchi A. , Hansson M.
Published: February 2020

We analyzed the chemical compositions of dust and sea‐salt particles in the EPICA Dome C (EDC) ice core during 26–7 kyr BP using an ice‐sublimation technique and compared the results with existing data of the Dome Fuji (DF) ice core. Combined with ion concentration data, our data suggested similar sea‐salt fluxes in both cores and significantly lower dust flux in the EDC core. The differences in modal size and aspect ratio of dust particles between the two cores support the dominance of Patagonian source suggested by earlier works. The compositions of calcic dust showed major change at ~17 kyr BP, possibly reflecting a relative increase in dust transported via the upper troposphere. The calcium sulfate fraction was higher in the DF core than in the EDC core after ~17 kyr BP, suggesting that higher Patagonian dust contribution to the DF region. Abundant NaCl particles were found in the DF core in comparison with the EDC core from the LGM to early Holocene, possibly because of the high concentration of terrestrial dust in the DF core that reduced acid availability for sea‐salt modification. During the Holocene, the lower NaCl fraction and Cl−/Na+ ratio in the EDC core suggested that most Cl− was lost to the atmosphere from snow at Dome C, while it was preserved at Dome Fuji as NaCl and solid solution.
Suborbital Hydrological Variability Inferred From Coupled Benthic and Planktic Foraminiferal‐Based Proxies in the Southeastern Mediterranean During the Last 19 ka
Authors: Le Houedec S. , Mojtahid M. , Bicchi E. , de Lange G. J. , Hennekam R.
Published: February 2020

We present a high‐resolution study covering the past 19 ka from the southeastern Mediterranean Sea, based on benthic foraminiferal faunas and their stable oxygen and carbon isotopes. These data are integrated with previously published and newly acquired planktic foraminiferal data from the same sediment core in order to investigate the benthic‐planktic coupling and its response to past suborbital climate variability. On a millennial timescale, foraminiferal communities and their isotopic signatures vary following three main time periods (late glacial, sapropel S1 [~10.1–6.5 ka], and mid‐Holocene to Late Holocene). Within these intervals, we identified short‐timescale changes related to the carbon export and hydrological conditions. During the deglaciation, and except for the Younger Dryas, the coupled benthic‐planktic data indicate an overall poorly mixed water column with a low productivity. During S1 event, our data confirm the presence of a highly stratified water column, with enhanced primary productivity export to the deep sea, being associated to high Nile River activity. While the foraminiferal ecosystem is strongly driven by the combined influence of overturning circulation and the Nile River activity until the end of the African humid period, we suggest a more regional eastern Mediterranean climatic‐driven response of the foraminiferal community over the mid‐Holocene to Late Holocene. A strong multicentennial variability, probably associated to solar forcing, was found for both benthic and planktic records, and a supplementary 1,600‐year mode was found for the benthic data, suggesting a potential overturning circulation‐driven forcing for the latter.
Cooling and Vertical Motions of Crustal Wedges Prior to, During, and After Lateral Extrusion in the Eastern Alps: New Field Kinematic and Fission Track Data from the Mur‐Mürz Fault System
Authors: van Gelder I. E. , Willingshofer E. , Andriessen P. A. M. , Schuster R. , Sokoutis D.
Published: February 2020

New structural and thermochronological (zircon and apatite fission track) data from the eastern most Alps highlight distinct deformation phases affecting the Austroalpine unit along a major sinistral strike‐slip fault system, the Mur‐Mürz fault (MMF). The data link deformation to vertical motions prior to, during, and after the main phase of lateral extrusion of the orogen. Zircon fission track ages document rapid (ca. 15 °C/Myr) and diachronous (eastward younging) cooling and rock exhumation during the latest Cretaceous to Paleocene. Subsequent regional Eocene to early Miocene cooling below the closure temperature of the apatite fission track system occurred at slow rates (ca. 2 °C/Myr), suggesting that the region was not subject to major surface uplift and erosion during that period. Fault kinematic analysis along the MMF document pre‐extrusion NNW‐SSE contraction, middle Miocene syn‐extrusion NE‐SW to NNE‐SSW directed shortening, and Late Miocene E‐W contraction. All phases are characterized by strike‐slip fault regimes. Formation of the complex MMF zone triggered the exhumation of small, fault‐bound crustal blocks within the fault zone as documented by middle Miocene apatite fission track ages. Overall, ages are similar on both sides of the fault suggesting that lateral extrusion along the MMF was not associated with significant differential vertical motions. Local Pliocene rock cooling and exhumation was probably related to the buttressing effect of the underthrust Bohemian basement spur. Whereas large‐scale, post‐extrusion surface uplift of the extruding crustal wedges, such as the “Styrian block,” must have been related to long‐wavelength deformation processes affecting the easternmost Alps.
Experimental Estimates of Optical Backscattering Associated With Submicron Particles in Clear Oceanic Waters
Authors: Zhang Xiaodong , Hu Lianbo , Xiong Yuanheng , Huot Yannick , Gray Deric
Published: February 2020

The volume scattering functions for bulk and two submicron size fractions (passing through 0.7 μm GF/F and 0.2 μm membrane filters) were measured in the North Pacific Ocean using a LISST‐VSF to assess the contributions by submicron particles to the overall particle scattering. The contribution by submicron particles increased generally with scattering angle and peaked around 110°. The total backscattering by both submicron fractions did not vary, but that by larger particles increased, with the trophic level. Consequently, the fractional backscattering contribution by submicron particles decreased from approximately 50% to 30% as the chlorophyll‐a concentration increased from <0.1 to 0.3 mg m−3. Despite the experiment covering a limited range of trophic levels, our results confirm that backscattering by submicron particles in clear ocean waters is significant and seems to form a background independent of the backscattering by larger particles.
PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma
Authors: Soni Himanshu , Bode Julia , Nguyen Chi D. L. , Puccio Laura , Neßling Michelle , Piro Rosario M. , Bub Jonas , Phillips Emma , Ahrends Robert , Eipper Betty A. , Tews Björn , Goidts Violaine
Published: February 2020

PKR-like kinase (PERK) plays a significant role in inducing angiogenesis in various cancer types including glioblastoma. By proteomics analysis of the conditioned medium from a glioblastoma cell line treated with a PERK inhibitor, we showed that peptidylglycine α-amidating monooxygenase (PAM) expression is regulated by PERK under hypoxic conditions. Moreover, PERK activation via CCT020312 (a PERK selective activator) increased the cleavage and thus the generation of PAM cleaved cytosolic domain (PAM sfCD) that acts as a signaling molecule from the cytoplasm to the nuclei. PERK was also found to interact with PAM, suggesting a possible involvement in the generation of PAM sfCD. Knockdown of PERK or PAM reduced the formation of tubes by HUVECs in vitro. Furthermore, in vivo data highlighted the importance of PAM in the growth of glioblastoma with reduction of PAM expression in engrafted tumor significantly increasing the survival in mice. In summary, our data revealed PAM as a potential target for antiangiogenic therapy in glioblastoma.
Developments in continuous therapy and maintenance treatment approaches for patients with newly diagnosed multiple myeloma
Authors: Dimopoulos Meletios A. , Jakubowiak Andrzej J. , McCarthy Philip L. , Orlowski Robert Z. , Attal Michel , Bladé Joan , Goldschmidt Hartmut , Weisel Katja C. , Ramasamy Karthik , Zweegman Sonja , Spencer Andrew , Huang Jeffrey S. Y. , Lu Jin , Sunami Kazutaka , Iida Shinsuke , Chng Wee-Joo , Holstein Sarah A. , Rocci Alberto , Skacel Tomas , Labotka Richard , Palumbo Antonio , Anderson Kenneth C.
Published: February 2020

The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. “Continuous therapy” commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients’ quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.
Epigenetic specifications of host chromosome docking sites for latent Epstein-Barr virus
Authors: Kim Kyoung-Dong , Tanizawa Hideki , De Leo Alessandra , Vladimirova Olga , Kossenkov Andrew , Lu Fang , Showe Louise C. , Noma Ken-ichi , Lieberman Paul M.
Published: February 2020

Epstein-Barr virus (EBV) genomes persist in latently infected cells as extrachromosomal episomes that attach to host chromosomes through the tethering functions of EBNA1, a viral encoded sequence-specific DNA binding protein. Here we employ circular chromosome conformation capture (4C) analysis to identify genome-wide associations between EBV episomes and host chromosomes. We find that EBV episomes in Burkitt’s lymphoma cells preferentially associate with cellular genomic sites containing EBNA1 binding sites enriched with B-cell factors EBF1 and RBP-jK, the repressive histone mark H3K9me3, and AT-rich flanking sequence. These attachment sites correspond to transcriptionally silenced genes with GO enrichment for neuronal function and protein kinase A pathways. Depletion of EBNA1 leads to a transcriptional de-repression of silenced genes and reduction in H3K9me3. EBV attachment sites in lymphoblastoid cells with different latency type show different correlations, suggesting that host chromosome attachment sites are functionally linked to latency type gene expression programs.
FMN reduces Amyloid-β toxicity in yeast by regulating redox status and cellular metabolism
Authors: Chen Xin , Ji Boyang , Hao Xinxin , Li Xiaowei , Eisele Frederik , Nyström Thomas , Petranovic Dina
Published: February 2020

Alzheimer’s disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-β peptides (Aβ) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce Aβ42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH + NAD+) and NADPH/(NADPH + NADP+) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and α-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of Aβ42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.
A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity
Authors: Nelson Louisa , Tighe Anthony , Golder Anya , Littler Samantha , Bakker Bjorn , Moralli Daniela , Murtuza Baker Syed , Donaldson Ian J. , Spierings Diana C. J. , Wardenaar René , Neale Bethanie , Burghel George J. , Winter-Roach Brett , Edmondson Richard , Clamp Andrew R. , Jayson Gordon C. , Desai Sudha , Green Catherine M. , Hayes Andy , Foijer Floris , Morgan Robert D. , Taylor Stephen S.
Published: February 2020

High-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a “living biobank” of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making.
A conserved strategy of chalcone isomerase-like protein to rectify promiscuous chalcone synthase specificity
Authors: Waki Toshiyuki , Mameda Ryo , Nakano Takuya , Yamada Sayumi , Terashita Miho , Ito Keisuke , Tenma Natsuki , Li Yanbing , Fujino Naoto , Uno Kaichi , Yamashita Satoshi , Aoki Yuichi , Denessiouk Konstantin , Kawai Yosuke , Sugawara Satoko , Saito Kazuki , Yonekura-Sakakibara Keiko , Morita Yasumasa , Hoshino Atsushi , Takahashi Seiji , Nakayama Toru
Published: February 2020

Land plants produce diverse flavonoids for growth, survival, and reproduction. Chalcone synthase is the first committed enzyme of the flavonoid biosynthetic pathway and catalyzes the production of 2′,4,4′,6′-tetrahydroxychalcone (THC). However, it also produces other polyketides, including p-coumaroyltriacetic acid lactone (CTAL), because of the derailment of the chalcone-producing pathway. This promiscuity of CHS catalysis adversely affects the efficiency of flavonoid biosynthesis, although it is also believed to have led to the evolution of stilbene synthase and p-coumaroyltriacetic acid synthase. In this study, we establish that chalcone isomerase-like proteins (CHILs), which are encoded by genes that are ubiquitous in land plant genomes, bind to CHS to enhance THC production and decrease CTAL formation, thereby rectifying the promiscuous CHS catalysis. This CHIL function has been confirmed in diverse land plant species, and represents a conserved strategy facilitating the efficient influx of substrates from the phenylpropanoid pathway to the flavonoid pathway.
Improved betulinic acid biosynthesis using synthetic yeast chromosome recombination and semi-automated rapid LC-MS screening
Authors: Gowers G.-O. F. , Chee S. M. , Bell D. , Suckling L. , Kern M. , Tew D. , McClymont D. W. , Ellis T.
Published: February 2020

Synthetic biology, genome engineering and directed evolution offer innumerable tools to expedite engineering of strains for optimising biosynthetic pathways. One of the most radical is SCRaMbLE, a system of inducible in vivo deletion and rearrangement of synthetic yeast chromosomes, diversifying the genotype of millions of Saccharomyces cerevisiae cells in hours. SCRaMbLE can yield strains with improved biosynthetic phenotypes but is limited by screening capabilities. To address this bottleneck, we combine automated sample preparation, an ultra-fast 84-second LC-MS method, and barcoded nanopore sequencing to rapidly isolate and characterise the best performing strains. Here, we use SCRaMbLE to optimise yeast strains engineered to produce the triterpenoid betulinic acid. Our semi-automated workflow screens 1,000 colonies, identifying and sequencing 12 strains with between 2- to 7-fold improvement in betulinic acid titre. The broad applicability of this workflow to rapidly isolate improved strains from a variant library makes this a valuable tool for biotechnology.
Glucose, Cyc8p and Tup1p regulate biofilm formation and dispersal in wild Saccharomyces cerevisiae
Authors: Van Nguyen Phu , Plocek Vítězslav , Váchová Libuše , Palková Zdena
Published: February 2020

Saccharomyces cerevisiae is a mainly beneficial yeast, widely used in the food industry. However, there is growing evidence of its potential pathogenicity, leading to fungemia and invasive infections. The medical impact of yeast pathogens depends on formation of biofilms: multicellular structures, protected from the environment. Cell adhesion is a prerequisite of biofilm formation. We investigated the adherence of wild and genetically modified S. cerevisiae strains, formation of solid–liquid interface biofilms and associated regulation. Planktonic and static cells of wild strain BRF adhered and formed biofilms in glucose-free medium. Tup1p and Cyc8p were key positive and negative regulators, respectively. Glucose caused increased Cyc8p levels and blocked cell adhesion. Even low glucose levels, comparable with levels in the blood, allowed biofilm dispersal and release of planktonic cells. Cyc8p could thus modulate cell adhesion in different niches, dependently on environmental glucose level, e.g., high-glucose blood versus low-glucose tissues in host organisms.
Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk
Authors: Jacinta-Fernandes Ana , Xavier Joana M. , Magno Ramiro , Lage Joel G. , Maia Ana-Teresa
Published: February 2020

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed tocis-regulate the expression of genes. We hypothesise thatcis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms—TargetScan and miRanda—to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ($$P\le 5\times {10}^{-8}$$P≤5×10−8) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3′-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we proposeRNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediatedcis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supportingcis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.
The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia
Authors: Castello Julia , Cortés Marisol , Malave Lauren , Kottmann Andreas , Sibley David R. , Friedman Eitan , Rebholz Heike
Published: February 2020

The dopamine D5 receptor (D5R) is a Gαs-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.
Quantifying residue-specific conformational dynamics of a highly reactive 29-mer peptide
Authors: Lindemann William R. , Evans Ethan D. , Mijalis Alexander J. , Saouaf Olivia M. , Pentelute Bradley L. , Ortony Julia H.
Published: February 2020

Understanding structural transitions within macromolecules remains an important challenge in biochemistry, with important implications for drug development and medicine. Insight into molecular behavior often requires residue-specific dynamics measurement at micromolar concentrations. We studied MP01-Gen4, a library peptide selected to rapidly undergo bioconjugation, by using electron paramagnetic resonance (EPR) to measure conformational dynamics. We mapped the dynamics of MP01-Gen4 with residue-specificity and identified the regions involved in a structural transformation related to the conjugation reaction. Upon reaction, the conformational dynamics of residues near the termini slow significantly more than central residues, indicating that the reaction induces a structural transition far from the reaction site. Arrhenius analysis demonstrates a nearly threefold decrease in the activation energy of conformational diffusion upon reaction (8.0 kBT to 3.4 kBT), which occurs across the entire peptide, independently of residue position. This novel approach to EPR spectral analysis provides insight into the positional extent of disorder and the nature of the energy landscape of a highly reactive, intrinsically disordered library peptide before and after conjugation.
Waterfowl occurrence and residence time as indicators of H5 and H7 avian influenza in North American Poultry
Authors: Humphreys John M. , Ramey Andrew M. , Douglas David C. , Mullinax Jennifer M. , Soos Catherine , Link Paul , Walther Patrick , Prosser Diann J.
Published: February 2020

Avian influenza (AI) affects wild aquatic birds and poses hazards to human health, food security, and wildlife conservation globally. Accordingly, there is a recognized need for new methods and tools to help quantify the dynamic interaction between wild bird hosts and commercial poultry. Using satellite-marked waterfowl, we applied Bayesian joint hierarchical modeling to concurrently model species distributions, residency times, migration timing, and disease occurrence probability under an integrated animal movement and disease distribution modeling framework. Our results indicate that migratory waterfowl are positively related to AI occurrence over North America such that as waterfowl occurrence probability or residence time increase at a given location, so too does the chance of a commercial poultry AI outbreak. Analyses also suggest that AI occurrence probability is greatest during our observed waterfowl northward migration, and less during the southward migration. Methodologically, we found that when modeling disparate facets of disease systems at the wildlife-agriculture interface, it is essential that multiscale spatial patterns be addressed to avoid mistakenly inferring a disease process or disease-environment relationship from a pattern evaluated at the improper spatial scale. The study offers important insights into migratory waterfowl ecology and AI disease dynamics that aid in better preparing for future outbreaks.
An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity
Authors: Peytam Fariba , Adib Mehdi , Shourgeshty Reihaneh , Firoozpour Loghman , Rahmanian-Jazi Mahmoud , Jahani Mehdi , Moghimi Setareh , Divsalar Kouros , Faramarzi Mohammad Ali , Mojtabavi Somayeh , Safari Fatemeh , Mahdavi Mohammad , Foroumadi Alireza
Published: February 2020

In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones.
Instability Resistance Training improves Working Memory, Processing Speed and Response Inhibition in Healthy Older Adults: A Double-Blinded Randomised Controlled Trial
Authors: Eckardt Nils , Braun Claudia , Kibele Armin
Published: February 2020

Aging is associated with declines in physical and cognitive performance. While there is no doubt about beneficial effects of physical exercise on proxies of strength and balance, the overall evidence for positive effects of resistance and balance training on executive functions is rather inconsistent. Whether the simultaneous exercising of strength and balance, i.e., instability resistance training, promotes executive functions in older adults is unknown. In the present trial, we tested the effects of unstable vs. stable resistance training on executive functions. Sixty-eight healthy older adults aged 65–79 years were randomly assigned to either an instability free-weight resistance training or one of two stable machine-based resistance training programs. Each group exercised twice a week on non-consecutive days for 10 weeks. Four tests to evaluate specific domains of executive functions were administered prior and following training: working memory, processing speed, response inhibition and set-shifting. The instability resistance training group improved working memory, processing speed and response inhibition from pre to post-test. In contrast, we found no improvements in executive functions for both stable resistance training groups. Our results demonstrate that 10 weeks of instability resistance training suffice to improve executive functions in older adults.
Climate model variability leads to uncertain predictions of the future abundance of stream macroinvertebrates
Authors: Kakouei Karan , Domisch Sami , Kiesel Jens , Kail Jochem , Jähnig Sonja C.
Published: February 2020

Climate change has the potential to alter the flow regimes of rivers and consequently affect the taxonomic and functional diversity of freshwater organisms. We modeled future flow regimes for the 2050 and 2090 time horizons and tested how flow regimes impact the abundance of 150 macroinvertebrate species and their functional trait compositions in one lowland river catchment (Treene) and one mountainous river catchment (Kinzig) in Europe. We used all 16 global circulation models (GCMs) and regional climate models (RCMs) of the CORDEX dataset under the RCP 8.5 scenario to calculate future river flows. The high variability in relative change of flow among the 16 climate models cascaded into the ecological models and resulted in substantially different predicted abundance values for single species. This variability also cascades into any subsequent analysis of taxonomic or functional freshwater biodiversity. Our results showed that flow alteration effects are different depending on the catchment and the underlying species pool. Documenting such uncertainties provides a basis for the further assessment of potential climate-change impacts on freshwater taxa distributions.
Machine Learning Algorithms for Predicting the Recurrence of Stage IV Colorectal Cancer After Tumor Resection
Authors: Xu Yucan , Ju Lingsha , Tong Jianhua , Zhou Cheng-Mao , Yang Jian-Jun
Published: February 2020

The aim of this study is to explore the feasibility of using machine learning (ML) technology to predict postoperative recurrence risk among stage IV colorectal cancer patients. Four basic ML algorithms were used for prediction—logistic regression, decision tree, GradientBoosting and lightGBM. The research samples were randomly divided into a training group and a testing group at a ratio of 8:2. 999 patients with stage 4 colorectal cancer were included in this study. In the training group, the GradientBoosting model’s AUC value was the highest, at 0.881. The Logistic model’s AUC value was the lowest, at 0.734. The GradientBoosting model had the highest F1_score (0.912). In the test group, the AUC Logistic model had the lowest AUC value (0.692). The GradientBoosting model’s AUC value was 0.734, which can still predict cancer progress. However, the gbm model had the highest AUC value (0.761), and the gbm model had the highest F1_score (0.974). The GradientBoosting model and the gbm model performed better than the other two algorithms. The weight matrix diagram of the GradientBoosting algorithm shows that chemotherapy, age, LogCEA, CEA and anesthesia time were the five most influential risk factors for tumor recurrence. The four machine learning algorithms can each predict the risk of tumor recurrence in patients with stage IV colorectal cancer after surgery. Among them, GradientBoosting and gbm performed best. Moreover, the GradientBoosting weight matrix shows that the five most influential variables accounting for postoperative tumor recurrence are chemotherapy, age, LogCEA, CEA and anesthesia time.
Continued versus Suspended Cardiac Resynchronization Therapy after Left Ventricular Assist Device Implantation
Authors: Roukoz Henri , Bhan Adarsh , Ravichandran Ashwin , Ahmed Mustafa M. , Bhat Geetha , Cowger Jennifer , Abdullah Munazzah , Dhawan Rahul , Trivedi Jaimin R. , Slaughter Mark S. , Gopinathannair Rakesh
Published: February 2020

Cardiac resynchronization therapy (CRT) improves outcomes in heart failure patients with wide QRS complex. However, CRT management following continuous flow Left Ventricular Assist Device (LVAD) implant vary: some centers continue CRT while others turn off the left ventricular (LV) lead at LVAD implant. We sought to study the effect of continued CRT versus turning off CRT pacing following continuous flow LVAD implantation. A comprehensive retrospective multicenter cohort of 295 patients with LVAD and pre-existing CRT was studied. CRT was programmed off after LVAD implant in 44 patients. We compared their outcomes to the rest of the cohort using univariate and multivariate models. Mean age was 60 ± 12 years, 83% were males, 52% had ischemic cardiomyopathy and 54% were destination therapy. Mean follow-up was 2.4 ± 2.0 years, and mean LVAD support time was 1.7 ± 1.4 years. Patients with CRT OFF had a higher Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) mean profile (3.9 vs 3.3, p = 0.01), more secondary prevention indication for a defibrillator (64.9% vs 44.5%, p = 0.023), and more pre-LVAD ventricular arrhythmias (VA) (77% vs 60%, p = 0.048). There were no differences between the CRT OFF and CRT ON groups in overall mortality (Log rank p = 0.32, adjusted HR = 1.14 [0.54–2.22], p = 0.71), heart transplantation, cardiac and noncardiac mortality, all cause hospitalizations, hospitalizations for ICD shocks, and number and frequency of ICD shocks or anti-tachycardia pacing therapy. There were no differences in post LVAD atrial arrhythmias (AA) (Adjusted OR = 0.45 [0.18–1.06], p = 0.31) and ventricular arrhythmias (OR = 0.65 [0.41–1.78], p = 0.41). There was no difference in change in LVEF, LV end diastolic and end systolic diameters between the 2 groups. Our study suggests that turning off CRT pacing after LVAD implantation in patients with previous CRT pacing did not affect mortality, heart transplantation, device therapies or arrhythmia burden. A prospective study is needed to confirm these findings.
Observer-Agent Kinematic Similarity Facilitates Action Intention Decoding
Authors: De Marco Doriana , Scalona Emilia , Bazzini Maria Chiara , Avanzini Pietro , Fabbri-Destro Maddalena
Published: February 2020

It is well known that the kinematics of an action is modulated by the underlying motor intention. In turn, kinematics serves as a cue also during action observation, providing hints about the intention of the observed action. However, an open question is whether decoding others’ intentions on the basis of their kinematics depends solely on how much the kinematics varies across different actions, or rather it is also influenced by its similarity with the observer motor repertoire. The execution of reach-to-grasp and place actions, differing for target size and context, was recorded in terms of upper-limb kinematics in 21 volunteers and in an actor. Volunteers had later to observe the sole reach-to-grasp phase of the actor’s actions, and predict the underlying intention. The potential benefit of the kinematic actor-participant similarity for recognition accuracy was evaluated. In execution, both target size and context modulated specific kinematic parameters. More importantly, although participants performed above chance in intention recognition, the similarity of motor patterns positively correlated with recognition accuracy. Overall, these data indicate that kinematic similarity exerts a facilitative role in intention recognition, providing further support to the view of action intention recognition as a visuo-motor process grounded in motor resonance.