bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hydrological Cycle and Climate
Authors: Dolman Han
Published: June 2019

Water is a key part of the Earth system and interacts with climate through a variety of mechanisms. The chapter initially describes the effect of atmospheric moisture on the lapse rate and then discusses cloud formation and the main global reservoirs and fluxes, including precipitation, and discharge into the oceans. Atmospheric transport of water vapour, together with its relation to precipitation, is then discussed. It is shown that meridional transport can occur with a few very strong events, through atmospheric rivers. The difference between evaporation over the ocean and that over land is shown, with the help of data from Earth observation satellites, and the recycling of water is shown to depend very much on locality. Finally, the importance of frozen water on climate is described, using the recent decrease in Arctic sea ice, and the variability in ice sheet extent and consequent sea levels during the Last Glacial Maximum.
What Is the Case against Muslims?
Authors: Huq Aziz Z.
Published: June 2019

Widespread aversive sentiment against Muslim co-citizens and migrants persists among the European and American publics. On both sides of the Atlantic, new political formations have challenged established parties by leveraging recent exogenous shocks—economic crisis, migration surge, and terrorism wave—to stake a claim for political power on avowedly anti-Muslim grounds. For now, naked appeals to animus remain exceptional. Instead, specific disputes or policy disagreements work as prisms. They refract and blend anti-Muslim sentiment into larger, more neutral, and broadly appealing justifications. This chapter examines this ideological and political conjunction through the lens of three specific policy disputes, each of which conjoins anti-Muslim sentiment with a neutral political principle. These disputes concern the veil, the mosque, and the terrorist profile. Respectively, these disputes integrate anti-Muslim policy vectors into the programmatic aims of securing liberal freedoms, national culture, and public order: Ambitions that can be invoked without a superficial taint of animus. Close examination of the terms of each of these public debates, however, reveals unravelling inconsistencies and internal contradictions. The actual behaviour or beliefs of Muslims have little purchase within these arguments. A naturalized category of “Muslims” with affinities to anti-Jews and anti-black stereotypes, instead does intellectual work. As a result, each of the three goals avowedly pursued in anti-Muslim polemicals—liberalism, national culture, and public order—can be conditionally embraced, and can further conduce to rejections of specific anti-Muslim positions. The chapter concludes by considering whether an insistence on the mundane and the empirical, rather than the symbolic, is a viable political strategy.
Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation
Authors: Jayabalan Aravinth Kumar , Griffin Diane E. , Leung Anthony K. L.
Published: June 2019

Formation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1. We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADP-ribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions.
Increasing pulse energy of 5Hz rTMS improves its efficacy in inducing excitatory aftereffects
Authors: Halawa I , Reichert K , Anil S , Sommer M , Paulus W
Published: June 2019

Introduction

High frequency repetitive transcranial magnetic stimulation induces excitation when applied to the motor cortex as reflected by the increase MEP amplitudes after the stimulation. The effects differ according to pulse width, probably due to higher content of energy in the wider pulses and their ability to cause wider activation in comparison to shorter pulse shapes. Here we focus on the aftereffects generated with high frequency controllable pulse TMS (cTMS) with different pulse widths.

Objectives

To investigate the influence of pulse energy by using different stimulation intensities and pulse widths on the excitatory plastic aftereffects of high frequency (HF) rTMS.

Methods

Using a controllable pulse stimulator TMS (cTMS), we stimulated the hand motor cortex with 5 Hz rTMS applying 1200 bidirectional pulses with the main component widths of 80, 100 and 120 microseconds. 14 healthy subjects were initially investigated for six randomized sessions first with 80% RMT for anterior-posterior (AP) and posterior-anterior (PA). Then three more sessions using same pulse widths were added for 90% RMT anterior-posterior (AP).

Results

80% HF rTMS did not produce any significant excitation in either AP or PA direction. 90% RMT AP stimulation with 100 and 120 microsecond-wide pulses were more excitatory, when compared to the 80 microsecond-wide pulses. We also found a correlation between the individual pulse energy and the plastic outcome of each session.

Conclusions

HF rTMS with wider pulses is more effective in producing excitatory aftereffects, an effect that correlated with the higher energy content of wider pulses and higher intensity.

Significance

The findings here suggest that wider pulses are capable of inducing more excitation, a fact that could contribute to better results in future clinical studies performed with wider pulses.
Guillain-Barre syndrome outbreak in Peru: Association with polymorphisms in IL-17, ICAM-1 and CD1
Authors: Jaramillo-Valverde Luis , Levano Kelly S , Villanueva Isolina , Hidalgo Meylin , Cornejo Marco , Mazzetti Pilar , Cornejo-Olivas Mario , Sanchez Cesar , Poterico Julio A , Valdivia-Silva Julio , Guio Heinner
Published: June 2019

Guillain-Barre Syndrome (GBS) is considered a complex disorder with significant environmental effect and genetic susceptibility. Genetic polymorphisms in CD1E, CD1A, IL-17 and/or ICAM-1 genes had been proposed as susceptibility genetic variants for GBS mainly in Caucasian population. This study explores the association between selected polymorphisms in these genes and GBS susceptibility in confirmed GBS cases reported in mestizo population from northern Peru during the most recent GBS outbreak of May 2018. A total of 9 non-related cases and 11 controls were sequenced for the polymorphic regions of CD1A, CD1E, IL-17 and ICAM-1 genes. We found a significant protective association between heterozygous GA genotype in ICAM-1 gene (241Gly / Arg) and GBS (p <0.047). IL-17 was monomorphic in both controls and patients. No significant differences were found in the frequency of SNPs in CD1A and CD1E between the group with GBS patients and healthy controls. Further studies with larger sample size will be required to validate these findings.
Hybrid histidine kinase activation by cyclic di-GMP-mediated domain liberation
Authors: Dubey Badri N. , Agustoni Elia , Böhm Raphael , Kaczmarczyk Andreas , Mangia Francesca , von Arx Christoph , Jenal Urs , Hiller Sebastian , Plaza-Menacho Iván , Schirmer Tilman
Published: June 2019

Cytosolic hybrid histidine kinases (HHKs) constitute major signalling nodes that control various biological processes, but their input signals and how these are processed are largely unknown. InCaulobacter crescentus, the HHK ShkA is essential for accurate timing of the G1-S cell cycle transition and is regulated by the corresponding increase in the level of the second messenger c-di-GMP. Here, we use a combination of X-ray crystallography, NMR spectroscopy, functional analyses and kinetic modelling to reveal the regulatory mechanism of ShkA. In the absence of c-di-GMP, ShkA predominantly adopts a compact domain arrangement that is catalytically inactive. C-di-GMP binds to the dedicated pseudo-receiver domain Rec1 thereby liberating the canonical Rec2 domain from its central position where it obstructs the large-scale motions required for catalysis. Thus, c-di-GMP cannot only stabilize domain interactions, but also engage in domain dissociation to allosterically control activity. Enzyme kinetics data are consistent with conformational selection of the ensemble of active domain constellations by the ligand.
A Hidden Markov Modeling Approach for Identifying Tumor Subclones in Next-Generation Sequencing Studies
Authors: Choo-Wosoba Hyoyoung , Albert Paul S. , Zhu Bin
Published: June 2019

Allele-specific copy number alteration (ASCNA) analysis is for identifying copy number abnormalities in tumor cells. Unlike normal cells, tumor cells are heterogeneous as a combination of dominant and minor subclones with distinct copy number profiles. Estimating the clonal proportion and identifying mainclone and subclone genotypes across the genome is important for understanding tumor progression. Several ASCNA tools have recently been developed, but they have been limited to the identification of subclone regions, and not the genotype of subclones. In this paper, we propose subHMM, a hidden Markov model-based approach that estimates both subclone region as well as region-specific subclone genotype and clonal proportion. We specify a hidden state variable representing the conglomeration of clonal genotype and subclone status. We propose a two-step algorithm for parameter estimation, where in the first step, a standard hidden Markov model with this conglomerated state variable is fit. Then, in the second step, region-specific estimates of the clonal proportions are obtained by maximizing region-specific pseudo-likelihoods. We apply subHMM to study renal cell carcinoma datasets in The Cancer Genome Atlas. In addition, we conduct simulation studies that show the good performance of the proposed approach. The R package is available online at https://dceg.cancer.gov/tools/analysis/subhmm. somatic copy number alteration; tumor heterogeneity; E-M algorithm; forward-backward algorithm.
Disinfectant residuals in drinking water systems select for mycobacterial populations with intrinsic antimicrobial resistance
Authors: Sevillano Maria , Dai Zihan , Calus Szymon , Bautista-de los Santos Quyen M , Eren A. Murat , van der Wielen Paul W.J.J. , Ijaz Umer Z. , Pinto Ameet J.
Published: June 2019

Antimicrobial resistance (AMR) in drinking water has received less attention than counterparts in the urban water cycle. While culture-based techniques or gene-centric PCR have been used to probe the impact of treatment approaches (e.g., disinfection) on AMR in drinking water, to our knowledge there is no systematic comparison of AMR traits between disinfected and disinfectant residual-free drinking water systems. We use metagenomics to assess the associations between disinfectant residuals and AMR prevalence and its host association in full-scale drinking water distribution systems (DWDSs). The differences in AMR profiles between DWDSs are associated with the presence or absence of disinfectant. Further, AMR genes and mechanisms enriched in disinfected systems are associated with drug classes primarily linked to nontuberculous mycobacteria (NTM). Finally, evaluation of metagenome assembled genomes (MAGs) of NTM indicates that they possess AMR genes conferring intrinsic resistance to key antibiotics, whereas such NTM genomes were not detected in disinfectant residual free DWDSs. Thus, disinfection may not only influence the AMR profiles of the drinking water microbiome but also select for NTM with intrinsic AMR.
Genome assembly and characterization of a complex zfBED-NLR gene-containing disease resistance locus in Carolina Gold Select rice with Nanopore sequencing
Authors: Read Andrew C. , Moscou Matthew J. , Zimin Aleksey V. , Pertea Geo , Meyer Rachel S. , Purugganan Michael D. , Leach Jan E. , Triplett Lindsay R. , Salzberg Steven L. , Bogdanove Adam J.
Published: June 2019

Background

Long-read sequencing facilitates assembly of complex genomic regions. In plants, loci containing nucleotide-binding, leucine-rich repeat (NLR) disease resistance genes are an important example of such regions. NLR genes make up one of the largest gene families in plants and are often clustered, evolving via duplication, contraction, and transposition. We recently mapped the Xo1 locus for resistance to bacterial blight and bacterial leaf streak, found in the American heirloom rice variety Carolina Gold Select, to a region that in the Nipponbare reference genome is rich in NLR genes.

Results

Toward identification of the Xo1 gene, we combined Nanopore and Illumina reads to generate a high-quality genome assembly for Carolina Gold Select. We identified 529 full or partial NLR genes and discovered, relative to the reference, an expansion of NLR genes at the Xo1 locus. One NLR gene at Xo1 has high sequence similarity to the cloned, functionally similar Xa1 gene. Both harbor an integrated zfBED domain and near-identical, tandem, C-terminal repeats. Across diverse Oryzeae, we identified two sub-clades of such NLR genes, varying in the presence of the zfBED domain and the number of repeats.

Conclusions

Whole genome sequencing combining Nanopore and Illumina reads effectively resolves NLR gene loci, providing context as well as content. Our identification of an Xo1 candidate is an important step toward mechanistic characterization, including the role(s) of the zfBED domain. Further, the Carolina Gold Select genome assembly will facilitate identification and exploitation of other useful traits in this historically important rice variety.
Redox-mediated Kick-Start of Mitochondrial Energy Metabolism drives Resource-efficient Seed Germination
Authors: Nietzel Thomas , Mostertz Jörg , Ruberti Cristina , Wagner Stephan , Moseler Anna , Fuchs Philippe , Müller-Schüssele Stefanie J. , Benamar Abdelilah , Poschet Gernot , Büttner Michael , Née Guillaume , Møller Ian Max , Lillig Christopher H. , Macherel David , Finkemeier Iris , Wirtz Markus , Hell Rüdiger , Meyer Andreas J. , Hochgräfe Falko , Schwarzländer Markus
Published: June 2019

Seeds preserve a far developed plant embryo in a quiescent state. Seed metabolism relies on stored resources and is re-activated to drive germination when the external conditions are favorable. Since the switchover from quiescence to re-activation provides a remarkable case of a cell physiological transition we investigated the earliest events in energy and redox metabolism ofArabidopsisseeds at imbibition. By developing fluorescent protein biosensing in intact seeds, we observed ATP accumulation and oxygen uptake within minutes, indicating rapid activation of mitochondrial respiration, which coincided with a sharp transition from an oxidizing to a more reducing thiol redox environment in the mitochondrial matrix. To identify individual operational protein thiol switches, we captured the fast release of metabolic quiescencein organelloand devised quantitative iodoacetyl tandem mass tag-based (iodoTMT) thiol redox proteomics. The redox state across all Cys-peptides was shifted towards reduction from 27.1 % to 13.0 %. A large number of Cys-peptides (412) were redox-switched, representing central pathways of mitochondrial energy metabolism, including the respiratory chain and each enzymatic step of the tricarboxylic acid cycle (TCA). Active site Cys-peptides of glutathione reductase 2, NADPH-thioredoxin reductase a/b and thioredoxin-o1 showed the strongest responses. Germination of seeds lacking those redox proteins was associated with markedly enhanced respiration and deregulated TCA cycle dynamics suggesting decreased resource efficiency of energy metabolism. Germination in aged seeds was strongly impaired. We identify a global operation of thiol redox switches that is required for optimal usage of energy stores by the mitochondria to drive efficient germination.
Gene Loss and Evolution of the Plastome
Authors: Mohanta Tapan Kumar , Mishra Awdhesh Kumar , Khan Adil , Hashem Abeer , Abd_Allah Elsayed Fathi , Al-Harrasi Ahmed
Published: June 2019

Chloroplasts are unique organelles within the plant cells and are responsible for sustaining life forms on the earth due to their ability to conduct photosynthesis. Multiple functional genes within the chloroplast are responsible for a variety of metabolic processes that occur in the chloroplast. Considering its fundamental role in sustaining life on the earth, it is important to identify the level of diversity present in the chloroplast genome, what genes and genomic content have been lost, what genes have been transferred to the nuclear genome, duplication events, and the overall origin and evolution of the chloroplast genome. Our analysis of 2511 chloroplast genomes indicated that the genome size and number of coding DNA sequences (CDS) in the chloroplasts genome of algae are higher relative to other lineages. Approximately 10.31% of the examined species have lost the inverted repeats (IR) in the chloroplast genome that span across all the lineages. Genome-wide analyses revealed the loss of the Rbcl gene in parasitic and heterotrophic plants occurred approximately 56 Ma ago. PsaM, Psb30, ChlB, ChlL, ChlN, and Rpl21 were found to be characteristic signature genes of the chloroplast genome of algae, bryophytes, pteridophytes, and gymnosperms; however, none of these genes were found in the angiosperm or magnoliid lineage which appeared to have lost them approximately 203–156 Ma ago. A variety of chloroplast-encoded genes were lost across different species lineages throughout the evolutionary process. The Rpl20 gene, however, was found to be the most stable and intact gene in the chloroplast genome and was not lost in any of the analyzed species, suggesting that it is a signature gene of the plastome. Our evolutionary analysis indicated that chloroplast genomes evolved from multiple common ancestors ~1293 Ma ago and have undergone vivid recombination events across different taxonomic lineages.
How does individual variation in sociality influence fitness in prairie voles?
Authors: Sabol Anne C. , Lambert Connor T. , Keane Brian , Solomon Nancy G. , Dantzer Ben
Published: June 2019

Comparative studies aid in our understanding of specific conditions favoring the initial evolution of different types of social behaviors, yet there is much unexplained intraspecific variation in the expression of social behavior that comparative studies have not yet addressed. The proximate causes of this individual variation in social behavior within a species have been examined in some species but its fitness consequences have been less frequently investigated. In this study, we quantified the fitness consequences of variation in the sociality of prairie voles (Microtus ochrogaster). We characterized sociality of voles in semi-natural enclosures using an automated behavioral tracking system paired with social network analyses to quantify the degree of spatial and temporal co-occurrence of different voles. We then assessed the relationship between sociality with mating success (number of different conspecifics with which an individual produced offspring) and reproductive success (total number of offspring surviving to first capture). We measured the number of social connections each individual had with all voles and only with opposite-sex voles by calculating unweighted degree through social network analyses. Both female and male voles varied in the number of social connections they had with all conspecifics and with opposite-sex conspecifics. Voles with an intermediate number of social connections with voles of both sexes had higher mating success overall. In our analyses that considered all social connections with voles of both sexes, voles with an intermediate number of social connections produced more offspring. Males with a very high or low number of social connections also had the lowest average body mass. Overall, our results suggest some limit on the fitness benefits of sociality. Although there was substantial individual-variation in our measure of vole social behavior, intermediate levels of social connections may be most favorable.
Scale-dependent effects of geography, host ecology, and host genetics on diversity of a stickleback parasite metacommunity
Authors: Bolnick Daniel I. , Resetarits Emlyn J. , Ballare Kimberly , Stuart Yoel E. , Stutz William E.
Published: June 2019

Many metacommunities are distributed across habitat patches that are themselves aggregated into groups. Perhaps the clearest example of this nested metacommunity structure comes from multi-species parasite assemblages, which occupy individual hosts that are aggregated into host populations. At both spatial scales, we expect parasite community diversity in a given patch (either individual host or population) to depend on patch characteristics that affect colonization rates and species sorting. But, are these patch effects consistent across spatial scales? Or, do different processes govern the distribution of parasite community diversity among individual hosts, versus among host patches? To answer these questions, we document the distribution of parasite richness among host individuals and among populations in a metapopulation of threespine stickleback (Gasterosteus aculeatus). We find some host traits (host size, gape width) are associated with increased parasite richness at both spatial scales. Other patch characteristics affect parasite richness only among individuals (sex), or among populations (lake size, lake area, elevation, and population mean heterozygosity). These results demonstrate that some rules governing parasite richness in this metacommunity are shared across scales, while others are scale-specific.
EpiSort: Enumeration of cell types using targeted bisulfite sequencing
Authors: Aran Dvir , Dover Ron S. , Lundy Karen E. , Leipold Michael D. , Xuhuai Ji , McDevitt Shana L. , Davis Mark M. , Butte Atul J.
Published: June 2019

The cellular composition of tumors is now recognized as an essential phenotype, with implications to diagnostic, progression and therapy efficacy. A tool for accurate profiling of the tumor microenvironment is lacking, as single-cell methods and computational approaches are not applicable or suffer from low accuracy. Here we present EpiSort, a novel strategy based on targeted bisulfite sequencing, which allows the accurate enumeration of 23 cell types and may be applicable to cancer studies.
The C-terminal non-catalytic domain of Mkp-1 phosphatase harbors a complex signal for rapid proteasome degradation in enterocytes
Authors: Wang Jin , Grishin Anatoly , Delaplain Patrick T. , Gayer Christopher P. , Ford Henri R.
Published: June 2019

Mitogen-activated kinase phosphatase Mkp-1 is an essential negative regulator of innate immune responses. In enterocytes, Mkp-1, which is transiently expressed in response to Toll-like receptor (TLR) ligands, plays a role as an initial step in establishing tolerance to bacteria and their pro-inflammatory molecules. Mkp-1 has a very short half-life (about 30 min) in IEC-6 enterocytes. Here we examined the mechanism of Mkp-1 rapid degradation in IEC-6 cells. Immunoprecipitation and proteolysis inhibitor analysis indicated that Mkp-1 is monoubiquitinated and degraded by proteasome. Dominant negative ubiquitin increased Mkp-1 half-life, indicating involvement of ubiquitination in Mkp-1 degradation. Stability of Mkp-1 is not affected by LPS treatment, consistent with constitutive degradation. U0126, a potent and selective inhibitor of extracellular response kinase (ERK) had negligible effect on the stability of both intrinsic and ectopically expressed Mkp-1, therefore enterocytes, unlike other cell types, do not regulate Mkp-1 degradation via ERK-dependent phosphorylation. C-Truncations of the C-terminal non-catalytic domain (at amino acids 306, 331, and 357), the 306-330 deletion obliterating the potential PEST domains, as well as S296A mutation, but not S323A, S358A, or S363A mutations in potential ERK phosphorylation sites dramatically stabilized Mkp-1. C-terminal fusion of the non-catalytic C-terminal domain of Mkp-1 conferred accelerated degradation on the intrinsically stable green fluorescent protein. According to these results, rapid degradation of Mkp-1 in IEC-6 enterocytes is ubiquitin-proteasome-dependent and ERK-independent. Multiple elements of the C-terminal non-catalytic domain play essential roles in the formation of the complex rapid degradation signal.
Stop codon-proximal 3′UTR introns in vertebrates can elicit EJC-dependent Nonsense-Mediated mRNA Decay
Authors: Gangras Pooja , Gallagher Thomas L. , Patton Robert D. , Yi Zhongxia , Parthun Michael A. , Tietz Kiel T. , Deans Natalie C. , Bundschuh Ralf , Amacher Sharon L. , Singh Guramrit
Published: June 2019

The Exon Junction Complex (EJC) regulates many steps in post-transcriptional gene expression and is essential for cellular function and organismal development; however, EJC-regulated genes and genetic pathways during development remain largely unknown. To study EJC function during zebrafish development, we first established that zebrafish EJCs mainly bind ∼24 nucleotides upstream of exon-exon junctions, and are also detected at more distant non-canonical positions. We then generated mutations in two zebrafish EJC core genes, rbm8a and magoh, and observed that homozygous mutant embryos show paralysis, muscle disorganization, neural cell death, and motor neuron outgrowth defects. Coinciding with developmental defects, mRNAs subjected to Nonsense-Mediated mRNA Decay (NMD) due to translation termination ≥ 50 nts upstream of the last exon-exon junction are upregulated in EJC mutant embryos. Surprisingly, several transcripts containing 3′UTR introns (3′UI) < 50 nts downstream of a stop codon are also upregulated in EJC mutant embryos. These proximal 3′UI-containing transcripts are also upregulated in NMD-compromised zebrafish embryos, cultured human cells, and mouse embryonic stem cells. Loss of function of foxo3b, one of the upregulated proximal 3′UI-containing genes, partially rescues EJC mutant motor neuron outgrowth. In addition to foxo3b, 166 other genes contain a proximal 3′UI in zebrafish, mouse and humans, and these genes are enriched in nervous system development and RNA binding functions. A proximal 3′UI-containing 3′UTR from one of these genes, HNRNPD, is sufficient to reduce steady state transcript levels when fused to a β-globin reporter in HeLa cells. Overall, our work shows that genes with stop codon-proximal 3′UIs encode a new class of EJC-regulated NMD targets with critical roles during vertebrate development.
GDF15 and the beneficial actions of metformin in pre-diabetes
Authors: Coll Anthony P , Chen Michael , Taskar Pranali , Rimmington Debra , Patel Satish , Tadross John , Cimino Irene , Yang Ming , Welsh Paul , Virtue Samuel , Goldspink Deborah A. , Miedzybrodzka Emily , Tung Y. C. Loraine , Rodriguez-Cuenca Sergio , Tomaz Rute A. , Harding Heather P. , Melvin Audrey , Yeo Giles S.H. , Preiss David , Vidal-Puig Antonio , Vallier Ludovic , Ron David , Gribble Fiona M. , Reimann Frank , Sattar Naveed , Savage David B. , Allan Bernard B. , O’Rahilly Stephen
Published: June 2019

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk, by lowering body weight, fat mass and circulating insulin levels through mechanisms that are incompletely understood. Recent observational studies reporting the association of metformin use and circulating levels of GDF15 led us to hypothesize that GDF15, which signals through a specific receptor complex in the hindbrain to reduce body weight, might mediate these effects. We measured GDF15 in people without diabetes from a randomized placebo-controlled trial of metformin. Over 18 months, participants allocated metformin lost significant weight and levels of GDF15 were persistently elevated compared to placebo. The change in plasma GDF15 in this study correlated positively with weight loss. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. The insulin sensitising effects of metformin determined by insulin tolerance were abolished in mice lacking GDF15. Metformin significantly reduced fasting glucose and insulin levels in wild type but not in mice lacking GDF15. In summary, metformin increases the circulating levels of GDF15, which appears to be necessary for many of its actions as a metabolic chemopreventive agent.
Computational model demonstrates that Ndc80-associated proteins strengthen kinetochore-microtubule attachments in metaphase
Authors: Campbell Samuel , Amin Mohammed Abdullahel , Varma Dileep , Bidone Tamara Carla
Published: June 2019

Chromosome segregation is mediated by spindle microtubules that attach to kinetochore via dynamic protein complexes, such as Ndc80, Ska, Cdt1 and ch-TOG during mitotic metaphase. While experimental studies have previously shown that these proteins and protein complexes are all essential for maintaining a stable kinetochore-microtubule interface, their exact roles in this process remains elusive. In this study, we employed experimental and computational methods in order to characterize how these proteins can strengthen kMT attachments in both non load-bearing and load-bearing conditions, typical of prometaphase and metaphase, respectively. Immunofluorescence staining of Hela cells showed that the levels of Ska and Cdt1 significantly increase from prometaphase to metaphase. Our new computational model showed that, by incorporating binding and unbinding of each protein complex, coupled with a biased diffusion mechanism, the displacement of a possible complex formed by Ndc80-Ska-Cdt1 is significantly higher than that formed by Ndc80 alone or Ndc80-Ska. In addition, when we use Ndc80/ch-TOG in the model, rupture force and time of attachment of the kMT interface increases. These results support the hypothesis that Ndc80-associated proteins strengthen kMT attachments and that it is the interplay between kMT protein complexes in metaphase that ensures stable attachments.
Improved Sensitivity in Low-Input Proteomics using Micro-Pillar Array-based Chromatography
Authors: Stadlmann Johannes , Hudecz Otto , Krššáková Gabriela , Van Raemdonck Gert , Op De Beeck Jeff , Desmet Gert , Penninger Josef M. , Jacobs Paul , Mechtler Karl
Published: June 2019

Capitalizing on the massive increase in sample concentrations which are produced by extremely low elution volumes, nano-LC-ESI-MS/MS is currently one of the most sensitive analytical technologies for the comprehensive characterization of complex protein samples.

However, despite tremendous technological improvements made in the production and the packing of monodisperse spherical particles for nano-flow HPLC, current state-of-the-art systems still suffer from limits in operation at the maximum potential of the technology.

With the recent introduction of the µPAC system, which provides perfectly ordered micro-pillar array based chromatographic support materials, completely new chromatographic concepts for optimization towards the needs of ultra-sensitive proteomics become available.

Here we report on a series of benchmarking experiments comparing the performance of a commercially available 50 cm micro-pillar array column to a widely used nano-flow HPLC column for the proteomics analysis of 10 ng tryptic HeLa cell digest.

Comparative analysis of LC-MS/MS-data corroborated that micro-pillar array cartridges provide outstanding chromatographic performance, excellent retention time stability, increase sensitivity in the analysis of low-input proteomics samples, and thus repeatedly yielded almost twice as many unique peptide and unique protein group identifications when compared to conventional nano-flow HPLC columns.
The lncRNAs Implicated in Redox Regulation in Ybx1 Deficient Zebrafish Larvae
Authors: Huang Chen , Zhu Bo , Leng Dongliang , Ge Wei , Zhang Xiaohua Douglas
Published: June 2019

Ybx1 has been demonstrated as a crucial gene in embryogenesis, reproduction as well as development in various vertebrates such as mouse and zebrafish. However, the underlying lncRNA-mediated mechanisms require deep investigation. Particularly, the importance of lncRNA to vertebrate development is controversial and questionable since many studies have yielded contradictory conclusions for the same lncRNAs. In the present study, in order to disclose the lncRNAs implicated in vertebrate development, a systematic transcriptome analysis is conducted based on the RNA sequencing data derived from ybx1 homozygous mutant zebrafish on day5 (day5_ybx1-/-) as well as wild type zebrafish on day5 and day6 (day5_ybx1+/+, day6_ybx1+/+). A high-confidence dataset of zebrafish lncRNAs is detected using a stepwise filtering pipeline. Differential expression analysis and co-expression network analysis reveal that several lncRNAs probably act on duox and noxo1a, the genes related to redox (reduction–oxidation reaction) processes which are triggered by ybx1 disruption. Validation by an experimental study on three selected lncRNAs indicates that knockdown of all selected lncRNAs leads to morphological deformation of larvae. In addition, our experiments effectively support the prediction of network analysis in many interaction patterns between the selected lncRNAs and the two redox genes (duox, noxo1a). In short, our study provides new insights into the function and mechanism of lncRNAs implicated in zebrafish embryonic development and demonstrates the importance of lncRNAs in vertebrate development.

Author Summary

LncRNAs has been emerged as key regulatory layers because of their multiple functions in diverse biological processes and pathways. However, there is disagreement about the roles of lncRNAs in vertebrate development Some cases demonstrated that lncRNAs was important to development. Others showed that lncRNAs just have feeble functions in development. On the other hand, Ybx1 processing multi-functions has been well demonstrated as a key protein to most vertebrate in development. Hence, aimed at disclosure of key lncRNAs implicated in vertebrate development as well as their possible roles, we performed a systematic transcriptome analysis based on the deep RNA sequencing data of ybx1 homozygous mutant zebrafish and wild type zebrafish. Our analysis successfully revealed several lncRNAs probably target on the redox-related genes. Furthermore, our experiments validated the importance of these lncRNAs to zebrafish embryo development. This study is the first to utilize Ybx1 as breakpoint to identify key lncRNA related to vertebrate development and provides new insights into underlying mechanisms of lncRNAs in development.
Computing, analyzing and comparing the radius of gyration and hydrodynamic radius in conformational ensembles of intrinsically disordered proteins
Authors: Ahmed Mustapha Carab , Crehuet Ramon , Lindorff-Larsen Kresten
Published: June 2019

The level of compaction of an intrinsically disordered protein may affect both its physical and biological properties, and can be probed via different types of biophysical experiments. Small-angle X-ray scattering (SAXS) probe the radius of gyration (Rg) whereas pulsed-field-gradient nuclear magnetic resonance (NMR) diffusion, fluorescence correlation spectroscopy and dynamic light scattering experiments can be used to determine the hydrodynamic radius (Rh). Here we show how to calculate Rg and Rh from a computationally-generated conformational ensemble of an intrinsically disordered protein. We further describe how to use a Bayesian/Maximum Entropy procedure to integrate data from SAXS and NMR diffusion experiments, so as to derive conformational ensembles in agreement with those experiments.
Variation in protein coding genes identifies information flow as a contributor to animal complexity
Authors: Dean Jack , Cardoso Daniela Lopes , Sharpe Colin
Published: June 2019

Across the metazoans there is a trend towards greater organismal complexity. How complexity is generated, however, is uncertain. Since C.elegans and humans have approximately the same number of genes, the explanation will depend on how genes are used, rather than their absolute number. Functional diversity is a measure that quantifies the isoforms, domains and paralogues of a gene. In this paper we determine functional diversity for each protein-coding gene in the human genome and its orthologues across eight commonly used model organisms. From this we derive the Compx list of genes that correlate positively with their increase in cell-type number. We then select genes common to the Compx list and the ExAC list, whose genes show minimal variation across many human genomes, and identify genes with common functions, notably in chromatin structure, RNA splicing, vesicular transport and ubiquitin-mediated protein degradation. Together these functions reveal that information flow within the cell relates to cell-type number, used as a measure of organismal complexity.
Significant texture improvement in single-crystalline-like materials on low-cost flexible metal foils through growth of silver thin films
Authors: Li Yongkuan , Sun Sicong , Gao Ying , Yao Yao , Galstyan Eduard , Rudra Pratap , Rathi Monika , Dutta Pavel , Pouladi Sara , Ryou Jae Hyun , Selvamanickam Venkat
Published: June 2019

Low texture spreads of single-crystalline-like materials are critical for high performance of low-cost flexible semiconductors and second-generation high-temperature superconductors based on metal foils. For texture improvement, a single-crystalline-like Ag film is epitaxially grown on an ion-beam-assisted deposition TiN substrate using magnetron sputtering. Ultra-low texture spreads are found in the thin Ag film (∼330 nm), with an out-of-plane texture spread (Δω) of ∼1.03° and an in-plane texture spread (Δϕ) of ∼1.34°. Compared with the texture spreads of the TiN substrate, Δω and Δϕ of the Ag film are reduced by ∼42 and ∼79%, respectively. Applying this Ag buffer, the texture spreads of a single-crystalline-like Ge film are reduced by ∼37% (Δω) and ∼36% (Δϕ). Factors contributing to the texture improvement by Ag are studied using single-crystalline-like Ag films with various thicknesses.
Crystal structures and Hirshfeld surface analysis of [κ2-P,N-{(C6H5)2(C5H5N)P}Re(CO)3Br]·2CHCl3 and the product of its reaction with piperidine, [P-{(C6H5)2(C5H5N)P}(C5H11N)Re(CO)3Br]
Authors: Palominos Franco , Muñoz Carolina , Oyarzun Poldie , Saldías Marianela , Vega Andrés
Published: June 2019

The coordination of the ligands with respect to the central atom in the complex bromidotricarbonyl[diphenyl(pyridin-2-yl)phosphane-κ2
N,P]rhenium(I) chloroform disolvate, [ReBr(C17H14NP)(CO)3]·2CHCl3 or [κ2-P,N-{(C6H5)2(C5H5N)P}Re(CO)3Br]·2CHCl3, (I·2CHCl3), is best described as a distorted octahedron with three carbonyls in a facial conformation, a bromide atom, and a biting P,N-diphenylpyridylphosphine ligand. Hirshfeld surface analysis shows that C—Cl...H interactions contribute 26%, the distance of these interactions are between 2.895 and 3.213 Å. The reaction between I and piperidine (C5H11N) at 313 K in dichloromethane leads to the partial decoordination of the pyridylphosphine ligand, whose pyridyl group is replaced by a piperidine molecule, and the complex bromidotricarbonyl[diphenyl(pyridin-2-yl)phosphane-κP](piperidine-κN)rhenium(I), [ReBr(C5H11N)(C17H14NP)(CO)3] or [P-{(C6H5)2(C5H5N)P}(C5H11N)Re(CO)3Br] (II). The molecule has an intramolecular N—H...N hydrogen bond between the non-coordinated pyridyl nitrogen atom and the amine hydrogen atom from piperidine with D...A = 2.992 (9) Å. Thermogravimetry shows that I·2CHCl3 losses 28% of its mass in a narrow range between 318 and 333 K, which is completely consistent with two solvating chloroform molecules very weakly bonded to I. The remaining I is stable at least to 573 K. In contrast, II seems to lose solvent and piperidine (12% of mass) between 427 and 463 K, while the additional 33% loss from this last temperature to 573 K corresponds to the release of 2-pyridylphosphine. The contribution to the scattering from highly disordered solvent molecules in II was removed with the SQUEEZE routine [Spek (2015). Acta Cryst. C71, 9-18] in PLATON. The stated crystal data for M
r, μ etc. do not take this solvent into account.
Crystal structures oftrans-diaqua(3-R-1,3,5,8,12-pentaazacyclotetradecane)copper(II) isophthalate hydrates (R= benzyl or pyridin-3-ylmethyl)
Authors: Andriichuk Irina L. , Tsymbal Liudmyla V. , Arion Vladimir B. , Lampeka Yaroslaw D.
Published: June 2019

The asymmetric units of the title compounds,trans-diaqua(3-benzyl-1,3,5,8,12-pentaazacyclotetradecane-κ4N1,N5,N8,N12)copper(II) isophthalate monohydrate, [Cu(C16H29N5)(H2O)2](C8H4O4)·H2O, (I), andtrans-diaqua[3-(pyridin-3-ylmethyl)-1,3,5,8,12-pentaazacyclotetradecane-κ4N1,N5,N8,N12]copper(II) isophthalate 0.9-hydrate, [Cu(C15H28N6)(H2O)2](C8H4O4)·0.9H2O, (II) consist of one diaqua macrocyclic cation, one dicarboxylate anion and uncoordinated water molecule(s). In each compound, the metal ion is coordinated by the four secondary N atoms of the macrocyclic ligand and the mutuallytransO atoms of the water molecules in a tetragonally distorted octahedral geometry. The average equatorial Cu—N bond lengths are significantly shorter than the average axial Cu—O bond lengths [2.020 (9)versus2.495 (12) Å and 2.015 (4)versus2.507 (7) Å for (I) and (II), respectively]. The coordinated macrocyclic ligand in the cations of both compounds adopts the most energetically favorabletrans-III conformation. In the crystals, the complex cations and counter-anions are connectedviahydrogen-bonding interactions between the N—H groups of the macrocycles and the O—H groups of coordinated water molecules as the proton donors and the O atoms of the carboxylate as the proton acceptors. Additionally, as a result of O—H...O hydrogen bonding with the coordinated and water molecules of crystallization, the isophthalate dianions form layers lying parallel to the (\overline{1}01) and (100) planes in (I) and (II), respectively.
Crystal structure and the DFT and MEP study of 4-benzyl-2-[2-(4-fluorophenyl)-2-oxoethyl]-6-phenylpyridazin-3(2H)-one
Authors: Daoui Said , Faizi Md. Serajul Haque , Kalai Fouad El , Saddik Rafik , Dege Necmi , Karrouchi Khalid , Benchat Noureddine
Published: June 2019

The title pyridazin-3(2H)-one derivative, C25H19FN2O2, crystallizes with two independent molecules (A and B) in the asymmetric unit. In molecule A, the 4-fluorophenyl ring, the benzyl ring and the phenyl ring are inclined to the central pyridazine ring by 86.54 (11), 3.70 (9) and 84.857 (13)°, respectively. In molecule B, the corresponding dihedral angles are 86.80 (9), 10.47 (8) and 82.01 (10)°, respectively. In the crystal, the A molecules are linked by pairs of C—H...F hydrogen bonds, forming inversion dimers with an R
2
2(28) ring motif. The dimers are linked by C—H...O hydrogen bonds and a C—H...π interaction, forming columns stacking along the a-axis direction. The B molecules are linked to each other in a similar manner and form columns separating the columns of A molecules.
(1R,2S,4r)-1,2,4-Triphenylcyclopentane-1,2-diol and (1R,2S,4r)-4-(2-methoxyphenyl)-1,2-diphenylcyclopentane-1,2-diol: application as initiators for ring-opening polymerization of ∊-caprolactone
Authors: Komarov Pavel D. , Minyaev Mikhail E. , Churakov Andrei V. , Roitershtein Dmitrii M. , Nifant'ev Ilya E.
Published: June 2019

Reductive cyclization of 1,3,5-triphenyl- and 3-(2-methoxyphenyl)-1,5-diphenylpentane-1,5-diones by zinc in acetic acid medium leads to the formation of 1,2,4-triphenylcyclopentane-1,2-diol [1,2,4-Ph3C5H5-1,2-(OH)2, C23H22O2, (I)] and 4-(2-methoxyphenyl)-1,2-diphenylcyclopentane-1,2-diol [4-(2-MeOC6H4)-1,2-Ph2C5H5-1,2-(OH)2, C24H24O3, (II)]. Their single crystals have been obtained by crystallization from a THF/hexane solvent mixture. Diols (I) and (II) crystallize in orthorhombic (Pbca) and triclinic (P\overline{1}) space groups, respectively, at 150 K. Their asymmetric units comprise one [in the case of (I)] and three [in the case of (II)] crystallographically independent molecules of the achiral (1R,2S,4r)-diol isomer. Each hydroxyl group is involved in one intramolecular and one intermolecular O—H...O hydrogen bond, forming one-dimensional chains. Compounds (I) and (II) have been used successfully as precatalyst activators for the ring-opening polymerization of ∊-caprolactone.
6-Methyluracil: a redetermination of polymorph (II)
Authors: Portalone Gustavo
Published: June 2019

6-Methyluracil, C5H6N2O2, exists in two crystalline phases: form (I), monoclinic, space group P21/c [Reck et al. (1988). Acta Cryst. A44, 417–421] and form (II), monoclinic, space group C2/c [Leonidov et al. (1993). Russ. J. Phys. Chem.
67, 2220–2223]. The structure of polymorph (II) has been redetermined providing a significant increase in the precision of the derived geometric parameters. In the crystal, molecules form ribbons approximately running parallel to the c-axis direction through N—H...O hydrogen bonds. The radical differences observed between the crystal packing of the two polymorphs may be responsible in form (II) for an increase in the contribution of the polar canonical forms C—(O−)=N—H+ relative to the neutral canonical form C(=O)—N—H induced by hydrogen-bonding interactions.
Relation between early e-WOM and average TV ratings
Authors: Bae Giwoong , Kim Hye-Jin
Published: June 2019

Purpose

The purpose of this paper is to investigate the relation between average ratings (viewership) and the volume and valence of electronic word of mouth (e-WOM) for early episodes of TV shows.

Design/methodology/approach

Linear regression was performed in which the dependent variable is average TV ratings and main independent variables are volume and valence of e-WOM. The study used a Breusch–Pagan test to detect heteroscedasticity. Accordingly, the model is analyzed using heteroscedasticity-consistent standard error estimators.

Findings

The results show that the volume of the early e-WOM does not significantly contribute to explaining average ratings, but the valence does.

Originality/value

Because the advertising revenue of television broadcasters is determined according to expected TV ratings, the average ratings should be predicted as early as possible. This study shows that analyzing early e-WOM helps predict average ratings.