bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the CALCB/RAMP1-axis inhibits growth of Ewing sarcoma
Authors: Dallmayer Marlene , Li Jing , Ohmura Shunya , Alba-Rubio Rebeca , Baldauf Michaela C. , Hölting Tilman L. B. , Musa Julian , Knott Max M. L. , Stein Stefanie , Cidre-Aranaz Florencia , Wehweck Fabienne S. , Romero-Pérez Laura , Gerke Julia S. , Orth Martin F. , Marchetto Aruna , Kirchner Thomas , Bach Horacio , Sannino Giuseppina , Grünewald Thomas G. P. 
Published: December 2018

ABSTRACTEwing sarcoma (EwS) is an aggressive cancer caused by chromosomal translocations generating fusions of theEWSR1gene withETStranscription factors (in 85%FLI1). EWSR1-FLI1 induces gene expression via binding to enhancer-like GGAA-microsatellites, whose activity increases with the number of consecutive GGAA-repeats.Herein, we investigate the role of the secretory neuropeptide CALCB (calcitonin related polypeptide β) in EwS, which signals via the CGRP-(calcitonin gene-related peptide) receptor complex, containing RAMP1 (receptor activity modifying protein 1) as crucial part for receptor specificity. Analysis of 2,678 gene expression microarrays comprising 50 tumor entities and 71 normal tissue types revealed thatCALCBis specifically and highly overexpressed in EwS. Time-course knockdown experiments showed thatCALCBexpression is tightly linked to that ofEWSR1-FLI1. Consistently, gene set enrichment analyses of genes whose expression in primary EwS is correlated to that ofCALCBindicated that it is co-expressed with other EWSR1-FLI1 target genes and associated with signatures involved in stemness and proliferation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data for EWSR1-FLI1 and histone marks from EwS cells demonstrated that EWSR1-FLI1 binds to a GGAA-microsatellite close toCALCB, which exhibits characteristics of an active enhancer. Reporter assays confirmed the strong EWSR1-FLI1- and length-dependent enhancer activity of this GGAA-microsatellite. Mass-spectrometry analyses of supernatants of EwS cell cultures demonstrated that CALCB is secreted by EwS cells. While short-term RNA interference-mediatedCALCBknockdown had no effect on proliferation and clonogenic growth of EwS cellsin vitro, its long-term knockdown decreased EwS growthin vitroandin vivo. Similarly, knockdown ofRAMP1reduced clonogenic/spheroidal growth and tumorigenicity, and small-molecule inhibitors directed against the CGRP-receptor comprising RAMP1 reduced growth of EwS.Collectively, our findings suggest thatCALCBis a direct EWSR1-FLI1 target and that targeting the CALCB/RAMP1-axis may offer a new therapeutic strategy for inhibition of EwS growth.
LARP1 is a major phosphorylation substrate of mTORC1
Authors: Fonseca Bruno D. , Jia Jian-Jun , Hollensen Anne K. , Pointet Roberta , Hoang Huy-Dung , Niklaus Marius R. , Pena Izabella A. , Lahr Roni M. , Smith Ewan M. , Hearnden Jaclyn , Wang Xu-Dong , Yang An-Dao , Celucci Giovanna , Graber Tyson E. , Dajadian Christopher , Yu Yonghao , Damgaard Christian K. , Berman Andrea J. , Alain Tommy 
Published: December 2018

AbstractThe mammalian target of rapamycin complex 1 (mTORC1) controls critical cellular functions such as protein synthesis, lipid metabolism, protein turnover and ribosome biogenesis through the phosphorylation of multiple substrates. In this study, we examined the phosphorylation of a recently identified target of mTORC1: La-related protein 1 (LARP1), a member of the LARP superfamily. Previously, we and others have shown that LARP1 plays an important role in repressing TOP mRNA translation downstream of mTORC1. LARP1 binds the 7-methylguanosine triphosphate (m7Gppp) cap moiety and the adjacent 5’terminal oligopyrimidine (5’TOP) motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 plays a critical role in the control of TOP mRNA translationviaLARP1 but the precise mechanism by which this occurs is incompletely understood. The data described herein help to elucidate this process. Specifically, it show that: (i) mTORC1 interacts with LARP1, but not other LARP superfamily members,viathe C-terminal region that comprises the DM15 domain, (ii) mTORC1 pathway controls the phosphorylation of multiple (up to 26) serine and threonine residues on LARP1in vivo, (iii) mTORC1 regulates the binding of LARP1 to TOP mRNAs and (iv) phosphorylation of S689 by mTORC1 is particularly important for the association of the DM15 domain of LARP1 with the 5’UTR of RPS6 TOP mRNA. These data reveal LARP1 as a major substrate of mTORC1.
Comparison of acoustic and elastic full‐waveform inversion of 2D towed‐streamer data in the presence of salt
Authors: Thiel Niklas , Hertweck Thomas , Bohlen Thomas 
Published: December 2018

ABSTRACTOver the last years, full‐waveform inversion has become an important tool in the list of processing and imaging technologies available to the industry. For marine towed‐streamer data, full‐waveform inversion is typically applied using an acoustic approximation because S‐waves do not propagate in water and elastic effects in recorded data are generally assumed to be small. We compare acoustic and elastic modelling and full‐waveform inversion for a field data set acquired offshore Angola over sediments containing a salt body with significant topology. Forward modelling tests reveal that such geological structures lead to significant mode conversions at interfaces and, consequently, to significant relative amplitude differences when elastically and acoustically modelled traces are compared. Using an acoustic approach for modelling in full‐waveform inversion therefore leads to problems matching the synthetic data with the field data, even for recorded pressure data and with trace normalization applied. Full‐waveform inversion is unable to find consistent model updates. Applying elastic full‐waveform inversion leads to more consistent and reliable model updates with less artefacts, at the expense of additional computation cost. Although two‐dimensional marine towed‐streamer data are least favourable for the application of full‐waveform inversion compared to three‐dimensional data or ocean‐bottom data, it is recommended to check on the existence of elastic effects before deciding on the final processing and imaging approach.
Fasting insulin resistance affects the prevalence of metabolically healthy obesity in Brazilian adolescents
Authors: Marra Nivea Fazanaro , Bechere Fernandes Maria Teresa , de Melo Maria Edna , da Cruz Rodrigo Marques , Tess Beatriz Helena 
Published: December 2018

AbstractAimWe aimed to assess the influence of fasting insulin resistance on metabolically healthy obesity (MHO) prevalence in adolescents and to identify associated factors.MethodsThis retrospective, registry‐based, cross‐sectional study included 418 (51.9% girls) 10‐ to 18‐year‐old adolescents with obesity from a tertiary outpatient clinic in Sao Paulo, Brazil, between 2009 and 2013. The prevalence of MHO was estimated according to two definitions: (i) no cardiometabolic risk factors (CMRF) by the International Diabetes Federation parameters and (ii) no CMRF and homeostatic model assessment for insulin resistance <3.16. Adjusted prevalence ratios and 95% confidence intervals (CI) evaluated the association of gender, age, pubertal stages, skin colour and degree of obesity with MHO.ResultsMetabolically healthy obesity prevalence was lower in definition II than definition I (12.7%; 95% CI 9.1–16.3% versus 43.1%; 95% CI 38.0–48.2%, respectively). Adjusted results showed negative association between severe obesity and MHO by both definitions (p ≤ 0.01). Male and later pubertal stages were also less likely to have MHO, but neither remained significant in definition II.ConclusionMetabolically healthy obesity prevalence decreased when insulin resistance was part of the definition. Detecting pre‐clinical insulin resistance may improve the management of treatment‐seeking adolescents, especially when they present no CMRF.
Effect of inotuzumab ozogamicin on the QT interval in patients with haematologic malignancies using QTc‐concentration modelling
Authors: Hibma Jennifer E. , Kantarjian Hagop M. , DeAngelo Daniel J. , Boni Joseph P. 
Published: December 2018

AimThe aim of this study was to characterize the effect of inotuzumab ozogamicin on QT interval in patients with B‐cell malignancies.MethodsData were pooled from three clinical studies including 250 patients (n = 2743) who received inotuzumab ozogamicin monotherapy. Patients with relapsed/refractory acute lymphoblastic leukaemia (NCT01564784 and NCT01363297) received 1.8 mg m−2 per cycle in divided doses (mean Cmax 371 ng ml−1; considered therapeutic) and patients with relapsed/refractory non‐Hodgkin lymphoma (NCT00868608) received 1.8 mg m−2 per cycle as a single dose (mean Cmax 569 ng ml−1; considered supratherapeutic). Triplicate 12‐lead electrocardiograms were performed at baseline and predefined time points postdose with paired pharmacokinetic collections. The exposure–response relationship between corrected QT interval (QTc: QT interval corrected using population‐specific formula [QTcS] or QT interval corrected using Fridericia's formula [QTcF]) and inotuzumab ozogamicin concentration was characterized using a linear mixed‐effects model, and simulations were performed using the final validated model. Full model development involved testing for covariates that may account for part of the identified variability.ResultsQTc intervals had a small but positive correlation with inotuzumab ozogamicin concentration. Based on 1000 simulations, median (upper 95% CI) QTcS and QTcF changes from baseline were <10 ms at both therapeutic (2.70 ms [5.40 ms] and 2.53 ms [4.92 ms], respectively) and supratherapeutic (4.14 ms [8.28 ms] and 3.87 ms [7.54 ms], respectively) concentrations.ConclusionsInotuzumab ozogamicin (1.8 mg m−2 per cycle) is not predicted to pose a clinically significant safety risk for QT prolongation in patients with acute lymphoblastic leukaemia or non‐Hodgkin lymphoma.
Fire? They don't give a dung! The resilience of dung beetles to fire in a tropical savanna
Authors: Nunes Cássio A. , Beiroz Wallace , da Silva Pedro G. , Braga Rodrigo F. , Fernandes G. Wilson , Neves Frederico De S. 
Published: December 2018

1. Disturbance is a strong driver of community assembly and fire has long been recognised as one of the main disturbances of terrestrial ecosystems. This study tested the resilience of dung beetles to fire events in campos rupestres, which is a tropical savanna ecosystem that evolved under a frequent fire regime, by assessing the resistance and recovery of their communities.2. Dung beetles were sampled before and after a fire event and the effect of fire on dung beetle richness, abundance, mean community biomass and composition was tested. The effects of time since last fire and fire frequency on the community were also tested.3. No effect of fire occurrence, time since last fire and fire frequency on any community variable was found.4. Some non‐mutually exclusive mechanisms promoting the resistance and recovery of dung beetles in campos rupestres could be acting in synergy. One potential mechanism is the mismatched seasonality between fire events and dung beetle occurrence, as fires occur during the dry season and dung beetles are present above ground during the rainy season. Furthermore, dung beetles are insects that remain buried during most of their lifetime, which could protect individuals from being burned. Another potential mechanism is the replacement of species in burned areas by the movement of individuals from unburned areas, attracted by resources and/or by metacommunity dynamics.5. It is concluded that in this ‘fire‐dependent’ ecosystem, dung beetle communities are resilient to fire and seem not to be structured by this disturbance.
Do depicted suggestions of portion size on‐pack impact how much (un)healthy food children consume
Authors: Aerts Goele , Smits Tim 
Published: December 2018

AbstractIn previous decades, portion and pack sizes of many foods tended to increase while, more recently, some foods started to downsize. These changes in actual portion sizes typically get coverage but less attention is given to the suggested portion sizes for multi‐serving food packages, and to what the impact is of the depicted portion sizes on‐pack. Using two studies with a mixed experimental design among young children, this paper examines the effects of depicted suggestions of portion size manipulation (regular vs. large—‘large’ corresponds to how brands typically depict portions). Both studies used a 2 × 2 × 2 crossover design, with the suggested portion size and food type as within‐ and order as between‐subjects manipulation. In Study 1, we used snacks (grapes and chocolate nuts). In Study 2, we compared two bread spreads (chocolate and cheese). In both the studies, we found that children ate more when presented with the larger depiction of the suggested portion size compared to the regular one. In Study 1, however, we found that children consumed more calories from the chocolate nut than the grape snack, while children did eat more grams of this healthier grape snack. We also showed that consumption in grams only differed between portion sizes when given grapes, which might be due to a possible ceiling effect of chocolate nut consumption. In Study 2, we also found a main effect for spread type as children ate more of chocolate compared to cheese spread. Our results indicate that this subtle on‐pack cue is persuasive. Moreover, policy makers and also marketers could use these insights to stimulate healthy eating in children.
Drivers of species richness and abundance of marine macrophytes on shallow tropical reefs of north‐western Australia
Authors: Olsen Ylva S. , Mattio Lydiane , Zavala Perez Andrea , Babcock Russ C. , Thompson Damian , Haywood Michael D.E. , Keesing John , Kendrick Gary A. 
Published: December 2018

AbstractAimMarine macrophytes are important components of tropical reefs that are influenced by environmental conditions and biotic interactions. Here, we aimed to identify the factors that shape macrophyte communities on shallow reefs in a region with limited anthropogenic impacts, but that is influenced by periodic disturbances from cyclones and marine heatwaves.LocationPilbara coast, Western Australia.MethodsMacrophyte species richness and biomass were assessed at 75 shallow reefs along 300 km of shoreline in November 2013 and May 2014. The influence of 28 predictor variables including seascape descriptors, physico‐chemical variables, and herbivore abundances were evaluated using distance based linear models (DistLM), redundancy analyses (dbRDA), and full‐subsets multiple regressions.ResultsWe identified 188 macrophyte species; 60% were Rhodophyta, whereas Phaeophyceae made up 67% of the biomass. Macrophyte assemblages did not show any broad‐scale patterns but a number of key drivers were identified, including sea surface temperature, salinity, and sediment uniformity. Two of the main predictors of macrophyte abundance and species richness were rugosity and coral cover rather than herbivory, unlike what has been demonstrated for many reefs globally. Availability of space therefore appears to be a major factor on these reefs and it is possible that macrophytes benefit from periodic disturbances as they can free up space through physical removal of organisms.Main conclusionsMacrophyte assemblages along the Pilbara coast show no distinct large‐scale patterns; instead, local biotic and environmental drivers such as rugosity appear to be structuring assemblages. We propose that natural disturbance plays a key role on these shallow reefs by increasing substrate availability. Data on the long‐term community structure of macroalgae, in particular how communities respond to heatwaves and cyclones, would improve our ability to manage these reefs and predict potential “phase shifts” which can have severe ecological and economic consequences.
Pre‐Pleistocene origin of phylogeographical breaks in African rain forest trees: New insights from Greenwayodendron (Annonaceae) phylogenomics
Authors: Migliore Jérémy , Kaymak Esra , Mariac Cédric , Couvreur Thomas L. P. , Lissambou Brandet‐Junior , Piñeiro Rosalía , Hardy Olivier J. 
Published: December 2018

AbstractAimPalaeoecological records indicate that Pleistocene glaciations affected the African rain forest, probably causing its fragmentation, which could explain phylogeographical breaks documented in many tree species. This refuge hypothesis was further tested through species distribution models, hindcasting persistence during the Last Glacial Maximum. However, previous studies failed to estimate with sufficient precision the divergence time between phylogeographical entities to confirm their Pleistocene origin. Developing genomic tools on a representative tree of mature rain forests, we test if parapatric genetic clusters documented in widespread tree species can be interpreted as the legacy of past population fragmentation during the last glacial period(s).LocationTropical Africa, Guineo‐Congolian forests.TaxonGreenwayodendron (Annonaceae).MethodsTo further test the Pleistocene refuge hypothesis by molecular dating, we sequenced the plastome of 145 individuals of the shade‐tolerant rain forest tree Greenwayodendron suaveolens and congeneric species, and genotyped the same samples using nuclear microsatellites to identify genetic clusters.ResultsFive plastid phylogroups of G. suaveolens occur in parapatry throughout Central Africa, following a spatial pattern generally congruent with genetic clusters. Four of them diverged 3.5–4.5 Ma, whereas the fifth one, located in the Cameroon volcanic line (CVL), diverged 8.3 Ma, in the range of divergence times between Greenwayodendron species, highlighting the key role of the CVL in hosting ancient lineages. Within phylogroups, most nodes were dated from 0.9 to 3.2 Myr and a correlation between haplotype divergence and spatial distance was still perceptible, indicating a slow population dynamic.Main conclusionsThe phylogeographical structures of Central African trees probably established during the Pliocene or early Pleistocene, and while they might have been reinforced during subsequent glacial–interglacial cycles, interglacial phases did not lead to genetic homogenization. Therefore, interpreting phylogeographical patterns of African trees must account for a much deeper past than previously assumed, and cannot be limited to the last glacial period.
Bayesian spatio‐temporal reconstruction reveals rapid diversification and Pleistocene range expansion in the widespread columnar cactus Pilosocereus
Authors: Lavor Pâmela , Calvente Alice , Versieux Leonardo M. , Sanmartin Isabel 
Published: December 2018

ABSTRACTAimPilosocereus is one of the richest and most widespread genera of columnar cacti, extending from south‐west USA to southern Brazil. Most species occur in the seasonally dry tropical forest biome but can also be found in xeric microhabitats inside woody savannas (Cerrado) and moist forests (Brazilian Atlantic forest). The genus exhibits a highly disjunct distribution across the Neotropics. Using a 90% complete species‐level phylogeny, we reconstructed the spatio‐temporal evolution of Pilosocereus to explore the historical factors behind the species richness of Neotropical dry formations.LocationSouth America, Mesoamerica, Caribbean, south‐western North America.TaxonGenus Pilosocereus (Cactaceae, Cactoideae, Cereeae).MethodsWe used plastid and nuclear DNA sequences and Bayesian inference to estimate phylogenetic relationships and lineage divergence times. Ancestral ranges were inferred within the Pilosocereus subgenus Pilosocereus s. s. clade using the Dispersal–Extinction–Cladogenesis model in a Bayesian framework to account for parameter estimation uncertainty and the effect of geographical distance on dispersal rates.ResultsPilosocereus was recovered as polyphyletic, with representatives of other Cereeae nested within. The Pilosocereus subgenus Pilosocereus s. s. clade originated around the Pliocene–Pleistocene transition (2.7 Ma), probably within the Caatinga seasonally dry tropical forest (SDTF) formation. Species divergences were dated in the Middle and Upper Pleistocene, often constrained to the same geographic region but also associated to migration events to other xeric habitats in Mesoamerica and northern South America; dispersal rates were not dependent on distance.Main conclusionsDiversification dynamics in the Pilosocereus subgenus Pilosocereus s. s. clade agree with other infrageneric studies in cacti. Species divergence was rapid, driven by in situ diversification and migration events between SDTF dry formations and xeric microhabitats within other biomes and probably linked to Pleistocene climatic changes. This dynamic history differs from that found in woody SDTF lineages, which are older in age and characterized by low‐dispersal rates and long‐term isolation.
LncRNA HOXA‐AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF‐κB signalling
Authors: Zhu Xinxing , Yu Jinjin , Du Jiang , Zhong Genshen , Qiao Liang , Lin Juntang 
Published: December 2018

AbstractAs is previously reported, mesenchymal stem cells have potential ability to differentiate into osteocytes. However, the underlying mechanism during this biological process is poorly understood. In the present study, we identify a novel long non‐coding RNA named HOXA‐AS2 as a critical regulator during the formation of osteogenesis. Attenuation of HOXA‐AS2 can reduce the calcium deposition and repress the alkaline phosphatase activity. Moreover, the expressions of osteogenic marker genes are markedly downregulated after HOXA‐AS2 depletion. Mechanistically, we found HOXA‐AS2 can regulate the transcriptional activity of NF‐κB, a critical inhibitor of osteogenesis. More importantly, HOXA‐AS2 knockdown could result in the transcriptional repression of the osteogenic master transcription factor SP7 by a NF‐κB/HDAC2‐coordinated H3K27 deacetylation mechanism. Based on these studies, we conclude that HOXA‐AS2 may serve as a promising therapeutic target for bone tissue repair and regeneration in the near future.
Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells
Authors: Zheng Jianjian , Mao Yuqing , Dong Peihong , Huang Zhiming , Yu Fujun 
Published: December 2018

AbstractHOXA transcript at the distal tip (HOTTIP) has been shown to be up‐regulated in a variety of cancers and is identified as an oncogenic long noncoding RNA. However, the biological role of HOTTIP in liver fibrosis is unclear. Here, we reported that HOTTIP was specifically overexpressed in activated hepatic stellate cells (HSCs). HOTTIP knockdown suppressed the activation and proliferation of HSCs. Luciferase reporter assay showed that HOTTIP and serum response factor (SRF) were targets of miR‐150. RNA binding protein immunoprecipitation assay indicated the interaction between miR‐150 and HOTTIP. Further study revealed that HOTTIP increased SRF expression as a competing endogenous RNA for miR‐150, thus prompting HSC activation. Taken together, we provide a novel HOTTIP‐miR‐150‐SRF signalling cascade in liver fibrosis.