bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of oral epithelial EphA2-EFGR signaling by Candida albicans virulence factors
Authors: Swidergall Marc , Solis Norma V. , Millet Nicolas , Huang Manning Y. , Lin Jianfeng , Phan Quynh T. , Lazarus Michael D. , Wang Zeping , Mitchell Aaron P. , Filler Scott G.
Published: December 2018

During oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects β-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the Ece1/Candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and Ece1/Candidalysin during OPC. We found that Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells in vitro. They also work together to cause OPC in mice. EGFR and EphA2 constitutively associate with each other as part of a physical complex and are mutually dependent for C. albicans-induced activation. In vitro, either Als3 or Ece1/Candidalysin is required for C. albicans to activate EGFR, sustain EphA2 activation, and stimulate epithelial cells to secrete CXCL8/IL-8 and CCL20. In the mouse model of OPC, Ece1/Candidalysin alone activates EGFR and induces CXCL1/KC and CCL20 production. Ece1/Candidalysin is also necessary for the production of IL-1α and IL-17A independently of Als3 and EGFR. These results delineate the complex interplay between host cell receptors and C. albicans virulence factors during the induction of OPC and the resulting oral inflammatory response.

Author summary

Oropharyngeal candidiasis occurs when the fungus Candida albicans proliferates in the mouth. The disease is characterized by fungal invasion of the superficial epithelium and a localized inflammatory response. Two C. albicans virulence factors contribute to the pathogenesis of OPC, Als3 which enables the organisms to adhere to and invade host cells and Ece1/Candidalysin which is pore-forming toxin that damages host cells. Two epithelial cell receptors, ephrin type-A receptor 2 (EphA2) and the epidermal growth factor receptor (EGFR) are activated by C. albicans. Here, we show that EphA2 and EGFR form part of complex and that each receptor is required to activate the other. Als3 and Ece1/Candidalysin function in the same pathway to damage epithelial cells. In isolated epithelial cells, both of these virulence factors activate EphA2 and EGFR, and stimulate the production of inflammatory mediators. In the mouse model of OPC, Ece1/Candidalysin elicits of a subset of the oral inflammatory response. Of the cytokines and chemokines induced by this toxin, some require the activation of EGFR while others are induced independently of EGFR. This work provides a deeper understanding of the interactions among C. albicans virulence factors and host cell receptors during OPC.
Symmetry breaking in the embryonic skin triggers a directional and sequential front of competence during plumage patterning
Authors: Bailleul Richard , Dinh Carole Desmarquet-Trin , Hidalgo Magdalena , Curantz Camille , Touboul Jonathan , Manceau Marie
Published: December 2018

The development of an organism involves the formation of patterns from initially homogeneous surfaces in a reproducible manner. Simulations of various theoretical models recapitulate final states of natural patterns1-4yet drawing testable hypotheses from those often remains difficult4,5. Consequently, little is known on pattern-forming events. Here, we extend modeling to reproduce not only the final plumage pattern of birds, but also the observed natural variation in its dynamics of emergence in five species. We built a unified model intrinsically generating the directionality, sequence, and duration of patterning, and usedin vivoexperiments to test its parameter-based predictions. We showed that while patterning duration is controlled by overall cell proliferation, its directional and sequential progression result from a pre-pattern: an initial break in surface symmetry launches a traveling front of increased cell density that defines domains with self-organizing capacity. These results show that universal mechanisms combining pre-patterning and self-organization govern the timely emergence of the plumage pattern in birds.
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

Ewing 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

The 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

Over 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

Aim

We aimed to assess the influence of fasting insulin resistance on metabolically healthy obesity (MHO) prevalence in adolescents and to identify associated factors.

Methods

This 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.

Results

Metabolically 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.

Conclusion

Metabolically 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

Aim

The aim of this study was to characterize the effect of inotuzumab ozogamicin on QT interval in patients with B‐cell malignancies.

Methods

Data 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.

Results

QTc 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.

Conclusions

Inotuzumab 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.
MicroRNA single‐nucleotide polymorphisms and diabetes mellitus: A comprehensive review
Authors: Zhang Yanfen , Bai Ruocen , Liu Chong , Ma Chunyan , Chen Xin , Yang Jun , Sun Dandan
Published: December 2018

Diabetes mellitus (DM) has become the third major chronic non‐communicable disease affecting global public health, following cancer and cardiovascular and cerebrovascular diseases. Although previous studies have found a correlation between microRNA (miRNA) and the development of DM, thus far, most reviews have focused on the studies describing the changes in miRNA expression profiles and the mechanisms by which miRNAs‐induce DM. However, reviews summarizing the effect of miRNA single‐nucleotide polymorphisms on the developmental stages of DM and its complications are still needed. Studies on the variation of miRNAs will not only help to further understand the role that genetic factors play in DM, but will also have important implications for treatment and disease prognosis.
BETWEEN SCYLLA AND CHARYBDIS: INCOME DISTRIBUTION, CONSUMER CREDIT, AND BUSINESS CYCLES
Authors: Cardaci Alberto , Saraceno Francesco
Published: December 2018

We introduce a macroeconomic model with heterogeneous households and an aggregate banking sector in order to analyze the impact of rising income inequality under different credit scenarios. Growing inequality produces debt‐led consumption boom dynamics when the banking sector is characterized by a lower capital requirement and a higher willingness to lend. Instead, when inequality rises but the banking sector is highly regulated, aggregate demand and output fall. Our results also yield new insights on the appropriate fiscal policy reaction to stabilize the economy: acting on the progressivity of the tax system seems more effective than a proactive countercyclical fiscal policy. (JEL C63, D31, E62, G01)
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

In 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

Aim

Marine 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.

Location

Pilbara coast, Western Australia.

Methods

Macrophyte 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.

Results

We 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 conclusions

Macrophyte 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

Aim

Palaeoecological 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).

Location

Tropical Africa, Guineo‐Congolian forests.

Taxon

Greenwayodendron (Annonaceae).

Methods

To 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.

Results

Five 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 conclusions

The 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

Aim

Pilosocereus 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.

Location

South America, Mesoamerica, Caribbean, south‐western North America.

Taxon

Genus Pilosocereus (Cactaceae, Cactoideae, Cereeae).

Methods

We 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.

Results

Pilosocereus 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 conclusions

Diversification 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

As 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

HOXA 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.
New therapeutic strategy of hinokitiol in haemorrhagic shock‐induced liver injury
Authors: Lu Wan‐Jung , Lin Kuan‐Hung , Tseng Mei‐Fang , Yuan Kuo‐Ching , Huang Hung‐Chang , Sheu Joen‐Rong , Chen Ray‐Jade
Published: December 2018

Haemorrhagic shock and resuscitation (HS/R) may cause global ischaemia‐reperfusion injury, which can result in systemic inflammation, multiorgan failure (particularly liver failure) and high mortality. Hinokitiol, a bioactive tropolone‐related compound, exhibits antiplatelet and anti‐inflammatory activities. Targeting inflammatory responses is a potential strategy for ameliorating hepatic injury during HS/R. Whether hinokitiol prevents hepatic injury during HS/R remains unclear. In the present study, we determined the role of hinokitiol following HS/R. The in vivo assays revealed that hinokitiol markedly attenuated HS/R‐induced hepatic injury. Hinokitiol could inhibited NF‐κB activation and IL‐6 and TNF‐α upregulation in liver tissues. Moreover, hinokitiol reduced caspase‐3 activation, upregulated Bax and downregulated Bcl‐2. These findings suggest that hinokitiol can ameliorate liver injury following HS/R, partly through suppression of inflammation and apoptosis. Furthermore, the in vitro data revealed that hinokitiol significantly reversed hypoxia/reoxygenation (H/R)‐induced cell death and apoptosis in the primary hepatocytes. Hinokitiol prevented H/R‐induced caspase‐3 activation, PPAR cleavage, Bax overexpression and Bcl‐2 downregulation. Moreover, hinokitiol attenuated H/R‐stimulated NF‐κB activation and reduced the levels of IL‐6 and TNF‐α mRNAs, suggesting that hinokitiol can protect hepatocytes from H/R injury. Collectively, our data suggest that hinokitiol attenuates liver injury following HS/R, partly through the inhibition of NF‐κB activation.
CD83+CCR7+ NK cells induced by interleukin 18 by dendritic cells promote experimental autoimmune uveitis
Authors: Fu Qiang , Man Xuejing , Wang Xin , Song Nannan , Li Yuanbin , Xue Jiangnan , Sun Yufei , Lin Wei
Published: December 2018

Natural killer (NK) cells have been reported to play a pathological role in autoimmune uveitis. However, the mechanisms regarding NK cells in uveitis and factors that affect NK‐cell activation in this condition remain unclear. Here, we report that the number of CD3‐NK1.1+CD83+CCR7+ cells is increased in the inflamed eyes within a mouse model of experimental autoimmune uveitis (EAU), and these cells express elevated levels of NKG2D, CD69 and IFN‐γ. Adoptively transferring CD83+CCR7+NK cells aggravates EAU symptoms and increases the number of CD4+IFN‐γ+T cells and dendritic cells (DCs) within the eye. These CD83+CCR7+NK cells then promote the maturation of DCs and IFN‐γ expression within T cells as demonstrated in vitro. Furthermore, IL‐18, as primarily secreted by DCs in the eyes, is detected to induce CD83+CCR7+NK cells. In EAU mice, anti‐IL‐18R antibody treatment also decreases retinal tissue damage, as well as the number of infiltrating CD83+CCR7+NK cells, T cells and DCs in the inflamed eyes and spleens of EAU mice. These results suggest that CD83+CCR7+NK cells, as induced by IL‐18 that primarily secreted by DCs, play a critical pathological role in EAU. Anti‐IL‐18R antibody might serve as a potential therapeutic agent for uveitis through its capacity to inhibit CD83+CCR7+NK cells infiltration.
Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma
Authors: Muth A. , Crona J. , Gimm O. , Elmgren A. , Filipsson K. , Stenmark Askmalm M. , Sandstedt J. , Tengvar M. , Tham E.
Published: December 2018

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first‐degree relatives (and second‐degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy‐catecholamines and bi‐annual rapid whole‐body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre‐symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow‐up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.
Mixotrophic in vitro cultivations: the way to go astray in plant physiology
Authors: Ševčíková Hana , Lhotáková Zuzana , Hamet Jaromír , Lipavská Helena
Published: December 2018

Rate of photosynthesis and related plant carbohydrate status are crucial factors affecting plant vigor. Sugars providing carbon and energy sources serve also as important signaling molecules governing plant growth and development through a complex regulatory network. These facts are often neglected when mixotrophic cultivation of plants in vitro is used, where artificial exogenous sugar supply hinders studies of metabolism as well as sugar‐driven developmental processes. We compared the growth, selected gas‐exchange parameters and sugar metabolism characteristics in four model plants, potato (Solanum tuberosum ‘Lada’), tobacco (Nicotiana tabacum ‘Samsun’), rapeseed (Brassica napus ‘Asgard’) and strawberry (Fragaria vesca), under both photomixotrophic (PM) and photoautotrophic (PA) conditions. To ensure PA conditions, we used our improved sun caps that serve as gas and light permeable covers for cultivation vessels. We found bigger biomass accumulation, larger leaf areas, higher stomatal conductance and higher instantaneous water use efficiency and lower root sugar contents in PA plants compared to PM ones. However, for other characteristics (root biomass, root/shoot ratio, pigment contents, leaf sugar and starch levels and transpiration rates), a strong species‐dependent reactions to the exogenous sugar supply was noted, which does not allow to create a general view on the overall impact of PM nutrition under in vitro conditions.
Multilocus phylogeny and taxonomy of pikas of the subgenus Ochotona (Lagomorpha, Ochotonidae)
Authors: Lissovsky Andrey A. , Yatsentyuk Svetlana P. , Koju Narayan P.
Published: December 2018

A complete set of pika taxa, belonging to the subgenus Ochotona, was studied using craniometric and multilocus genetic analyses. We examined 1,007 skulls, covering the entire distribution range of the subgenus, as well as the mitochondrial COI gene and three nuclear introns in 31 specimens, representing nearly all taxa in question. An additional set of 167 COI gene sequences and 357 cytb gene sequences was analysed to enlarge the geographical extent of genetic data and to compare the results with previous publications. We found that the subgenus consists of eight species. One of them, Ochotona morosa, is elevated to the full species rank for the first time. The name of this species is given preliminarily and should be studied additionally. Several cases of interspecies hybridisation were found, which indicates that mitochondrial DNA cannot be used for species identification in this subgenus. Taxon Ochotona qionglaiensis, which was recently described as a separate species, represents a relic mitochondrial lineage of Ochotona thibetana. Another recently described species, Ochotona yarlungensis, is a Nubra pika with its native mitochondrial DNA, firstly found for this species. Intraspecies variation was analysed for several species for the first time. Thus, new subspecies (Ochotona thibetana fengii ssp. n.) was found within O. thibetana.
Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions
Authors: Orlicky David J. , Libby Andrew E. , Bales Elise S. , McMahan Rachel H. , Monks Jenifer , La Rosa Francisco G. , McManaman James L.
Published: December 2018

Key points

Wild‐type mice and mice with hepatocyte‐specific or whole‐body deletions of perilipin‐2 (Plin2) were used to define hepatocyte and extra‐hepatocyte effects of altered cellular lipid storage on obesity and non‐alcoholic fatty liver disease (NAFLD) pathophysiology in a Western‐diet (WD) model of these disorders.

Extra‐hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD‐fed mice.

Hepatocyte and extra‐hepatic actions of Plin2 mediate fatty liver formation in WD‐fed mice through distinct mechanisms.

Hepatocyte‐specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice.

Non‐alcoholic fatty liver disease (NAFLD) is an obesity‐ and insulin resistance‐related metabolic disorder with progressive pathology. Perilipin‐2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate hepatocyte‐specific and extra‐hepatocyte Plin2 mechanisms regulating the effects of obesity and insulin resistance on NAFLD pathophysiology in mice fed an obesogenic Western‐style diet (WD). Total Plin2 deletion (Plin2‐Null) fully protected WD‐fed mice from obesity, insulin resistance, adipose inflammation, steatohepatitis (NASH) and liver fibrosis found in WT animals. Hepatocyte‐specific Plin2 deletion (Plin2‐HepKO) largely protected against NASH and fibrosis and partially protected against steatosis in WD‐fed animals, but it did not protect against obesity, insulin resistance, or adipose inflammation. Significantly, total or hepatocyte‐specific Plin2 deletion impaired WD‐induced monocyte recruitment and pro‐inflammatory macrophage polarization found in livers of WT mice. Analyses of the molecular and cellular processes mediating steatosis, inflammation and fibrosis identified differences in total and hepatocyte‐specific actions of Plin2 on the mechanisms promoting NAFLD pathophysiology. Our results demonstrate that hepatocyte‐specific actions of Plin2 are central to the initiation and pathological progression of NAFLD in obese and insulin‐resistant mice through effects on immune cell recruitment and fibrogenesis. Conversely, extra‐hepatocyte Plin2 actions promote NAFLD pathophysiology through effects on obesity, inflammation and insulin resistance. Our findings provide new insight into hepatocyte and extra‐hepatocyte mechanisms underlying NAFLD development and progression.
Numerical Study of Flame Shapes and Structures in a Two-Stage Two-Injection Aeronautical Burner With Variable Fuel Staging Using Eulerian Large Eddy Simulations
Authors: Cheneau Benoit , Vié Aymeric , Ducruix Sébastien
Published: December 2018

The aim of the present work is to evaluate the ability of large eddy simulation (LES) to predict flame shape and structures in a two-stage two-injection burner representative of new generation staged aeronautical engine: the Banc à Injection Multiple pour les Écoulements Réactifs (BIMER) burner. This combustor is a unique design because of an additional parameter, the staging factor, which controls the fuel mass flow rate splitting between the two swirl stages. Experiments conducted on the BIMER combustor at atmospheric pressure and for a constant power output have revealed that the shape of the flame changes with the staging factor; this shape also depends on the staging factor evolution history (SFEH). Targeting a single operating point and three staging situations, the objectives are to prove the ability of our simulation strategy to predict the proper shapes by reproducing these stabilization processes and to participate in their explanation, using numerical post-treatments. After validation through comparisons with experiments, our study focuses on these three configurations, two of them only differing by their SFEH. Remarkably, correct flame shapes are obtained numerically for the same operating point, fuel staging factors and SFEH. Qualitative and quantitative comparisons show very satisfactory agreement. In a second step, the three flame shapes are analyzed in depth. The key role played by the central and corner recirculation zones in the flames' existence and stabilization processes is emphasized. An original composition space analysis highlights the combustion regimes observed in these three cases, confirming the distinct stabilization scenarios proposed here for the three operating points.
Mechanics of Three-Dimensional Printed Lattices for Biomedical Devices
Authors: Egan Paul F. , Bauer Isabella , Shea Kristina , Ferguson Stephen J.
Published: December 2018

Advances in three-dimensional (3D) printing are enabling the design and fabrication of tailored lattices with high mechanical efficiency. Here, we focus on conducting experiments to mechanically characterize lattice structures to measure properties that inform an integrated design, manufacturing, and experiment framework. Structures are configured as beam-based lattices intended for use in novel spinal cage devices for bone fusion, fabricated with polyjet printing. Polymer lattices with 50% and 70% porosity were fabricated with beam diameters of 0.4–1.0mm, with measured effective elastic moduli from 28MPa to 213MPa. Effective elastic moduli decreased with higher lattice porosity, increased with larger beam diameters, and were highest for lattices compressed perpendicular to their original build direction. Cages were designed with 50% and 70% lattice porosities and included central voids for increased nutrient transport, reinforced shells for increased stiffness, or both. Cage stiffnesses ranged from 4.1kN/mm to 9.6kN/mm with yielding after 0.36–0.48mm displacement, thus suggesting their suitability for typical spinal loads of 1.65kN. The 50% porous cage with reinforced shell and central void was particularly favorable, with an 8.4kN/mm stiffness enabling it to potentially function as a stand-alone spinal cage while retaining a large open void for enhanced nutrient transport. Findings support the future development of fully integrated design approaches for 3D printed structures, demonstrated here with a focus on experimentally investigating lattice structures for developing novel biomedical devices.
"A ball in a cage"
Authors: Mada Razvan O. , Tomoaia Raluca , Sasarman Vasile , Encica Svetlana , Bindea Dan
Published: December 2018

.
Education in ultrasonography -a stringent and constant necessity
Authors: Badea Radu
Published: December 2018

.
Morphological distinction and sexual dimorphism in divergent clades of Neurergus kaiseri (Amphibia: Salamandridae)
Authors: Khoshnamvand Hadi , Malekian Mansoureh , Keivany Yazdan
Published: December 2018

Morphological differentiation and sexual dimorphism in the two genetically distinct clades (Northern and Southern clades) of the Lorestan newt, Neurergus kaiseri, was evaluated for 72 live specimens, using five body- and nine head-related characters and eight calculated ratios. Principle component analysis of morphological characters confirmed that the Lorestan newt populations are well separated into two distinct groups, suggesting that a taxonomic revision in N. kaiseri may be required because of significant molecular, morphological and ecological differences between these clades. Sexual dimorphism in N. kaiseri includes body size and shape. Females were clearly larger than males in most body- and head-related variables and males had relatively greater head width and eye length. Sexual dimorphism in this species may be linked to sexual selection and ecological differences between sexes. However, many aspects of the ecology and reproductive biology of this species remain unknown.
Composition of the diet of the Iberian common toad (Bufo spinosus, Daudin, 1803) in central Spain
Authors: Vallvé Álvaro , Sánchez-Iglesias Iván
Published: December 2018

We describe the diet of the Iberian common toad (Bufo spinosus) in a locality in central Spain. The sample consisted of individuals that were road-killed in road M-301 between Madrid and San Martín de la Vega during their seasonal migration events in spring and fall. The diet of B. spinosus comprises up to 42 different taxonomic families of invertebrates, of which Julidae, Carabidae, Staphylinidae, and Formicidae were the most abundant. When considering the biomass of these prey, the results were consistent except for Formicidae, whose importance is limited (2.63% of the total biomass). Biomass estimations for Julidae were compared to empirically obtained data, which showed a high content of inorganic matter (41.4%) in these invertebrates. Nevertheless, Julidae is still the leading contributor in consumed biomass in our samples (42%). We highlight the occurrence of supposedly unpalatable (Lampyridae) and nutritionally poor items (vegetal matter and fecal pellets of lagomorphs).
Dynamic thermal emission control with InAs-based plasmonic metasurfaces
Authors: Park Junghyun , Kang Ju-Hyung , Liu Xiaoge , Maddox Scott J. , Tang Kechao , McIntyre Paul C. , Bank Seth R. , Brongersma Mark L.
Published: December 2018

Scientists and engineers revealed a way to electrically control heat transfer on demand in a nano-optical device.