bluuebunny/crossref_metadata_2025 huggingface dataset:
The mapping of cancer incidence and mortality trends in the UK from 1980–2013 reveals a potential for overdiagnosis
Authors: Oke Jason L. , O’Sullivan Jack W. , Perera Rafael , Nicholson Brian D.
Published: September 2018

The incidence of cancer in the United Kingdom has increased significantly over the last four decades. The aim of this study was to examine trends in UK cancer incidence and mortality by cancer site and assess the potential for overdiagnosis. Using Cancer Research UK incidence and mortality data for the period (1971–2014) we estimated percentage change in incidence and mortality rates and the incidence-mortality ratio (IMR) for cancers in which incidence had increased >50%. Incidence and mortality trend plots were used to assess the potential for overdiagnosis. Incidence rates increased from 67% (uterine) to 375% (melanoma). Change in mortality rates ranged from −69% (cervical) to +239% (liver). The greatest divergences occurred in uterine (IMR = 132), prostate (IMR = 9.6), oral (IMR = 9.8) and thyroid cancer (IMR = 5.3). Only in liver cancer did mortality track incidence (IMR = 1.1). For four cancer sites; uterine, prostate, oral and thyroid, incidence and mortality trends are suggestive of overdiagnosis. Trends in melanoma and kidney cancer suggest potential overdiagnosis and an underlying increase in true risk, whereas for cervical and breast cancer, trends may also reflect improvements in treatments or earlier diagnosis. A more detailed analysis is required to fully understand these patterns.
A systems-approach reveals human nestin is an endothelial-enriched, angiogenesis-independent intermediate filament protein
Authors: Dusart Philip , Fagerberg Linn , Perisic Ljubica , Civelek Mete , Struck Eike , Hedin Ulf , Uhlén Mathias , Trégouët David-Alexandre , Renné Thomas , Odeberg Jacob , Butler Lynn M.
Published: September 2018

The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein.
An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation
Authors: Blancard Malorie , Debbiche Amal , Kato Koichi , Cardin Christelle , Sabrina Guichard , Gandjbakhch Estelle , Probst Vincent , Haissaguerre Michel , Extramiana Fabrice , Hocini Mélèze , Olivier Geoffroy , Leenhardt Antoine , Guicheney Pascale , Rougier Jean-Sébastien
Published: September 2018

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Cav1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Cav1.2 variants. Cav1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Cav1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Cavα1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Cavα1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Cavα1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.
The Role of p53 in Determining Mitochondrial Adaptations to Endurance Training in Skeletal Muscle
Authors: Beyfuss Kaitlyn , Erlich Avigail T. , Triolo Matthew , Hood David A.
Published: September 2018

p53 plays an important role in regulating mitochondrial homeostasis. However, it is unknown whether p53 is required for the physiological and mitochondrial adaptations with exercise training. Furthermore, it is also unknown whether impairments in the absence of p53 are a result of its loss in skeletal muscle, or a secondary effect due to its deletion in alternative tissues. Thus, we investigated the role of p53 in regulating mitochondria both basally, and under the influence of exercise, by subjecting C57Bl/6J whole-body (WB) and muscle-specific p53 knockout (mKO) mice to a 6-week training program. Our results confirm that p53 is important for regulating mitochondrial content and function, as well as proteins within the autophagy and apoptosis pathways. Despite an increased proportion of phosphorylated p53 (Ser15) in the mitochondria, p53 is not required for training-induced adaptations in exercise capacity or mitochondrial content and function. In comparing mouse models, similar directional alterations were observed in basal and exercise-induced signaling modifications in WB and mKO mice, however the magnitude of change was less pronounced in the mKO mice. Our data suggest that p53 is required for basal mitochondrial maintenance in skeletal muscle, but is not required for the adaptive responses to exercise training.
Spatial Characterization of Soybean Yield and Quality (Amino Acids, Oil, and Protein) for United States
Authors: Assefa Y. , Bajjalieh N. , Archontoulis S. , Casteel S. , Davidson D. , Kovács P. , Naeve S. , Ciampitti Ignacio A.
Published: September 2018

Continued economic relevancy of soybean is a function of seed quality. The objectives of this study were to: (i) assess the spatial association between soybean yield and quality across major US soybean producing regions, (ii) investigate the relationship between protein, oil, and yield with amino acids (AAs) composition, and (iii) study interrelationship among essential AAs in soybean seed. Data from soybean testing programs conducted across 14 US states from 2012 to 2016 period (n = 35,101 data points) were analyzed. Results indicate that for each Mg ha−1 yield increase, protein yield increased by 0.35 Mg protein ha−1 and oil yield improved by 0.20 Mg oil ha−1. Essential AA concentrations exhibit a spatial autocorrelation and there was a negative relationship between concentration of AA, protein, and oil, with latitude. There was a positive interrelationship with different degree of strength among all AAs, and the correlation between Isoleucine and Valine was the strongest (r = 0.93) followed by the correlation among Arginine, Leucine, Lysine, and Threonine (0.71 < r < 0.88). We concluded that the variability in genotype (G) x management (M) x environment (E) across latitudes influencing yield also affected soybean quality; AA, protein, and oil content in a similar manner.
Increased TIMP-3 expression alters the cellular secretome through dual inhibition of the metalloprotease ADAM10 and ligand-binding of the LRP-1 receptor
Authors: Scilabra Simone D. , Pigoni Martina , Pravatá Veronica , Schätzl Tobias , Müller Stephan A. , Troeberg Linda , Lichtenthaler Stefan F.
Published: September 2018

The tissue inhibitor of metalloproteinases-3 (TIMP-3) is a major regulator of extracellular matrix turnover and protein shedding by inhibiting different classes of metalloproteinases, including disintegrin metalloproteinases (ADAMs). Tissue bioavailability of TIMP-3 is regulated by the endocytic receptor low-density-lipoprotein receptor-related protein-1 (LRP-1). TIMP-3 plays protective roles in disease. Thus, different approaches have been developed aiming to increase TIMP-3 bioavailability, yet overall effects of increased TIMP-3in vivohave not been investigated. Herein, by using unbiased mass-spectrometry we demonstrate that TIMP-3-overexpression in HEK293 cells has a dual effect on shedding of transmembrane proteins and turnover of soluble proteins. Several membrane proteins showing reduced shedding are known as ADAM10 substrates, suggesting that exogenous TIMP-3 preferentially inhibits ADAM10 in HEK293 cells. Additionally identified shed membrane proteins may be novel ADAM10 substrate candidates. TIMP-3-overexpression also increased extracellular levels of several soluble proteins, including TIMP-1, MIF and SPARC. Levels of these proteins similarly increased upon LRP-1 inactivation, suggesting that TIMP-3 increases soluble protein levels by competing for their binding to LRP-1 and their subsequent internalization. In conclusion, our study reveals that increased levels of TIMP-3 induce substantial modifications in the cellular secretome and that TIMP-3-based therapies may potentially provoke undesired, dysregulated functions of ADAM10 and LRP-1.
Atorvastatin provides a new lipidome improving early regeneration after partial hepatectomy in osteopontin deficient mice
Authors: Nuñez-Garcia Maitane , Gomez-Santos Beatriz , Saenz de Urturi Diego , Mestre Daniela , Gonzalez-Romero Francisco , Buque Xabier , Gutiérrez-de Juan Virginia , Martinez-Chantar María Luz , Syn Wing-Kin , Fresnedo Olatz , Aspichueta Patricia
Published: September 2018

Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of phosphatidylcholine and triacylglycerol (TG) species primarily during the first 24 h after PH, with minimal effects on regeneration. Changes in the quiescent liver lipidome in OPN-KO mice included TG enrichment with linoleic acid and were associated with higher lysosome TG-hydrolase activity that maintained 24 h after PH but increased in WT mice. OPN-KO mice showed increased beta-oxidation 24 h after PH with less body weight loss. In OPN-KO mice, atorvastatin treatment induced changes in the lipidome 24 h after PH and improved liver regeneration while no effect was observed 48 h post-PH. These results suggest that increased dietary-lipid uptake in OPN-KO mice provides the metabolic precursors required for regeneration 24 h and 48 h after PH. However, atorvastatin treatment offers a new metabolic program that improves early regeneration when OPN is deficient.
A novel ulvan lyase family with broad-spectrum activity from the ulvan utilisation loci of Formosa agariphila KMM 3901
Authors: Konasani Venkat Rao , Jin Chunsheng , Karlsson Niclas G. , Albers Eva
Published: September 2018

Ulvan, which is one of the major structural polysaccharides of the cell walls of green macroalgae, is degraded by ulvan lyases via the β-elimination mechanism with the release of oligosaccharides that have unsaturated 4-deoxy-L-threo-hex-4-enopyranosiduronic acid (∆) at the non-reducing end. These ulvan lyases belong to the PL24 or PL25 or PL28 family in the CAZy database. In this study, we identify and biochemically characterise a periplasmic novel broad-spectrum ulvan lyase from Formosa agariphila KMM 3901. The lyase was overexpressed in Escherichia coli, and the purified recombinant enzyme depolymerised ulvan in an endolytic manner with a Km of 0.77 mg/ml, and displayed optimum activity at 40 °C and pH 8. This lyase also degraded heparan sulphate and chondroitin sulphate. Detailed analyses of the end-products of the enzymatic degradation of ulvan using 1H- and 13C-NMR and LC-MS revealed an unsaturated disaccharide (∆Rha3S) and a tetrasaccharide (∆Rha3S-Xyl-Rha) as the principal end-products. In contrast to the previously described ulvan lyases, this novel lyase is mostly composed of α-helices that form an (α/α)6 incomplete toroid domain and displays a remarkably broad-spectrum activity. This novel lyase is the first member of a new family of ulvan lyases.
Counterfactual Bell-State Analysis
Authors: Zaman Fakhar , Jeong Youngmin , Shin Hyundong
Published: September 2018

The Bell-state analysis to distinguish between the four maximally entangled Bell states requires the joint measurement on entangled particles. However, spatially separated parties cannot perform the joint measurement. In this paper, we present a counterfactual Bell-state analysis based on the chained quantum Zeno effect. This counterfactual analysis not only enables us to perform a complete Bell-state analysis, but also enables spatially separated parties to distinguish between the four Bell states without transmitting any physical particle over the channel.
Angiogenic Properties of ‘Leukocyte- and Platelet-Rich Fibrin’
Authors: Ratajczak Jessica , Vangansewinkel Tim , Gervois Pascal , Merckx Greet , Hilkens Petra , Quirynen Marc , Lambrichts Ivo , Bronckaers Annelies
Published: September 2018

Leukocyte- and Platelet-Rich Fibrin (L-PRF) is an autologous platelet concentrate, consisting of a fibrin matrix enriched with platelets, leukocytes and a plethora of cytokines and growth factors. Since L-PRF is produced bedside from whole blood without the use of an anti-coagulant, it is becoming a popular adjuvant in regenerative medicine. While other types of platelet concentrates have been described to stimulate blood vessel formation, little is known about the angiogenic capacities of L-PRF. Therefore, this study aimed to fully characterize the angiogenic potential of L-PRF. With an antibody array, the growth factors released by L-PRF were determined and high levels of CXC chemokine receptor 2 (CXCR-2) ligands and epidermal growth factor (EGF) were found. L-PRF induced in vitro key steps of the angiogenic process: endothelial proliferation, migration and tube formation. In addition, we could clearly demonstrate that L-PRF is able to induce blood vessel formation in vivo, the chorioallantoic membrane assay. In conclusion, we could demonstrate the angiogenic capacity of L-PRF both in vitro and in vivo, underlying the clinical potential of this easy-to-use platelet concentrate.
Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants
Authors: Falk Martin , Falková Iva , Kopečná Olga , Bačíková Alena , Pagáčová Eva , Šimek Daniel , Golan Martin , Kozubek Stanislav , Pekarová Michaela , Follett Shelby E. , Klejdus Bořivoj , Elliott K. Wade , Varga Krisztina , Teplá Olga , Kratochvílová Irena
Published: September 2018

In this work, we shed new light on the highly debated issue of chromatin fragmentation in cryopreserved cells. Moreover, for the first time, we describe replicating cell-specific DNA damage and higher-order chromatin alterations after freezing and thawing. We identified DNA structural changes associated with the freeze-thaw process and correlated them with the viability of frozen and thawed cells. We simultaneously evaluated DNA defects and the higher-order chromatin structure of frozen and thawed cells with and without cryoprotectant treatment. We found that in replicating (S phase) cells, DNA was preferentially damaged by replication fork collapse, potentially leading to DNA double strand breaks (DSBs), which represent an important source of both genome instability and defects in epigenome maintenance. This induction of DNA defects by the freeze-thaw process was not prevented by any cryoprotectant studied. Both in replicating and non-replicating cells, freezing and thawing altered the chromatin structure in a cryoprotectant-dependent manner. Interestingly, cells with condensed chromatin, which was strongly stimulated by dimethyl sulfoxide (DMSO) prior to freezing had the highest rate of survival after thawing. Our results will facilitate the design of compounds and procedures to decrease injury to cryopreserved cells.
A systems biology approach to explore the impact of maple tree dormancy release on sap variation and maple syrup quality
Authors: N’guyen Guillaume Quang , Martin Nathalie , Jain Mani , Lagacé Luc , Landry Christian R. , Filteau Marie
Published: September 2018

Maple sap is a complex nutrient matrix collected during spring to produce maple syrup. The characteristics of sap change over the production period and its composition directly impacts syrup quality. This variability could in part be attributed to changes in tree metabolism following dormancy release, but little is known about these changes in deciduous trees. Therefore, understanding the variation in sap composition associated with dormancy release could help pinpoint the causes of some defects in maple syrup. In particular, a defect known as “buddy”, is an increasing concern for the industry. This off-flavor appears around the time of bud break, hence its name. To investigate sap variation related to bud break and the buddy defect, we monitored sap variation with respect to a dormancy release index (Sbb) and syrup quality. First, we looked at variation in amino acid content during this period. We observed a shift in amino acid relative proportions associated with dormancy release and found that most of them increase rapidly near the point of bud break, correlating with changes in syrup quality. Second, we identified biological processes that respond to variation in maple sap by performing a competition assay using the barcoded Saccharomyces cerevisiae prototroph deletion collection. This untargeted approach revealed that the organic sulfur content may be responsible for the development of the buddy off-flavor, and that dormancy release is necessary for the appearance of the defect, but other factors such as microbial activity may also be contributing.
The imprinted gene Pw1/Peg3 regulates skeletal muscle growth, satellite cell metabolic state, and self-renewal
Authors: Correra Rosa Maria , Ollitrault David , Valente Mariana , Mazzola Alessia , Adalsteinsson Bjorn T. , Ferguson-Smith Anne C. , Marazzi Giovanna , Sassoon David A.
Published: September 2018

Pw1/Peg3 is an imprinted gene expressed from the paternally inherited allele. Several imprinted genes, including Pw1/Peg3, have been shown to regulate overall body size and play a role in adult stem cells. Pw1/Peg3 is expressed in muscle stem cells (satellite cells) as well as a progenitor subset of muscle interstitial cells (PICs) in adult skeletal muscle. We therefore examined the impact of loss-of-function of Pw1/Peg3 during skeletal muscle growth and in muscle stem cell behavior. We found that constitutive loss of Pw1/Peg3 function leads to a reduced muscle mass and myofiber number. In newborn mice, the reduction in fiber number is increased in homozygous mutants as compared to the deletion of only the paternal Pw1/Peg3 allele, indicating that the maternal allele is developmentally functional. Constitutive and a satellite cell-specific deletion of Pw1/Peg3, revealed impaired muscle regeneration and a reduced capacity of satellite cells for self-renewal. RNA sequencing analyses revealed a deregulation of genes that control mitochondrial function. Consistent with these observations, Pw1/Peg3 mutant satellite cells displayed increased mitochondrial activity coupled with accelerated proliferation and differentiation. Our data show that Pw1/Peg3 regulates muscle fiber number determination during fetal development in a gene-dosage manner and regulates satellite cell metabolism in the adult.
Single shot femtosecond laser nano-ablation of CVD monolayer graphene
Authors: Gil-Villalba A. , Meyer R. , Giust R. , Rapp L. , Billet C. , Courvoisier F.
Published: September 2018

We investigate ablation of CVD monolayer graphene by femtosecond pulses in the single shot regime. We show that the ablation probability of flat graphene drastically reduces for small illumination diameters even if the ablation threshold is exceeded. However, the presence of graphene wrinkles enhances the ablation probability. This is interpreted in terms of electron and energy diffusion within the graphene layer. This differentiated behavior is a drawback for single shot laser nanopatterning. The morphology of the holes with minimal diameter depends on the fluence distribution at ablation threshold. Strong fluence gradients due to strong focussing produce an explosive folding of graphene during ablation.
Microgravity induces autophagy via mitochondrial dysfunction in human Hodgkin’s lymphoma cells
Authors: Jeong Ae Jin , Kim Yoon Jae , Lim Min Hyuk , Lee Haeri , Noh Kumhee , Kim Byung-Hak , Chung Jin Woong , Cho Chung-Hyun , Kim Sungwan , Ye Sang-Kyu
Published: September 2018

Gravitational forces can impose physical stresses on the human body as it functions to maintain homeostasis. It has been reported that astronauts exposed to microgravity experience altered biological functions and many subsequent studies on the effects of microgravity have therefore been conducted. However, the anticancer mechanisms of simulated microgravity remain unclear. We previously showed that the proliferation of human Hodgkin’s lymphoma (HL) cells was inhibited when these cells were cultured in time-averaged simulated microgravity (taSMG). In the present study, we investigated whether taSMG produced an anticancer effect. Exposure of human HL cells to taSMG for 2 days increased their reactive oxygen species (ROS) production and NADPH oxidase family gene expression, while mitochondrial mass, ATPase, ATP synthase, and intracellular ATP levels were decreased. Furthermore, human HL cells exposed to taSMG underwent autophagy via AMPK/Akt/mTOR and MAPK pathway modulation; such autophagy was inhibited by the ROS scavenger N-acetylcysteine (NAC). These results suggest an innovative therapeutic approach to HL that is markedly different from conventional chemotherapy and radiotherapy.
Contrast-enhanced ultrasound tractography for 3D vascular imaging of the prostate
Authors: van Sloun Ruud J. G. , Demi Libertario , Schalk Stefan G. , Caresio Cristina , Mannaerts Christophe , Postema Arnoud W. , Molinari Filippo , van der Linden Hans C. , Huang Pingtong , Wijkstra Hessel , Mischi Massimo
Published: September 2018

Diffusion tensor tractography (DTT) enables visualization of fiber trajectories in soft tissue using magnetic resonance imaging. DTT exploits the anisotropic nature of water diffusion in fibrous structures to identify diffusion pathways by generating streamlines based on the principal diffusion vector. Anomalies in these pathways can be linked to neural deficits. In a different field, contrast-enhanced ultrasound is used to assess anomalies in blood flow with the aim of locating cancer-induced angiogenesis. Like water diffusion, blood flow and transport of contrast agents also shows a principal direction; however, this is now determined by the local vasculature. Here we show how the tractographic techniques developed for magnetic resonance imaging DTT can be translated to contrast-enhanced ultrasound, by first estimating contrast flow velocity fields from contrast-enhanced ultrasound acquisitions, and then applying tractography. We performed 4D in-vivo contrast-enhanced ultrasound of three human prostates, proving the feasibility of the proposed approach with clinically acquired datasets. By comparing the results to histopathology after prostate resection, we observed qualitative agreement between the contrast flow tracts and typical markers of cancer angiogenic microvasculature: higher densities and tortuous geometries in tumor areas. The method can be used in-vivo using a standard contrast-enhanced ultrasound protocol, opening up new possibilities in the area of vascular characterization for cancer diagnostics.
The intracellular proteome of African swine fever virus
Authors: Keßler Catharina , Forth Jan H. , Keil Günther M. , Mettenleiter Thomas C. , Blome Sandra , Karger Axel
Published: September 2018

African swine fever (ASF) is a viral disease that affects members of the Suidae family such as African bush pigs, warthogs, but also domestic pigs, and wild boar. It is transmitted by direct contact of naïve with infected animals, by soft ticks of the Ornithodoros genus, or indirectly by movement of infected animals, improper disposal of contaminated animal products or other sources related to human activity. The recent spread of ASF into Eastern and Central European countries is currently threatening the European pig industry. The situation is aggravated as to-date no efficient vaccine is available. African swine fever virus (ASFV) is a large enveloped ds DNA-virus encoding at least 150 open reading frames. Many of the deduced gene products have not been described, less functionally characterized. We have analysed ASFV protein expression in three susceptible mammalian cell lines representing a susceptible host (wild boar) and two non-susceptible species (human and green monkey) by mass spectrometry and provide first evidence for the expression of 23 so far uncharacterized ASFV ORFs. Expression levels of several newly identified ASFV proteins were remarkably high indicating importance in the viral replication cycle. Moreover, expression profiles of ASFV proteins in the three cell lines differed markedly.
Dynamics of error-related activity in deterministic learning - an EEG and fMRI study
Authors: Gawlowska Magda , Domagalik Aleksandra , Beldzik Ewa , Marek Tadeusz , Mojsa-Kaja Justyna
Published: September 2018

There is a close relationship between progress in learning and the error-monitoring system. EEG and fMRI studies using probabilistic learning have revealed the distinct dynamics of this system after response and feedback, i.e. an increase of error-related and a decrease of feedback-related activity in the anterior cingulate cortex (ACC). Based on the existing theories, it can be presumed that during deterministic learning feedback-related activity in ACC would also increase. Since these assumptions have not yet been confirmed, it can be only speculated based on the data from the probabilistic paradigms how the information is being integrated within the ACC during deterministic learning. Here we implemented the Paired Associate Deterministic Learning task to the EEG and fMRI experiments. The analysis of EEG data showed a significant increase in the amplitude for both ERN and FN. Similarly, the fMRI results showed an increase in response-related and feedback-related activity of the ACC in erroneous trials. Our findings are in line with the current theories of ACC function: increasing ACC activity can be linked to the detected discrepancy between expected and obtained outcomes. We argue that expectancy violations in the course of deterministic learning are signalled by both, internal and external evaluation system.
Author Correction: Maternal obesity-induced decreases in plasma, hepatic and uterine polyunsaturated fatty acids during labour is reversed through improved nutrition at conception
Authors: Muir Ronan , Liu Ge , Khan Raheela , Shmygol Anatoly , Quenby Siobhan , Gibson Robert Alan , Muhlhausler Beverly , Elmes Matthew
Published: September 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Local confinement of disease-related microbiome facilitates recovery of gorgonian sea fans from necrotic-patch disease
Authors: Quintanilla Elena , Ramírez-Portilla Catalina , Adu-Oppong Boahemaa , Walljasper Gretchen , Glaeser Stefanie P. , Wilke Thomas , Muñoz Alejandro Reyes , Sánchez Juan A.
Published: September 2018

Microbiome disruptions triggering disease outbreaks are increasingly threatening corals worldwide. In the Tropical Eastern Pacific, a necrotic-patch disease affecting gorgonian corals (sea fans, Pacifigorgia spp.) has been observed in recent years. However, the composition of the microbiome and its disease-related disruptions remain unknown in these gorgonian corals. Therefore, we analysed 16S rRNA gene amplicons from tissues of healthy colonies (n = 19) and from symptomatic-asymptomatic tissues of diseased colonies (n = 19) of Pacifigorgia cairnsi (Gorgoniidae: Octocorallia) in order to test for disease-related changes in the bacterial microbiome. We found that potential endosymbionts (mostly Endozoicomonas spp.) dominate the core microbiome in healthy colonies. Moreover, healthy tissues differed in community composition and functional profile from those of the symptomatic tissues but did not show differences to asymptomatic tissues of the diseased colonies. A more diverse set of bacteria was observed in symptomatic tissues, together with the decline in abundance of the potential endosymbionts from the healthy core microbiome. Furthermore, according to a comparative taxonomy-based functional profiling, these symptomatic tissues were characterized by the increase in heterotrophic, ammonia oxidizer and dehalogenating bacteria and by the depletion of nitrite and sulphate reducers. Overall, our results suggest that the bacterial microbiome associated with the disease behaves opportunistically and is likely in a state of microbial dysbiosis. We also conclude that the confinement of the disease-related consortium to symptomatic tissues may facilitate colony recovery.
Development of a deep residual learning algorithm to screen for glaucoma from fundus photography
Authors: Shibata Naoto , Tanito Masaki , Mitsuhashi Keita , Fujino Yuri , Matsuura Masato , Murata Hiroshi , Asaoka Ryo
Published: September 2018

The Purpose of the study was to develop a deep residual learning algorithm to screen for glaucoma from fundus photography and measure its diagnostic performance compared to Residents in Ophthalmology. A training dataset consisted of 1,364 color fundus photographs with glaucomatous indications and 1,768 color fundus photographs without glaucomatous features. A testing dataset consisted of 60 eyes of 60 glaucoma patients and 50 eyes of 50 normal subjects. Using the training dataset, a deep learning algorithm known as Deep Residual Learning for Image Recognition (ResNet) was developed to discriminate glaucoma, and its diagnostic accuracy was validated in the testing dataset, using the area under the receiver operating characteristic curve (AROC). The Deep Residual Learning for Image Recognition was constructed using the training dataset and validated using the testing dataset. The presence of glaucoma in the testing dataset was also confirmed by three Residents in Ophthalmology. The deep learning algorithm achieved significantly higher diagnostic performance compared to Residents in Ophthalmology; with ResNet, the AROC from all testing data was 96.5 (95% confidence interval [CI]: 93.5 to 99.6)% while the AROCs obtained by the three Residents were between 72.6% and 91.2%.
Label-free Evaluation of Myocardial Infarct in Surgically Excised Ventricular Myocardium by Raman Spectroscopy
Authors: Yamamoto Tsunehisa , Minamikawa Takeo , Harada Yoshinori , Yamaoka Yoshihisa , Tanaka Hideo , Yaku Hitoshi , Takamatsu Tetsuro
Published: September 2018

Understanding the viability of the ischemic myocardial tissue is a critical issue in determining the appropriate surgical procedure for patients with chronic heart failure after myocardial infarction (MI). Conventional MI evaluation methods are; however, preoperatively performed and/or give an indirect information of myocardial viability such as shape, color, and blood flow. In this study, we realize the evaluation of MI in patients undergoing cardiac surgery by Raman spectroscopy under label-free conditions, which is based on intrinsic molecular constituents related to myocardial viability. We identify key signatures of Raman spectra for the evaluation of myocardial viability by evaluating the infarct border zone myocardium that were excised from five patients under surgical ventricular restoration. We also obtain a prediction model to differentiate the infarcted myocardium from the non-infarcted myocardium by applying partial least squares regression-discriminant analysis (PLS-DA) to the Raman spectra. Our prediction model enables identification of the infarcted tissues and the non-infarcted tissues with sensitivities of 99.98% and 99.92%, respectively. Furthermore, the prediction model of the Raman images of the infarct border zone enabled us to visualize boundaries between these distinct regions. Our novel application of Raman spectroscopy to the human heart would be a useful means for the detection of myocardial viability during surgery.
Single Dose Administration of Taheebo Polyphenol Enhances Endurance Capacity in Mice
Authors: Yada Koichi , Suzuki Katsuhiko , Oginome Natsumi , Ma Sihui , Fukuda Youichi , Iida Akira , Radak Zsolt
Published: September 2018

Endurance capacity is important for maintenance of quality of life as well as performance of endurance athletes. In order to improve endurance, intake of nutritional supplements as well as exercise training is also important. Indeed, polyphenolic extracts from plants are known to improve endurance capacity via increase of fatty acid utilization, mitochondrial biogenesis or inhibition of oxidative stress. Taheebo, the extract obtained from inner bark of Tabebuia avellanedae has been reported to have beneficial effects for treatment of inflammation, oxidative stress and obesity. Here, we investigated the effects and mechanisms of polyphenol fraction of taheebo (taheebo polyphenol; TP) on endurance capacity of mice. Single dose administration of TP significantly increased running time until exhaustion. Acute TP administration increased blood glucose and muscle glycogen levels (p < 0.05) through alteration on expression level of genes involved with glycogen metabolism and gluconeogenesis. Furthermore, TP administration decreased exercise-induced increase of protein carbonyls in skeletal muscle. These results suggest that TP administration improve endurance capacity via up-regulation of skeletal muscle glycogen levels and maintenance of blood glucose by acceleration of gluconeogenesis as well as inhibition of exercise-induced oxidative stress. Single administration of TP also increased phosphorylation of AMP-activated protein kinase (AMPK) and gene expression level of sirtuin 1 (SIRT1) but did not change the marker of mitochondrial biogenesis.
The evolutionary conserved FOXJ1 target gene Fam183b is essential for motile cilia in Xenopus but dispensable for ciliary function in mice
Authors: Beckers Anja , Ott Tim , Schuster-Gossler Karin , Boldt Karsten , Alten Leonie , Ueffing Marius , Blum Martin , Gossler Achim
Published: September 2018

The transcription factor FOXJ1 is essential for the formation of motile cilia throughout the animal kingdom. Target genes therefore likely constitute an important part of the motile cilia program. Here, we report on the analysis of one of these targets, Fam183b, in Xenopus and mice. Fam183b encodes a protein with unknown function which is conserved from the green algae Chlamydomonas to humans. Fam183b is expressed in tissues harbouring motile cilia in both mouse and frog embryos. FAM183b protein localises to basal bodies of cilia in mIMCD3 cells and of multiciliated cells of the frog larval epidermis. In addition, FAM183b interacts with NUP93, which also localises to basal bodies. During frog embryogenesis, Fam183b was dispensable for laterality specification and brain development, but required for ciliogenesis and motility of epidermal multiciliated cells and nephrostomes, i.e. the embryonic kidney. Surprisingly, mice homozygous for a null allele did not display any defects indicative of disrupted motile ciliary function. The lack of a cilia phenotype in mouse and the limited requirements in frog contrast with high sequence conservation and the correlation of gene expression with the presence of motile cilia. This finding may be explained through compensatory mechanisms at sites where no defects were observed in our FAM183b-loss-of-function studies.
Genetic conflicts with Plasmodium parasites and functional constraints shape the evolution of erythrocyte cytoskeletal proteins
Authors: Sironi Manuela , Forni Diego , Clerici Mario , Cagliani Rachele
Published: September 2018

Plasmodium parasites exerted a strong selective pressure on primate genomes and mutations in genes encoding erythrocyte cytoskeleton proteins (ECP) determine protective effects against Plasmodium infection/pathogenesis. We thus hypothesized that ECP-encoding genes have evolved in response to Plasmodium-driven selection. We analyzed the evolutionary history of 15 ECP-encoding genes in primates, as well as of their Plasmodium-encoded ligands (KAHRP, MESA and EMP3). Results indicated that EPB42, SLC4A1, and SPTA1 evolved under pervasive positive selection and that episodes of positive selection tended to occur more frequently in primate species that host a larger number of Plasmodium parasites. Conversely, several genes, including ANK1 and SPTB, displayed extensive signatures of purifying selection in primate phylogenies, Homininae lineages, and human populations, suggesting strong functional constraints. Analysis of Plasmodium genes indicated adaptive evolution in MESA and KAHRP; in the latter, different positively selected sites were located in the spectrin-binding domains. Because most of the positively selected sites in alpha-spectrin localized to the domains involved in the interaction with KAHRP, we suggest that the two proteins are engaged in an arms-race scenario. This observation is relevant because KAHRP is essential for the formation of “knobs”, which represent a major virulence determinant for P. falciparum.
Relationship between the Second to Fourth Finger Length Ratio and Calcaneus Quantitative Ultrasound
Authors: Takahata Yoko , Hirokawa Kumi
Published: September 2018

This study aimed to characterize the relationship between the ratio of the length of the second and fourth fingers (2D:4D value) and the speed of sound of the calcaneus by quantitative ultrasound (QUS-SOS) in undergraduate female students. We recruited 138 young women with a mean age of 19.6 ± 1.4 years. The participants’ calcaneus QUS-SOS was measured using an ultrasound bone densitometer. We also measured the participants’ weight, height, and grip strength. A self-reported questionnaire was used to obtain information on participants’ secondary sexual characteristics, and exercise habits. The present study showed that the 2D:4D value of both hands was significantly correlated with the calcaneus QUS-SOS. The 2D:4D value of the left hand was also positively associated with the calcaneus QUS-SOS results in several respects. These findings suggest that the 2D:4D value may be useful for the screening of risk for a low bone quality in undergraduate female students.
Global patterns of change and variation in sea surface temperature and chlorophyll a
Authors: Dunstan Piers K. , Foster Scott D. , King Edward , Risbey James , O’Kane Terence J. , Monselesan Didier , Hobday Alistair J. , Hartog Jason R. , Thompson Peter A.
Published: September 2018

Changes over the scale of decades in oceanic environments present a range of challenges for management and utilisation of ocean resources. Here we investigate sources of global temporal variation in Sea Surface Temperature (SST) and Ocean Colour (Chl-a) and their co-variation, over a 14 year period using statistical methodologies that partition sources of variation into inter-annual and annual components and explicitly account for daily auto-correlation. The variation in SST shows bands of increasing variability with increasing latitude, while the analysis of annual variability in Chl-a shows mostly mid-latitude high variability bands. Covariation patterns of SST and Chl-a suggests several different mechanisms impacting Chl-a change and variance. Our high spatial resolution analysis indicates these are likely to be operating at relatively small spatial scales. There are large regions showing warming and rising of Chl-a, contrasting with regions that show warming and decreasing Chl-a. The covariation pattern in annual variation in SST and Chl-a reveals broad latitudinal bands. On smaller scales there are significant regional anomalies where upwellings are known to occur. Over decadal time scales both trend and variation in SST, Chl-a and their covariance is highly spatially heterogeneous, indicating that monitoring and resource management must be regionally appropriate.
Metabolic Alterations Associated with Atorvastatin/Fenofibric Acid Combination in Patients with Atherogenic Dyslipidaemia: A Randomized Trial for Comparison with Escalated-Dose Atorvastatin
Authors: Han Ji Soo , Kim Kyu , Jung Youngae , Lee Jae-Hwan , Namgung June , Lee Hae-Young , Suh Jon , Hwang Geum-Sook , Lee Sang-Hak
Published: September 2018

In the current study, the metabolic effects of atorvastatin dose escalation versus atorvastatin/fenofibric acid combination were compared using metabolomics analyses. Men and women with combined hyperlipidaemia were initially prescribed atorvastatin (10 mg, ≥4 weeks). Patients who reached low-density lipoprotein-cholesterol targets, but had triglyceride and high-density lipoprotein-cholesterol levels ≥150 mg/dL and <50 mg/dL, respectively, were randomized to receive atorvastatin 20 mg or atorvastatin 10 mg/fenofibric acid 135 mg for 12 weeks. Metabolite profiling of serum was performed and changes in metabolites after drug treatment in the two groups were compared. Analysis was performed using patients’ samples obtained before and after treatment. Of 89 screened patients, 37 who met the inclusion criteria were randomized, and 34 completed the study. Unlike that in the dose-escalation group, distinct clustering of both lipid and aqueous metabolites was observed in the combination group after treatment. Most lipid metabolites of acylglycerols and many of ceramides decreased, while many of sphingomyelins increased in the combination group. Atorvastatin dose escalation modestly decreased lysophosphatidylcholines; however, the effect of combination therapy was variable. Most aqueous metabolites decreased, while l-carnitine remarkably increased in the combination group. In conclusion, the atorvastatin/fenofibric acid combination induced distinct metabolite clustering. Our results provide comprehensive information regarding metabolic changes beyond conventional lipid profiles for this combination therapy.
Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation
Authors: Holtgrewe Manuel , Knaus Alexej , Hildebrand Gabriele , Pantel Jean-Tori , Santos Miguel Rodriguez de los , Neveling Kornelia , Goldmann Jakob , Schubach Max , Jäger Marten , Coutelier Marie , Mundlos Stefan , Beule Dieter , Sperling Karl , Krawitz Peter Michael
Published: September 2018

A genome-wide evaluation of the effects of ionizing radiation on mutation induction in the mouse germline has identified multisite de novo mutations (MSDNs) as marker for previous exposure. Here we present the results of a small pilot study of whole genome sequencing in offspring of soldiers who served in radar units on weapon systems that were emitting high-frequency radiation. We found cases of exceptionally high MSDN rates as well as an increased mean in our cohort: While a MSDN mutation is detected in average in 1 out of 5 offspring of unexposed controls, we observed 12 MSDNs in altogether 18 offspring, including a family with 6 MSDNs in 3 offspring. Moreover, we found two translocations, also resulting from neighboring mutations. Our findings indicate that MSDNs might be suited in principle for the assessment of DNA damage from ionizing radiation also in humans. However, as exact person-related dose values in risk groups are usually not available, the interpretation of MSDNs in single families would benefit from larger molecular epidemiologic studies on this new biomarker.
NMR spectroscopy enables simultaneous quantification of carbohydrates for diagnosis of intestinal and gastric permeability
Authors: Stryeck Sarah , Horvath Angela , Leber Bettina , Stadlbauer Vanessa , Madl Tobias
Published: September 2018

Increased intestinal or gastric permeability is one of the major hallmarks of liver cirrhosis. The current gold standard for diagnosis of aberrant gut permeability due to disease is the triple-sugar test, where carbohydrates are orally administered and urinary excretion is measured. Hereby, elevated lactulose levels indicate intestinal permeability, whereas increased sucrose levels reveal gastric permeability. However, reliable detection and quantification of these sugars in a complex biological fluid still remains challenging due to interfering substances. Here we used Nuclear Magnetic Resonance (NMR) spectroscopy with a simple and fast protocol, without any additional sample extraction steps, for straight-forward simultaneous quantification of sugars in urine in order to detect increased intestinal and gastric permeability. Collected urine samples were diluted in buffer and one- and two-dimensional proton spectra were recorded in order to reveal carbohydrate concentrations in individual urine samples containing mannitol, sucrose and/or lactulose. Overall, this article presents a fast and robust method for simultaneous quantification of different sugars down to low micro-molar concentrations for research studies and can be further extended for clinical studies with automation of the quantification process.
Resilience to climate variation in a spatially structured amphibian population
Authors: Weinbach A. , Cayuela H. , Grolet O. , Besnard A. , Joly P.
Published: September 2018

Understanding the impact of weather fluctuations on demographic parameters is of crucial interest to biodiversity research in a context of global climate change. Amphibians are valuable candidates for investigating this topic due to their strong physiological dependence on water availability and temperature. In this study, we took advantage of data from a long-term capture–mark–recapture (CMR) monitoring program of a great crested newt (Triturus cristatus) population inhabiting a 12-pond archipelago in southeastern France. We investigated the interactions between vital rates (survival and recruitment), the internal structure of the population, and climatic variables both at a local and a regional (North Atlantic Oscillation: NAO) scale. Overall, we found a weak relationship between climatic variables and the survival of large-bodied newts. The only strong relationship was found to be a high NAO index during the post-breeding period, suggesting that dry, hot summers negatively impact survival. In terms of recruitment, the results indicated that hot weather during the activity period had delayed deleterious effects on adult recruitment two years later, suggesting high larval and juvenile mortality due to unsuitable growing conditions. Recruitment was also impacted by a high NAO index during the overwintering period preceding recruitment, suggesting that mild weather increases the mortality of juveniles, probably by enhancing the depletion of energy reserves without any possibility of refueling.