bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploitation may influence the climate resilience of fish populations through removing high performance metabolic phenotypes
Authors: Duncan Murray I. , Bates Amanda E. , James Nicola C. , Potts Warren M.
Published: August 2019

Physiological rates and processes underpin the relationships between ectothermic organisms, such as fish, and their environment. The response and persistence of fish populations in an increasingly variable ocean is dependent on the distribution and diversity of physiological phenotypes. Growing evidence suggests that fisheries exploitation can selectively target certain physiological and behavioural phenotypes, which may shift exploited populations to altered physiological states. Here we test if commercial fisheries have the potential to do this in a “natural laboratory” along the South African coast. We compare metabolic traits of exploited and protected populations of the fish species, Chrysoblephus laticeps, which is a major component of the South African hook and line fishery. We find that high-performance aerobic scope phenotypes are reduced in the fished population. The most likely mechanism for this finding is a positive relationship between aerobic scope and capture vulnerability in passive-gear fisheries. Our results further highlight the selective nature of capture-fisheries and suggest that exploitation has the capacity to alter climate responses of fish populations on a physiological level. Our finding also implicates how Marine Protected Areas, through harbouring individuals with a greater diversity of physiological traits, may provide greater fish response diversity to environmental variability.
Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts
Authors: Nakashima Akitoshi , Cheng Shi-Bin , Kusabiraki Tae , Motomura Kenichiro , Aoki Aiko , Ushijima Akemi , Ono Yosuke , Tsuda Sayaka , Shima Tomoko , Yoshino Osamu , Sago Haruhiko , Matsumoto Kenji , Sharma Surendra , Saito Shigeru
Published: August 2019

Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.
The commensal Escherichia coli CEC15 reinforces intestinal defences in gnotobiotic mice and is protective in a chronic colitis mouse model
Authors: Escribano-Vazquez Unai , Verstraeten Sophie , Martin Rebeca , Chain Florian , Langella Philippe , Thomas Muriel , Cherbuy Claire
Published: August 2019

Escherichia coli is a regular inhabitant of the gut microbiota throughout life. However, its role in gut health is controversial. Here, we investigated the relationship between the commensal E. coli strain CEC15 (CEC), which we previously isolated, and the intestine in homeostatic and disease-prone settings. The impact of CEC was compared to that of the probiotic E. coli Nissle 1917 (Nissle) strain. The expression of ileal and colonic genes that play a key role in intestinal homeostasis was higher in CEC- and Nissle-mono-associated wild-type mice than in germfree mice. This included genes involved in the turnover of reactive oxygen species, antimicrobial peptide synthesis, and immune responses. The impact of CEC and Nissle on such gene expression was stronger in a disease-prone setting, i.e. in gnotobiotic IL10-deficient mice. In a chronic colitis model, CEC more strongly decreased signs of colitis severity (myeloperoxidase activity and CD3+ immune-cell infiltration) than Nissle. Thus, our study shows that CEC and Nissle contribute to increased expression of genes involved in the maintenance of gut homeostasis in homeostatic and inflammatory settings. We show that these E. coli strains, in particular CEC, can have a beneficial effect in a chronic colitis mouse model.
The potential role of scavengers in spreading African swine fever among wild boar
Authors: Probst Carolina , Gethmann Jörn , Amler Susanne , Globig Anja , Knoll Bent , Conraths Franz J.
Published: August 2019

Understanding the transmission patterns of African swine fever (ASF) among wild boar (Sus scrofa) is an issue of major interest, especially in the wake of the current ASF epidemic. Given the high stability of ASF-virus, there is concern about scavengers spreading infectious carcass material in the environment. Here, we describe scavenging activities on 32 wild boar carcasses in their natural habitat in Germany. Using digital cameras, we detected 22 vertebrates at the study sites, thereof two mammal and three bird species scavenging. The most frequently detected species was the raccoon dog Nyctereutes procyonoides (44% of all visits). Raccoon dogs, red foxes (Vulpes vulpes), and buzzards (Buteo buteo) scavenged in the warm and the cold season, while ravens (Corvus corax) and white-tailed eagles (Haliaeetus albicilla) scavenged only in the cold season. In summer, however, insects removed most of the carcass biomass. Although most of the material was consumed on the spot, foxes, raccoon dogs and ravens left the study sites in rare cases with a small piece of meat in their mouths or beaks. We conclude that scavengers represent a minor risk factor for spreading ASF, but may contribute to reducing local virus persistence by metabolizing infected carcasses.
Ensilication Improves the Thermal Stability of the Tuberculosis Antigen Ag85b and an Sbi-Ag85b Vaccine Conjugate
Authors: Wahid A. A. , Doekhie A. , Sartbaeva A. , van den Elsen J. M. H
Published: August 2019

There is an urgent need for the development of vaccine thermostabilisation methodologies as the maintenance of a continuous and reliable cold chain remains a major hurdle to the global distribution of safe and effective vaccines. Ensilication, a method that encases proteins in a resistant silica cage has been shown to physically prevent the thermal denaturation of a number of model proteins. In this study we investigate the utility of this promising approach in improving the thermal stability of antigens and vaccine conjugates highly relevant to the development of candidate tuberculosis vaccines, including antigen 85b conjugated with theStaphylococcus aureus-protein based adjuvant Sbi. Here we analyse the sensitivity of these constructs to thermal denaturation and demonstrate for the first time the benefits of ensilication in conferring these vaccine-relevant proteins with protection against temperature-induced loss of structure and function without the need for refrigeration. Our results reveal the potential of ensilication in facilitating the storage and transport of vaccines at ambient temperatures in the future and therefore in delivering life-saving vaccines globally, and in particular to remote areas of developing countries where disease rates are often highest.
A gravitational contribution to perceived body weight
Authors: Ferrè E. R. , Frett T. , Haggard P. , Longo M. R.
Published: August 2019

The weightlessness experienced by astronauts has fascinated scientists and the public. On Earth, body weight is given by Newton’s laws as mass times gravitational acceleration. That is, an object’s weight is determined by the pull of gravity on it. We hypothesised that perceived body weight is – like actual weight – dependent on the strength of gravity. If so, changes in the experienced strength of gravity should alter the experience of one’s own body weight. We asked participants to estimate the weight of two body parts, their hand or their head, both in normal terrestrial gravity (1 g) and during exposure to experimentally altered gravitational fields, 0 g and +1.8 g during parabolic flight and +1 g using a short arm human centrifuge. For both body parts, there was an increase in perceived weight during the experience of hypergravity, and a decrease during the experience of microgravity. Our results show that experimental alterations of gravity produce rapid changes in the perceived weight of specific individual body parts. Traditionally, research has focused on the social factors for weight perception, as in the putative role of mass media in eating disorders. Our results, in contrast, emphasize that the perception of body weight is highly malleable, and shaped by immediate sensory signals.
Pharmacologically-induced stress has minimal impact on judgement and attention biases in sheep
Authors: Monk Jessica E. , Belson Sue , Lee Caroline
Published: August 2019

The emotional impact of exposure to stressors has not been well quantified in animals. We hypothesised that exogenous induction of stress in sheep would induce a pessimistic judgement bias and increased attention towards a threatening stimulus, suggestive of a negative emotional state. Stress was induced pharmacologically by administering synthetic adrenocorticotropic hormone. Judgement bias was assessed using a spatial go/no-go task after exposure to acute stress (one injection), chronic stress (21 daily injections) and acute-on-chronic stress (2 min isolation after 28 daily injections). Attention bias was assessed during chronic stress only (22 daily injections). In contrast with our hypotheses, there was no strong evidence that Synacthen administration altered judgement bias or attention bias at any stage of the experiment. Stressed sheep were more likely to approach ambiguous locations than saline Control animals, however, statistical evidence for models fitting treatment group was very weak. Overall, our findings suggest that elevated levels of cortisol may not fully explain changes to judgement bias observed in previous studies after environmentally-induced stress. Further studies are required to better understand which aspects of environmentally-induced stress alter judgement bias and to further validate cognitive methods of assessing affect in sheep.
Recommendations to address uncertainties in environmental risk assessment using toxicokinetic-toxicodynamic models
Authors: Baudrot Virgile , Charles Sandrine
Published: August 2019

Providing reliable environmental quality standards (EQSs) is a challenging issue in environmental risk assessment (ERA). These EQSs are derived from toxicity endpoints estimated from dose-response models to identify and characterize the environmental hazard of chemical compounds released by human activities. These toxicity endpoints include the classicalx% effect/lethal concentrations at a specific timet(EC/LC(x,t)) and the new multiplication factors applied to environmental exposure profiles leading tox% effect reduction at a specific timet(MF(x,t), or denotedLP(x,t) by the EFSA). However, classical dose-response models used to estimate toxicity endpoints have some weaknesses, such as their dependency on observation time points, which are likely to differ between species (e.g., experiment duration). Furthermore, real-world exposure profiles are rarely constant over time, which makes the use of classical dose-response models difficult and may prevent the derivation ofMF(x,t). When dealing with survival or immobility toxicity test data, these issues can be overcome with the use of the general unified threshold model of survival (GUTS), a toxicokinetic-toxicodynamic (TKTD) model that provides an explicit framework to analyse both time- and concentration-dependent data sets as well as obtain a mechanistic derivation ofEC/LC(x,t) andMF(x,t) regardless ofxand at any timetof interest. In ERA, the assessment of a risk is inherently built upon probability distributions, such that the next critical step is to characterize the uncertainties of toxicity endpoints and, consequently, those of EQSs. With this perspective, we investigated the use of a Bayesian framework to obtain the uncertainties from the calibration process and to propagate them to model predictions, includingLC(x,t) andMF(x,t) derivations. We also explored the mathematical properties ofLC(x,t) andMF(x,t) as well as the impact of different experimental designs to provide some recommendations for a robust derivation of toxicity endpoints leading to reliable EQSs: avoid computingLC(x,t) andMF(x,t) for extremexvalues (0 or 100%), where uncertainty is maximal; computeMF(x,t) after a long period of time to take depuration time into account and test survival under pulses with different periods of time between them.
Population Genomics Analysis Revealed Origin and High-altitude Adaptation of Tibetan Pigs
Authors: Ma Yun-Fei , Han Xu-Man , Huang Cui-Ping , Zhong Li , Adeola Adeniyi C. , Irwin David M. , Xie Hai-Bing , Zhang Ya-Ping
Published: August 2019

Tibetan pig is native to the Qinghai-Tibet Plateau and has adapted to the high-altitude environmental condition such as hypoxia. However, its origin and genetic mechanisms underlying high-altitude adaptation still remain controversial and enigmatic. Herein, we analyze 229 genomes of wild and domestic pigs from Eurasia, including 63 Tibetan pigs, and detect 49.6 million high-quality variants. Phylogenomic and structure analyses show that Tibetan pigs have a close relationship with low-land domestic pigs in China, implying a common domestication origin. Positively selected genes in Tibetan pigs involved in high-altitude physiology, such as hypoxia, cardiovascular systems, UV damage, DNA repair. Three of loci with strong signals of selection are associated with EPAS1, CYP4F2, and THSD7A genes, related to hypoxia and circulation. We validated four non-coding mutations nearby EPAS1 and CYP4F2 showing reduced transcriptional activity in Tibetan pigs. A high-frequency missense mutation is found in THSD7A (Lys561Arg) in Tibetan pigs. The selective sweeps in Tibetan pigs was found in association with selection against non-coding variants, indicating an important role of regulatory mutations in Tibetan pig evolution. This study is important in understanding the evolution of Tibetan pigs and advancing our knowledge on animal adaptation to high-altitude environments.
An Effective Electric Dipole Model for Voltage-induced Gating Mechanism of Lysenin
Authors: Faouri Radwan Al , Krueger Eric , Govind Kumar Vivek , Fologea Daniel , Straub David , Alismail Hanan , Alfaori Qusay , Kight Alicia , Ray Jess , Henry Ralph , Moradi Mahmoud , Salamo Gregory
Published: August 2019

Lysenin is a pore-forming toxin, which self-inserts open channels into sphingomyelin containing membranes and is known to be voltage regulated. The mechanistic details of its voltage gating mechanism, however, remains elusive despite much recent efforts. Here, we have employed a novel combination of experimental and computational techniques to examine a model for voltage gating, that is based on the existence of an “effective electric dipole” inspired by recent reported structures of lysenin. We support this mechanism by the observations that (i) the charge-reversal and neutralization substitutions in lysenin result in changing its electrical gating properties by modifying the strength of the dipole, and (ii) an increase in the viscosity of the solvent increases the drag force and slows down the gating. In addition, our molecular dynamics (MD) simulations of membrane-embedded lysenin provide a mechanistic picture for lysenin conformational changes, which reveals, for the first time, the existence of a lipid-dependent bulge region in the pore-forming module of lysenin, which may explain the gating mechanism of lysenin at a molecular level.
Solar PV Power Potential is Greatest Over Croplands
Authors: Adeh Elnaz H. , Good Stephen P. , Calaf M. , Higgins Chad W.
Published: August 2019

Solar energy has the potential to offset a significant fraction of non-renewable electricity demands globally, yet it may occupy extensive areas when deployed at this level. There is growing concern that large renewable energy installations will displace other land uses. Where should future solar power installations be placed to achieve the highest energy production and best use the limited land resource? The premise of this work is that the solar panel efficiency is a function of the location’s microclimate within which it is immersed. Current studies largely ignore many of the environmental factors that influence Photovoltaic (PV) panel function. A model for solar panel efficiency that incorporates the influence of the panel’s microclimate was derived from first principles and validated with field observations. Results confirm that the PV panel efficiency is influenced by the insolation, air temperature, wind speed and relative humidity. The model was applied globally using bias-corrected reanalysis datasets to map solar panel efficiency and the potential for solar power production given local conditions. Solar power production potential was classified based on local land cover classification, with croplands having the greatest median solar potential of approximately 28 W/m2. The potential for dual-use, agrivoltaic systems may alleviate land competition or other spatial constraints for solar power development, creating a significant opportunity for future energy sustainability. Global energy demand would be offset by solar production if even less than 1% of cropland were converted to an agrivoltaic system.
Aortic remodelling induced by obstructive apneas is normalized with mesenchymal stem cells infusion
Authors: Rubies Cira , Dantas Ana-Paula , Batlle Montserrat , Torres Marta , Farre Ramon , Sangüesa Gemma , Montserrat Josep M. , Mont Lluis , Almendros Isaac , Guasch Eduard
Published: August 2019

Obstructive sleep apnea syndrome (OSA) promotes aortic dilatation, increased stiffness and accelerated atherosclerosis, but the mechanisms of vascular remodelling are not known. We aimed to assess vascular remodelling, its mechanisms, and the effect of mesenchymal stem cells (MSC) infusions in a clinically relevant rat model of chronic OSA involving recurrent airway obstructions leading thoracic pressure swings and intermittent hypoxia/hypercapnia (OSA-rats). Another group of rats were placed in the same setup without air obstructions (Sham-rats) and were considered controls. Our study demonstrates that chronic, non-invasive repetitive airway obstructions mimicking OSA promote remarkable structural changes of the descending thoracic aorta such as eccentric aortic hypertrophy due to an increased wall thickness and lumen diameter, an increase in the number of elastin fibers which, in contrast, get ruptured, but no changes in tunica media fibrosis. As putative molecular mechanisms of the OSA-induced vascular changes we identified an increase in reactive oxygen species and renin-angiotensin system markers and an imbalance in oxide nitric synthesis. Our results also indicate that MSC infusion blunts the OSA-related vascular changes, most probably due to their anti-inflammatory properties.
Dissociable electrophysiological correlates of semantic access of motor and non-motor concepts
Authors: Sokoliuk Rodika , Calzolari Sara , Cruse Damian
Published: August 2019

The notion of semantic embodiment posits that concepts are represented in the same neural sensorimotor systems that were involved in their acquisition. However, evidence in support of embodied semantics – in particular the hypothesised contribution of motor and premotor cortex to the representation of action concepts – is varied. Here, we tested the hypothesis that, consistent with semantic embodiment, sensorimotor cortices will rapidly become active while healthy participants access the meaning of visually-presented motor and non-motor action verbs. Event-related potentials revealed early differential processing of motor and non-motor verbs (164–203 ms) within distinct regions of cortex likely reflecting rapid cortical activation of differentially distributed semantic representations. However, we found no evidence for a specific role of sensorimotor cortices in supporting these representations. Moreover, we observed a later modulation of the alpha band (8–12 Hz) from 555–785 ms over central electrodes, with estimated generators within the left superior parietal lobule, which may reflect post-lexical activation of the object-directed features of the motor action concepts. In conclusion, we find no evidence for a specific role of sensorimotor cortices when healthy participants judge the meaning of visually-presented action verbs. However, the relative contribution of sensorimotor cortices to action comprehension may vary as a function of task goals.
High Glucose Environments Interfere with Bone Marrow-Derived Macrophage Inflammatory Mediator Release, the TLR4 Pathway and Glucose Metabolism
Authors: Ayala Thais Soprani , Tessaro Fernando Henrique Galvão , Jannuzzi Grasielle Pereira , Bella Leonardo Mendes , Ferreira Karen Spadari , Martins Joilson O.
Published: August 2019

Macrophages may be a crucial aspect of diabetic complications associated with the inflammatory response. In this study, we examined how hyperglycaemia, a common aspect of diabetes, modulates bone marrow-derived macrophages (BMDMs) under an inflammatory stimulus. To perform this study, BMDMs from non-diabetic and diabetic (60 mg/kg alloxan, i.v.) male C57BL/6 mice (CEUA/FCF/USP-488) were cultured under normal (5.5 mM) and high glucose (HG, 25 or 40 mM) conditions and stimulated or not stimulated with lipopolysaccharide (LPS, 100 ng/mL). Compared to the BMDMs from the normoglycaemic mice, the LPS-stimulated BMDMs from the diabetic mice presented reduced TLR4 expression on the cell surface, lower phagocytic capacity, and reduced secretion of NO and lactate but greater oxygen consumption and greater phosphorylation of p46 SAPK/JNK, p42 ERK MAPK, pAKT and pPKC-δ. When the BMDMs from the non-diabetic mice were cultured under high-glucose conditions and stimulated with LPS, TLR4 expression was reduced on the cell surface and NO and H2O2levels were reduced. In contrast, the diabetic BMDMs cultured under high glucose conditions presented increased levels of lactate and reduced phosphorylation of AKT, PKC-δ and p46 SAPK/JNK but enhanced phosphorylation of the p46 subunit of SAPK/JNK after LPS stimulation. High glucose levels appear to modify macrophage behaviour, affecting different aspects of diabetic and healthy BMDMs under the same LPS stimulus. Thus, hyperglycaemia leaves a glucose legacy, altering the basal steady state of macrophages.
Architecture of Anoteropora latirostris (Bryozoa, Cheilostomata) and implications for their biomineralization
Authors: Jacob D. E. , Ruthensteiner B. , Trimby P. , Henry H. , Martha S. O. , Leitner J. , Otter L. M. , Scholz J.
Published: August 2019

Cheilostome Bryozoa Anoteropora latirostris, a colonial marine invertebrate, constructs its skeleton from calcite and aragonite. This study presents firstly correlated multi-scale electron microscopy, micro-computed tomography, electron backscatter diffraction and NanoSIMS mapping. We show that all primary, coarse-grained platy calcitic lateral walls are covered by fine-grained fibrous aragonite. Vertical lateral walls separating autozooid chambers have aragonite only on their distal side. This type of asymmetric mineralization of lateral walls results from the vertical arrangement of the zooids at the growth margins of the colony and represents a type of biomineralization previously unknown in cheilostome bryozoans. NanoSIMS mapping across the aragonite-calcite interface indicates an organic layer between both mineral phases, likely representing an organic template for biomineralization of aragonite on the calcite layer. Analysis of crystallographic orientations show a moderately strong crystallographic preferred orientation (CPO) for calcite (7.4 times random orientation) and an overall weaker CPO for aragonite (2.4 times random orientation) with a high degree of twinning (45%) of the aragonite grains. The calculated Young’s modulus for the CPO map shows a weak mechanical direction perpendicular to the colony’s upper surface facilitating this organism’s strategy of clonal reproduction by fragmentation along the vertical zooid walls.
Genetics, morphology and diet of introduced populations of the ant-eating Texas Horned Lizard (Phrynosoma cornutum)
Authors: Heuring Courtney , Barber Diane , Rains Nathan , Erxleben Devin , Martin Cameron , Williams Dean , McElroy Eric J.
Published: August 2019

Introduced species can diverge from their source population when they become established in a new ecosystem. The Texas Horned Lizard (Phrynosoma cornutum) is native to the western United States (US) and was historically introduced to several locations in the southeastern US. We studied three introduced populations in South Carolina, US to determine if they exhibit dietary, morphological and genetic divergence from the native western US populations. We expected little divergence from western populations becauseP. cornutumis a specialist whose biology is largely shaped by its diet ofPogonomyrmexharvester ants. We show that the introduced populations have mixed ancestry between south Texas and more northern areas and experienced founder effects and genetic bottlenecks resulting in decreased genetic diversity. South Carolina lizards primarily consume ants (94%), but surprisingly, they did not eat harvester ants. Introduced lizards primarily eatDorymyrmexants, but each introduced population complementsDorymyrmexwith significantly different amounts of other species of ants, insects and plant matter. Introduced populations have smaller body size and have different limb and head shapes compared to western populations. This study demonstrates successful persistence of an introduced vertebrate that may be attributed to phenotypic change, even in the face of reduced genetic diversity.
Dysregulation of placental ABC transporters in a murine model of malaria-induced preterm labor
Authors: Fontes K. N. , Reginatto M. W. , Silva N. L. , Andrade C. B. V. , Bloise F. F. , Monteiro V. R. S. , Silva-Filho J. L. , Imperio G. E. , Pimentel-Coelho P. M. , Pinheiro A. A. S. , Matthews S. G. , Bloise E. , Ortiga-Carvalho T. M.
Published: August 2019

Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium-infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 (ABCA1), Abcb1b (P-glycoprotein), Abcb9 and Abcg2 (BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters’ expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.
Early life exposures shape the CD4+ T cell transcriptome, influencing proliferation, differentiation, and mitochondrial dynamics later in life
Authors: Burke Catherine G. , Myers Jason R. , Boule Lisbeth A. , Post Christina M. , Brookes Paul S. , Lawrence B. Paige
Published: August 2019

Early life environmental exposures drive lasting changes to the function of the immune system and can contribute to disease later in life. One of the ways environmental factors act is through cellular receptors. The aryl hydrocarbon receptor (AHR) is expressed by immune cells and binds numerous xenobiotics. Early life exposure to chemicals that bind the AHR impairs CD4+ T cell responses to influenza A virus (IAV) infection in adulthood. However, the cellular mechanisms that underlie these durable changes remain poorly defined. Transcriptomic profiling of sorted CD4+ T cells identified changes in genes involved in proliferation, differentiation, and metabolic pathways were associated with triggering AHR during development. Functional bioassays confirmed that CD4+ T cells from infected developmentally exposed offspring exhibit reduced proliferation, differentiation, and cellular metabolism. Thus, developmental AHR activation shapes T cell responsive capacity later in life by affecting integrated cellular pathways, which collectively alter responses later in life. Given that coordinated shifts in T cell metabolism are essential for T cell responses to numerous challenges, and that humans are constantly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses across the lifespan.
Paradoxical Role of Glypican-1 in Prostate Cancer Cell and Tumor Growth
Authors: Quach Nhat D. , Kaur Sukhneeraj Pal , Eggert Matthew W. , Ingram Lishann , Ghosh Deepraj , Sheth Sheela , Nagy Tamas , Dawson Michelle R. , Arnold Robert D. , Cummings Brian S.
Published: August 2019

Recent studies suggest that glypican-1 (GPC-1) is a biomarker for prostate cancer, but there are few studies elucidating the role of GPC-1 in prostate cancer progression. We observed high expression of GPC-1 in more aggressive prostate cancer cell lines such as PC-3 and DU-145. While inhibition of GPC-1 expression in PC-3 cells decreased cell growth and migration in vitro, it surprisingly increased cell proliferation and migration in DU-145 cells, suggesting that the role of GPC-1 is cell type-dependent. Further, GPC-1 inhibition increased PC-3 tumor size in NCr nude mice xenografts. We hypothesized that the discrepancy between the in vitro and in vivo data is mediated by stromal cells in the tumor microenvironment. Thus, we tested the effect of tumor conditioned media (TCM) on gene expression in human mesenchymal stem cells and fibroblasts. Treatment of stromal cells with TCM from PC-3 cells transfected with GPC-1 shRNA increased the expression of migration markers, endocrine/paracrine biomolecules, and extracellular matrix components. Additionally, the decreased cell growth in GPC-1 knockdown PC-3 cells was rescued by coculturing with stromal cells. These data demonstrate the paradoxical role that GPC-1 plays in prostate cancer cell growth by interacting with stromal cells and through ECM remodeling and endocrine/paracrine signaling.
CRISPR/Cas9-mediated mutagenesis of CAROTENOID CLEAVAGE DIOXYGENASE 8 in tomato provides resistance against the parasitic weed Phelipanche aegyptiaca
Authors: Bari Vinay Kumar , Nassar Jackline Abu , Kheredin Sally Marzouk , Gal-On Amit , Ron Mily , Britt Anne , Steele Daniel , Yoder John , Aly Radi
Published: August 2019

Broomrapes (Phelipanche aegyptiaca and Orobanche spp.) are obligate plant parasites that cause extreme damage to crop plants. The parasite seeds have strict requirements for germination, involving preconditioning and exposure to specific chemicals strigolactones [SLs] exuded by the host roots. SLs are plant hormones derived from plant carotenoids via a pathway involving the Carotenoid Cleavage Dioxygenase 8 (CCD8). Having no effective means to control parasitic weeds in most crops, and with CRISPR/Cas9 being an effective gene-editing tool, here we demonstrate that CRISPR/Cas9-mediated mutagenesis of the CCD8 gene can be used to develop host resistance to the parasitic weed P. aegyptiaca. Cas9/single guide (sg) RNA constructs were targeted to the second exon of CCD8 in tomato (Solanum lycopersicum L.) plants. Several CCD8Cas9 mutated tomato lines with variable insertions or deletions in CCD8 were obtained with no identified off-targets. Genotype analysis of T1 plants showed that the introduced CCD8 mutations are inherited. Compared to control tomato plants, the CCD8Cas9 mutant had morphological changes that included dwarfing, excessive shoot branching and adventitious root formation. In addition, SL-deficient CCD8Cas9 mutants showed a significant reduction in parasite infestation compared to non-mutated tomato plants. In the CCD8Cas9 mutated lines, orobanchol (SL) content was significantly reduced but total carotenoids level and expression of genes related to carotenoid biosynthesis were increased, as compared to control plants. Taking into account, the impact of plant parasitic weeds on agriculture and difficulty to constitute efficient control methods, the current study offers insights into the development of a new, efficient method that could be combined with various collections of resistant tomato rootstocks.
The relationship of comorbidities to mortality and cause of death in patients with differentiated thyroid carcinoma
Authors: Lee Young Ki , Hong Namki , Park Se Hee , Shin Dong Yeob , Lee Cho Rok , Kang Sang-Wook , Lee Jandee , Jeong Jong Ju , Nam Kee-Hyun , Chung Woong Youn , Lee Eun Jig
Published: August 2019

Understanding how comorbidities contribute to death in cancer patients is becoming an important topic. The present study assessed the role of comorbidities in overall mortality and causes of death in patients with differentiated thyroid carcinoma (DTC). This retrospective cohort study included 2070 patients who underwent thyroidectomy for DTC at a single institution between 2002 and 2005. Probabilities of overall, DTC-specific and other-cause death were examined according to the number of comorbidities, with consideration for competing events. The estimated 15-year cumulative incidences of overall, DTC-specific, and other-cause death were 7.3%, 1.6%, and 5.7%, respectively. Taking the group without comorbidities as a reference, we found that the group with 1–2 comorbidities and the group with ≥3 comorbidities had higher probabilities of other-cause death (subhazard ratios = 2.48 and 9.41, respectively; p < 0.01) and consequently shorter overall survival (hazard ratio = 1.95 and 5.33, respectively; p < 0.01), with adjustment for age, sex, and tumor-node-metastasis classification. In contrast, the probability of DTC-specific death was reduced in patients with ≥3 comorbidities (subhazard ratio = 6.81e-10, p < 0.01). For overall death, the relative proportion of death from DTC reduced when the number of comorbidities increased, and DTC-specific death was not observed in patients with ≥3 comorbidities. Our results show that death from DTC itself accounted for only a fraction of the overall deaths among patients who underwent surgery for DTC. Comorbidities increased overall mortality by increasing the probability of other-cause death. Patients with multiple comorbidities had a low probability of dying from DTC because they died earlier from comorbidities.
Therapeutic PD-L1 antibodies are more effective than PD-1 antibodies in blocking PD-1/PD-L1 signaling
Authors: De Sousa Linhares Annika , Battin Claire , Jutz Sabrina , Leitner Judith , Hafner Christine , Tobias Joshua , Wiedermann Ursula , Kundi Michael , Zlabinger Gerhard J. , Grabmeier-Pfistershammer Katharina , Steinberger Peter
Published: August 2019

Inhibitors of PD-1 signaling have revolutionized cancer therapy. PD-1 and PD-L1 antibodies have been approved for the treatment of cancer. To date, therapeutic PD-1 inhibitors have not been compared in a functional assay. We used an efficient T cell reporter platform to evaluate the efficacy of five clinically used PD-1 inhibitors to block PD-1 signaling. The half maximal effective concentrations (EC50) for nivolumab and pembrolizumab were 76.17 ng/ml (95% CI 64.95–89.34 ng/ml) and 39.90 ng/ml (34.01–46.80 ng/ml), respectively. The EC50 values of the PD-L1 inhibitors were 6.46 ng/ml (5.48–7.61 ng/ml), 6.15 ng/ml (5.24–7.21 ng/ml) and 7.64 ng/ml (6.52–8.96 ng/ml) for atezolizumab, avelumab, and durvalumab, respectively. In conclusion, a functional assay evaluating antibodies targeting PD-1 inhibition in vitro revealed that pembrolizumab is a slightly more effective PD-1 blocker than nivolumab, and that PD-L1 antibodies are superior to PD-1 antibodies in reverting PD-1 signaling.
Role of p53 isoforms in the DNA damage response during Drosophila oogenesis
Authors: Park Ji-Hong , Nguyen Tram Thi Ngoc , Lee Eun-Mi , Castro-Aceituno Veronica , Wagle Ram , Lee Kwang-Soon , Choi Juyoung , Song Young-Han
Published: August 2019

The tumor suppressor p53 is involved in the DNA damage response and induces cell cycle arrest or apoptosis upon DNA damage. Drosophila p53 encodes two isoforms, p53A and p53B, that induce apoptosis in somatic cells. To investigate the roles of Drosophila p53 isoforms in female germline cells, the DNA damage response was analyzed in the adult ovary. Early oogenesis was sensitive to irradiation and lok-, p53-, and hid-dependent cell death occurred rapidly after both low- and high-dose irradiation. Both p53 isoforms were responsible for this cell death. On the other hand, delayed cell death in mid-oogenesis was induced at a low level only after high-dose irradiation in a p53-independent manner. The daily egg production, which did not change after low-dose irradiation, was severely reduced after high-dose irradiation in p53 mutant females due to the loss of germline stem cells. When the p53A or p53B isoform was expressed in the germline cells in the p53 mutant females at levels that do not affect normal oogenesis, p53A, but not p53B, restored the fertility of the irradiated female. In summary, moderate expression of p53A is critical to maintain the function of germline stem cells during normal oogenesis as well as after high-dose irradiation.
Bacteria isolated from the cuticle of plant-parasitic nematodes attached to and antagonized the root-knot nematode Meloidogyne hapla
Authors: Topalović Olivera , Elhady Ahmed , Hallmann Johannes , Richert-Pöggeler Katja R. , Heuer Holger
Published: August 2019

Plant-parasitic nematodes are associated with specifically attached soil bacteria. To investigate these bacteria, we employed culture-dependent methods to isolate a representative set of strains from the cuticle of the infective stage (J2) of the root-knot nematode Meloidogyne hapla in different soils. The bacteria with the highest affinity to attach to J2 belonged to the genera Microbacterium, Sphingopyxis, Brevundimonas, Acinetobacter, and Micrococcus as revealed by 16S rRNA gene sequencing. Dynamics of the attachment of two strains showed fast adhesion in less than two hours, and interspecific competition for attachment sites. Isolates from the cuticle of M. hapla J2 attached to the lesion nematode Pratylenchus penetrans, and vice versa, suggesting similar attachment sites on both species. Removal of the surface coat by treatment of J2 with the cationic detergent CTAB reduced bacterial attachment, but did not prevent it. Some of the best attaching bacteria impaired M. hapla performance in vitro by significantly affecting J2 mortality, J2 motility and egg hatch. Most of the tested bacterial attachers significantly reduced the invasion of J2 into tomato roots, suggesting their beneficial role in soil suppressiveness against M. hapla.
Shape programming of polymeric based electrothermal actuator (ETA) via artificially induced stress relaxation
Authors: Sun Yu-Chen , Leaker Benjamin D. , Lee Ji Eun , Nam Ryan , Naguib Hani E.
Published: August 2019

Electrothermal actuators (ETAs) are a new generation of active materials that can produce different motions from thermal expansion induced by Joule heating. It is well-known that the degree of deformation is determined by the amount of Joule heating and the coefficient of thermal expansion (CTE) of the material. Previous works on polymeric ETAs are strongly focused on increasing electrical conductivity by utilizing super-aligned carbon nanotube (CNT) sheets. This allows greater deformation for the same drive voltage. Despite these accomplishments with low-voltage actuation, many of the ETAs were constructed to have basic geometries such as a simple cantilever shape. In this paper, it was discovered that shape of polymeric ETA can be programmed into a desired configuration by applying an induced stress relaxation mechanism and post secondary curing. By utilizing such effects, an ETA can be programmed into a curled resting state which allows the actuator to achieve an active bending angle over 540°, a value far greater than any previous studies. This shape programming feature also allows for tailoring the actuator configuration to a specific application. This is demonstrated here by fabricating a small crawling soft robot similar to mimic an inchworm motion.
Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test
Authors: Tomas Cara , Lodge Tiffany A. , Potter Michelle , Elson Joanna L. , Newton Julia L. , Morten Karl J.
Published: August 2019

The mitochondrial energy score (MES) protocol, developed by the Myhill group, is marketed as a diagnostic test for chronic fatigue syndrome/Myalgic Encephalomyelitis (CFS/ME). This study assessed the reliability and reproducibility of the test, currently provided by private clinics, to assess its potential to be developed as an NHS accredited laboratory test. We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group. Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.
Beta-blocker choice and exchangeability in patients with heart failure and chronic obstructive pulmonary disease: an Italian register-based cohort study
Authors: Sessa Maurizio , Mascolo Annamaria , Rasmussen Daniel Bech , Kragholm Kristian , Jensen Magnus Thorsten , Sportiello Liberata , Rafaniello Concetta , Tari Giuseppe Michele , Pagliaro Claudia , Andersen Morten , Rossi Francesco , Capuano Annalisa
Published: August 2019

Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases (Italy) were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio, OR 8.20; 95% Confidence Interval, 95% CI 1.30–51.80), cerebrovascular thrombosis (OR 7.06; 95% CI 1.14–43.68), chronic kidney disease (OR 4.32; 95% CI 1.16–16.02), and acute heart failure (OR 1.97; 95% CI 1.28–3.03) hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin (OR 3.00; 95% CI 1.24–7.24), fondaparinux (OR 2.47; 95% CI 1.17–5.21) or strontium ranelate (OR 2.03; 95% CI 1.06–3.90) redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.
Uniform two-dimensional crystals of polystyrene nanospheres fabricated by a surfactant-assisted spin-coating method with polyoxyethylene tridecyl ether
Authors: Park Byoungchoo , Na Seo Yeong , Bae In-Gon
Published: August 2019

Spin-coated self-assemblies of colloidal particles have been developed recently as an attractive close-packed monolayer of the particles for a variety of applications, but they are limited by the small area of their monolayers, especially given their low uniformity and monolayer coverage on large-area substrates. We report several noteworthy characteristics of a close-packed monolayer of polystyrene nanospheres (PS NSs) fabricated using a simple and inexpensive spin-coating method with a PS NS suspension mixed using the nonionic surfactant polyoxyethylene (12) tridecyl ether (PEO-TDE). In our study, we show that the PEO-TDE surfactant offers excellent wettability, surface tension, and a slow solvent evaporation rate of the PS NS suspension, similar to the conventional surfactant Triton X-100. We demonstrate that the relatively high monolayer coverage with reduced defects is produced when introducing the PEO-TDE surfactant. Specifically, monolayer coverage of more than 95% on a Si substrate was achieved, which is much better than that with the typical Triton X-100, and is one of the highest coverage rates realized by a spin-coating method. This excellent uniformity of the PS NS monolayer with high monolayer coverage is mainly attributed to the relatively low viscosity of the PS NS suspension, even at high concentrations of PEO-TDE. Moreover, the PEO-TDE surfactant provides highly uniform monolayers on a large-scale glass substrate even for large-sized PS NSs. We also highlight the fact that the PEO-TDE surfactant has another advantage in that the spin-coating process of the PS NS suspension can be done under common ambient laboratory conditions, unlike those required for the highly toxic Triton X-100. We therefore conclude that PEO-TDE can be a useful surfactant during the fabrication of close-packed monolayers for various applications owing to its simple and straightforward control of PS NSs, its uniform and high surface coverage, and due to the safety of the fabrication process.