bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversity ofKaryolysusandSchellackiafrom the Iberian lizardLacerta schreiberiwith sequence data from engorged ticks
Authors: Zechmeisterová Kristína , Goüy de Bellocq Joëlle , Široký Pavel
Published: August 2019

Apicomplexan haemoparasites of the generaSchellackiaReichenow, 1919, andKaryolysusLabbé, 1894, seem to be common in lizards and widespread across the world. For decades, their identification has been based on morphological descriptions and life cycle patterns, with molecular characterizations, applied only recently. We used molecular characterization to confirm the identification of haemoparasites detected by microscopy in blood smears ofLacerta schreiberiBedriaga, 1878, a lizard of the Iberian Peninsula. Since blood samples other than blood smears were not available from the studied lizards, 264 engorged ticksIxodes ricinus(Linneaus, 1758) collected from them were used as an alternative non-invasive source of haemoparasite DNA for molecular genetic analyses. Of the 48 blood smears microscopically examined, 31 were positive for blood parasites (64.6% prevalence). We identified trophozoites and gamonts similar toKaryolysus lacazei(Labbé, 1894) (24/48; 50%) andSchellackia-like sporozoites (20/48; 41.7%). Mixed infections with both species occurred in 13 blood smears (27.1%). Sequence data were obtained for both parasites from engorged ticks. Phylogenetic analyses placed our unique haemogregarine sequence within theKaryolysusclade, nevertheless, within substantial polytomy. Thus, according to its morphology and effect on the host cell, we refer to this haemogregarine asKaryolysuscf.lacazei. Besides theSchellackiasequences being identical to a previously identified haplotype, we also obtained sequences of three new closely related haplotypes.
The impacts of gender on seasonal retirement mobility and wellbeing
Authors: Xu Honggang , Wang Yuting
Published: August 2019

With the increase in personal mobility and improvements in living standards, seasonal mobility for health reasons is a well-observed phenomenon among retired people worldwide. Existing studies have shown that there are relationships between seasonal retirement mobility and wellbeing, and this study attempts to explore the effects of gender on these relationships. The framework of therapeutic mobility, which includes daily activities, sociality and context, was used to analyse this relationship. Qualitative methods including semi-structured interviews, non-participatory observation and mobile ethnography were used to collect data. This study finds that female seasonal senior migrants in Sanya have more abundant and meaningful daily activities and receive more emotional supports, and as a result, gain more benefits than males, and that these differences are related to their gender roles. Furthermore, while gender itself cannot explain all the differences, it works within the intersection of economic condition, age and family support. This study has enriched the literature on therapeutic mobility and has practical implications.
Apprenticeship in the Renaissance University: Student authorship and craft knowledge
Authors: Oosterhoff Richard J.
Published: August 2019

Argument

Students entered Renaissance universities as apprentices in the craft of books. In the decades around 1500, such university training began to involve not only manuscript circulation, but also the production and the use of books in the new medium of print. Through their role in the crafting of books, I show how a circle of students around Jacques Lefèvre d’Étaples gained the experience needed to become bookmen. Students took classroom manuscripts and brought them into print – the new print shop offered students a place in which to exchange labor for credibility as joint authors.
Curiosity, youth, and knowledge in the visual and textual culture of the Dutch Republic
Authors: Stronks Els
Published: August 2019

Argument

The imitation of adults was the dominant educational early modern model, as it had been from the classical era. Yet, from 1500 onward, this traditional model clashed with new pedagogical ideals that explored if and how the youthful mind differed from the adult. To investigate this clash, I examine individual and aggregate cases – taken from the Dutch (illustrated) textual culture – representing conceptualizations of what has been labelled “the curiosity family” (concepts such as curiosity, inquisitiveness, invention). As previously established, during the seventeenth century, curiosity turned from a vice to a virtue among adults. Textual evidence suggests that for the early modern Dutch youth, docility, long valued, remained the guiding ideal. Shortly after 1700, however, two changes can be detected: for youth, travel literature and travel as a metaphor became a means to explore the world without adults; and for adults, the experimental learning style of the young became a new learning model.
Educating physicians in seventeenth-century England
Authors: Barry Jonathan
Published: August 2019

Argument

The tension between theoretical and practical knowledge was particularly problematic for trainee physicians. Unlike civic apprenticeships in surgery and pharmacy, in early modern England there was no standard procedure for obtaining education in the practical aspects of the physician’s role, a very uncertain process of certification, and little regulation to ensure a suitable reward for their educational investment. For all the emphasis on academic learning and international travel, the majority of provincial physicians returned to practice in their home area, because establishing a practice owed more to networks of kinship, patronage and credit than to formal qualifications. Only when (and where) practitioners had to rely solely on their professional qualification to establish their status as young practitioners that the community could trust would proposals to reform medical education, such as those put forward to address a crisis of medicine in Restoration London, which are examined here, be converted into national regulation of medical education in the early nineteenth century, although these proposals prefigured many informal developments in medical training in the eighteenth century.
Late Spanish Fascists in a Changing World: Latin American Communists and East European Reformism, 1956–1975
Authors: Ruiz Carnicer Miguel Ángel
Published: August 2019

The main aim of this article is to show how the political evolution of Western and Eastern Europe during the Cold War cannot be fully understood without analysing the political experiences of countries like Spain, which were not at the centre of the period's political decisions but whose evolution was inspired and suggested by strategies outside the political mainstream. In this respect, the internal evolution of Francoist Spain from the mid-1950s through the 1960s portrays a peculiar political situation demonstrating the capillarity of political and social experiences across the Iron Curtain in Europe and Latin America. A minority of influential sectors linked to the Single Spanish Party, the Falange, pursued its own third way, ignoring the Cold War models. They instead looked to what was happening in Eastern Bloc countries, especially after the events in Hungary in 1956, as well as to the political experiments in Latin America, especially the Cuban revolution.
Discovering dad: paternal roles, responsibilities, and support needs as defined by fathers of children with complex cardiac conditions perioperatively
Authors: Robinson Jacob , Huskey David , Schalley Sabrina , Wratchford Dale , Hammel James , Weaver Meaghann S.
Published: August 2019

Background:

Understanding perceptions of family caregivers’ roles and responsibilities regarding their child with complex cardiac needs has potential to help care teams better support parents. Paternal experience has been under-explored in pediatric cardiac cohorts.

Methods:

Ten fathers of children undergoing cardiac surgery completed quantitative surveys on their knowledge needs and preferred format of communication. In face-to-face recorded interviews, they responded to open-ended questions about the definition of being a good father to a child with a complex cardiac condition, perceived paternal responsibilities, personal growth as a parent to a child with a complex heart condition, support needs, and recommendations to medical staff for paternal inclusion. Semantic content analysis was utilised. The study reports strictly followed COnsolidated criteria for REporting Qualitative research guidelines.

Results:

The fathers reported high preference for knowledge about the child’s heart condition, communication about the treatment plan, and desire for inclusion in the care of their child. Paternal role was defined thematically as: providing a supportive presence, being there, offering bonded insight, serving as strong provider, and acting as an informed advocate. The fathers revealed that their responsibilities sometimes conflicted as they strove to serve as an emotional and economic stabiliser for their family, while also wanting to be foundationally present for their child perioperatively.

Conclusion:

This study provides insight into paternal experience and strategies for paternal inclusion. This summary of the self-defined experience of the fathers of pediatric cardiac patients offers constructive and specific advice for medical teams.
Determining Factors of Monthly to Decadal Variability in Surface Solar Radiation in China: Evidences From Current Reanalyses
Authors: Feng Fei , Wang Kaicun
Published: August 2019

Clouds and aerosols play essential roles in regulating surface incident solar radiation (Rs). It has been suggested that the increased aerosol loading over China is a key factor for the decadal variability in Rs and can explain the bias in its trend from reanalyses because the reanalyses do not include the interannual variability of aerosols. In this study, we compare the Rs derived from sunshine duration at 2,400 weather stations in China and that from five reanalyses from 1980 to 2014. The determining factors for the biases in the mean values and trends of Rs from the reanalyses are examined, with the help of Rs and the cloud fraction (CF), from satellite and 2,400 weather stations. Our results show that all reanalyses overestimate the multiyear Rs by 24.10–40.00 W/m2 due to their underestimations of CF, which is more obvious in southern China. The biases in the simulated CF in the reanalyses can explain the biases in Rs by 55–41%, and the bias in clear‐sky surface solar radiation (Rc), which is primarily due to biases in aerosol loading, can explain 32–9% of the bias in Rs. The errors in the trend of the simulated CF can explain the errors in the Rs trends in the reanalyses by 73–12%, and the trend errors in the Rc can explain 43–30% of the trend error in Rs. Our study suggests that more work is needed to improve the simulation of aerosols, clouds, and aerosol‐cloud‐radiation interactions in the reanalyses.
A Global Survey on the Perceptions and Impacts of Gender Inequality in the Earth and Space Sciences
Authors: Popp Andrea L. , Lutz Stefanie R. , Khatami Sina , van Emmerik Tim H. M. , Knoben Wouter J. M.
Published: August 2019

The leaky pipeline phenomenon refers to the disproportionate decline of female scientists at higher academic career levels and is a major problem in the natural sciences. Identifying the underlying causes is challenging, and thus, solving the problem remains difficult. To better understand the reasons for the leaky pipeline, we assess the perceptions and impacts of gender bias and imbalance—two major drivers of the leakage—at different academic career levels with an anonymous survey in geoscience academia (n=1,220). The survey results show that both genders view male geoscientists as substantially more gender biased than female scientists. Moreover, female geoscientists are more than twice as likely to experience negative gender bias at their workplaces and scientific organizations compared to male geoscientists. There are also pronounced gender differences regarding (i) the relevance of role models, (ii) family‐friendly working conditions, and (iii) the approval of gender quotas for academic positions. Given the male dominance in senior career levels, our results emphasize that those feeling less impacted by the negative consequences of gender bias and imbalance are the ones in position to tackle the problem. We thus call for actions to better address gender biases and to ensure a balanced gender representation at decision‐making levels to ultimately retain more women in geoscience academia.
Projected Changes in Interannual Variability of Peak Snowpack Amount and Timing in the Western United States
Authors: Marshall Adrienne M. , Abatzoglou John T. , Link Timothy E. , Tennant Christopher J.
Published: August 2019

Interannual variability of mountain snowpack has important consequences for ecological and socioeconomic systems, yet changes in variability have not been widely examined under future climates. Physically based snowpack simulations for historical (1970–1999) and high‐emission scenario (RCP 8.5) mid‐21st century (2050–2079) periods were used to assess changes in the variability of annual maximum snow water equivalent (SWEmax) and SWEmax timing across the western United States. Models show robust declines in the interannual variability of SWEmax in regions where precipitation is projected to increasingly fall as rain. The average frequency of consecutive snow drought years (SWEmax < historical 25th percentile) is projected to increase from 6.6% to 42.2% of years. Models also project increases in the variability of SWEmax timing, suggesting reduced reliability of when SWEmax occurs. Differences in physiography and regional climate create distinct spatial patterns of change in snowpack variability that will require adaptive strategies for environmental resource management.
Analysis of Microseismicity Framing ML > 2.5 Earthquakes at The Geysers Geothermal Field, California
Authors: Bentz Stephan , Martínez‐Garzón Patricia , Kwiatek Grzegorz , Dresen Georg , Bohnhoff Marco
Published: August 2019

Preparatory mechanisms accompanying or leading to nucleation of larger earthquakes have been observed at both laboratory and field scales, but conditions favoring the occurrence of observable preparatory processes are still largely unknown. In particular, it remains a matter of debate why some earthquakes occur spontaneously without noticeable precursors as opposed to events that are preceded by an extended failure process. In this study, we have generated new high‐resolution seismicity catalogs framing the occurrence of 20 ML > 2.5 earthquakes at The Geysers geothermal field in California. To this end, a seismicity catalog of the 11 days framing each large event was created. We selected 20 sequences sampling different hypocentral depths and hydraulic conditions within the field. Seismic activity and magnitude frequency distributions displayed by the different earthquake sequences are correlated with their location within the reservoir. Sequences located in the northwestern part of the reservoir show overall increased seismic activity and low b values, while the southeastern part is dominated by decreased seismic activity and higher b values. Periods of high injection coincide with high b values and vice versa. These observations potentially reflect varying differential and mean stresses and damage of the reservoir rocks across the field. About 50% of analyzed sequences exhibit no change in seismicity rate in response to the large main event. However, we find complex waveforms at the onset of the main earthquake, suggesting that small ruptures spontaneously grow into or trigger larger events.
Coastal Upwelling Influences Hypoxia Spatial Patterns and Nearshore Dynamics in Lake Erie
Authors: Rowe M. D. , Anderson E. J. , Beletsky D. , Stow C. A. , Moegling S. D. , Chaffin J. D. , May J. C. , Collingsworth P. D. , Jabbari A. , Ackerman J. D.
Published: August 2019

Hypoxia, defined as dissolved oxygen (DO) < 2 mg/L, in the central basin of Lake Erie has been studied since the mid‐1900s. Even so, spatial patterns of hypoxia, and episodic hypoxia in nearshore areas where drinking water plant intakes are located, are not well characterized owing to limited observations and short‐term dynamics. We evaluated a physically based, DO model with respect to patterns of hypoxia observed in Lake Erie. The DO model used assigned rates of sediment and water column oxygen demand that were temperature dependent but otherwise spatially and temporally uniform. The DO model was linked to National Oceanic and Atmospheric Administration's (NOAA) Lake Erie Operational Forecasting System hydrodynamic model, an application of the Finite Volume Community Ocean Model (FVCOM). Model temperature and DO were compared with observations from ship‐based studies, real‐time sensor networks and an array of moored sensors that we deployed in 2017. In years with dominant southwesterly winds, persistent downwelling occurred along the south shore, which resulted in a thinner thermocline and earlier initiation of hypoxia along the south shore than the north. Occasional northeast winds temporarily reversed this pattern, causing upwelling along the south shore that brought hypoxic water to nearshore locations and water intakes. The DO model reproduced observed spatial and temporal patterns of hypoxia and revealed locations subject to episodes of hypoxia, including nearshore Ohio, north of Pelee Island, and near the Bass Islands. Model skill was limited in some respects, highlighting the importance of accurate simulation of the thermal structure and spatial patterns of oxygen demand rates.
Effect of Aerosols on the Ice Cloud Properties Over the Tibetan Plateau
Authors: Liu Yuzhi , Hua Shan , Jia Rui , Huang Jianping
Published: August 2019

With the highlight of environmental problems over the Tibetan Plateau (TP), aerosol pollution and the influence of this pollution on cloud properties are becoming a new area of research. Based on the aerosol index and cloud property parameters derived from satellite observations, in this study, the inconsistent effects of aerosols on ice cloud properties between daytime and nighttime over the TP are investigated. The results indicate that ice clouds are mainly distributed over the TP margin area, especially over the north slope, during both daytime and nighttime. The occurrence frequency of ice cloud is higher during the daytime than during the nighttime over the margin areas of the TP. Similarly, aerosols are mainly concentrated over the northern margin of the TP. A potential relationship may exist between the aerosol index and ice cloud properties. When the aerosol index increases from 0.05 to 0.17, the ice cloud droplet radius (ICDR) during the daytime decreases from 32.1 to 27.9 μm, while the ICDR during the nighttime remains almost constant (approximately 25 μm); furthermore, the ice water path (IWP) during the daytime decreases slightly due to the saturation effect, while the nocturnal IWP increases significantly. The changes in ice cloud optical depth (ICOD) during daytime and nighttime show significant and completely opposite trends. The removal of the influence of meteorological factors showed that aerosols have a more dominant influence than meteorological conditions on ice cloud properties (except for the nocturnal ICDR and IWP during the daytime).
Satellite Limb Observations of Unprecedented Forest Fire Aerosol in the Stratosphere
Authors: Bourassa Adam E. , Rieger Landon A. , Zawada Daniel J. , Khaykin Sergey , Thomason L. W. , Degenstein Doug A.
Published: August 2019

Intense forest fires in western North America during August 2017 caused smoke plumes that reached the stratosphere. While this phenomenon has often been observed, this particular event caused increases in stratospheric aerosol extinction at higher altitudes with greater magnitude than previously observed in the satellite record. Here we use multiple satellite limb sounding observations, which provide high sensitivity to thin aerosol layers and good vertical resolution, to show that enhancements in aerosol extinction from the fires reached as high as 23 km in altitude and persisted for more than 5 months. Within 1 month, the aerosol is observed to cover latitudes from 20°N to 60°N, which is essentially the northernmost limit of the observations. At midlatitudes between 15‐ and 20‐km altitudes, the sustained level of median aerosol extinction measured at 750 nm increased by almost an order of magnitude, from approximately 10−4 km−1 to nearly 10−3 km−1. Agreement between limb scatter and occultation measurements is generally within 20% despite potential bias due to modified aerosol shape and composition.
Convective Entrainment Rates Estimated From Aura CO and CloudSat/CALIPSO Observations and Comparison With GEOS‐5
Authors: Stanfield Ryan E. , Su Hui , Jiang Jonathan H. , Freitas Saulo R. , Molod Andrea M. , Luo Zhengzhao Johnny , Huang Lei , Luo Ming
Published: August 2019

Entrainment rate (λ) in convective parameterizations remains a sensitive parameter with much uncertainty in model simulations. This study estimates λ using carbon monoxide (CO) measurements jointly from the Microwave Limb Sounder and Tropospheric Emission Spectrometer onboard the Aura satellite, associated with deep convective cases identified by CloudSat and CALIPSO observations. CO is treated as a conserved quantity over convective transport time scales, and a simple entraining‐plume model is used to derive entrainment rates. The relationships of the observational estimates of λ as a function of convective height, environmental relative humidity, and convective available potential energy (CAPE) derived from Atmospheric Infrared Sounder data are compared with those from Goddard Earth Observing System Model (GEOS‐5) simulations. Bulk statistics of λ show that the values of λ are predominately below 20%/km for deep convection and the occurrence frequency of any λ decreases with increasing λ. Composite λ values are generally lower in the tropics compared to northern midlatitudes in both observations and the GEOS‐5 model. A decrease of λ with increasing convective height is found in both observations and model simulations. We also find that λ tends to decrease with increasing CAPE in the observation‐based λs and plume‐based GEOS‐5 λs, although the model given λs have a nonmonotonic relation with CAPE. The observed λs have a weak relation with lower‐to‐middle tropospheric relative humidity, while both GEOS‐5 plume‐based and given λ increase with increasing relative humidity.
Sensory cortex wiring requires preselection of short- and long-range projection neurons through an Egr-Foxg1-COUP-TFI network
Authors: Hou Pei-Shan , Miyoshi Goichi , Hanashima Carina
Published: August 2019

The bimodal requisite for a genetic program and external stimuli is a key feature of sensory circuit formation. However, the contribution of cell-intrinsic codes to directing sensory-specific circuits remains unknown. Here, we identify the earliest molecular program that preselects projection neuron types in the sensory neocortex. Mechanistically, Foxg1 binds to an H3K4me1-enriched enhancer site to repress COUP-TFI, where ectopic acquisition of Foxg1 in layer 4 cells transforms local projection neurons to callosal projection neurons with pyramidal morphologies. Removal of Foxg1 in long-range projection neurons, in turn, derepresses COUP-TFI and activates a layer 4 neuron-specific program. The earliest segregation of projection subtypes is achieved through repression of Foxg1 in layer 4 precursors by early growth response genes, the major targets of the transforming growth factor-β signaling pathway. These findings describe the earliest cortex-intrinsic program that restricts neuronal connectivity in sensory circuits, a fundamental step towards the acquisition of mammalian perceptual behavior.
Bis-naphthopyrone pigments protect filamentous ascomycetes from a wide range of predators
Authors: Xu Yang , Vinas Maria , Alsarrag Albatol , Su Ling , Pfohl Katharina , Rohlfs Marko , Schäfer Wilhelm , Chen Wei , Karlovsky Petr
Published: August 2019

It is thought that fungi protect themselves from predation by the production of compounds that are toxic to soil-dwelling animals. Here, we show that a nontoxic pigment, the bis-naphthopyrone aurofusarin, protects Fusarium fungi from a wide range of animal predators. We find that springtails (primitive hexapods), woodlice (crustaceans), and mealworms (insects) prefer feeding on fungi with disrupted aurofusarin synthesis, and mealworms and springtails are repelled by wheat flour amended with the fungal bis-naphthopyrones aurofusarin, viomellein, or xanthomegnin. Predation stimulates aurofusarin synthesis in several Fusarium species and viomellein synthesis in Aspergillus ochraceus. Aurofusarin displays low toxicity in mealworms, springtails, isopods, Drosophila, and insect cells, contradicting the common view that fungal defence metabolites are toxic. Our results indicate that bis-naphthopyrones are defence compounds that protect filamentous ascomycetes from predators through a mechanism that does not involve toxicity.
Proteogenomic landscape of squamous cell lung cancer
Authors: Stewart Paul A. , Welsh Eric A. , Slebos Robbert J. C. , Fang Bin , Izumi Victoria , Chambers Matthew , Zhang Guolin , Cen Ling , Pettersson Fredrik , Zhang Yonghong , Chen Zhihua , Cheng Chia-Ho , Thapa Ram , Thompson Zachary , Fellows Katherine M. , Francis Jewel M. , Saller James J. , Mesa Tania , Zhang Chaomei , Yoder Sean , DeNicola Gina M. , Beg Amer A. , Boyle Theresa A. , Teer Jamie K. , Ann Chen Yian , Koomen John M. , Eschrich Steven A. , Haura Eric B.
Published: August 2019

How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of which (Inflamed, Redox) comprise 87% of tumors. The Inflamed subtype is enriched with neutrophils, B-cells, and monocytes and expresses more PD-1. Redox tumours are enriched for oxidation-reduction and glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus. Proteomic subtypes are not associated with patient survival. However, B-cell-rich tertiary lymph node structures, more common in Inflamed, are associated with better survival. We identify metabolic vulnerabilities (TP63, PSAT1, and TFRC) in Redox. Our work provides a powerful resource for lung SCC biology and suggests therapeutic opportunities based on redox metabolism and immune cell infiltrates.
Three-dimensional aromaticity in an antiaromatic cyclophane
Authors: Nozawa Ryo , Kim Jinseok , Oh Juwon , Lamping Anna , Wang Yemei , Shimizu Soji , Hisaki Ichiro , Kowalczyk Tim , Fliegl Heike , Kim Dongho , Shinokubo Hiroshi
Published: August 2019

Understanding of interactions among molecules is essential to elucidate the binding of pharmaceuticals on receptors, the mechanism of protein folding and self-assembling of organic molecules. While interactions between two aromatic molecules have been examined extensively, little is known about the interactions between two antiaromatic molecules. Theoretical investigations have predicted that antiaromatic molecules should be stabilized when they stack with each other by attractive intermolecular interactions. Here, we report the synthesis of a cyclophane, in which two antiaromatic porphyrin moieties adopt a stacked face-to-face geometry with a distance shorter than the sum of the van der Waals radii of the atoms involved. The aromaticity in this cyclophane has been examined experimentally and theoretically. This cyclophane exhibits three-dimensional spatial current channels between the two subunits, which corroborates the existence of attractive interactions between two antiaromatic π-systems.
Highly efficient dandelion-like near-infrared light photoinitiator for free radical and thiol-ene photopolymerizations
Authors: Li Zhiquan , Zou Xiucheng , Shi Feng , Liu Ren , Yagci Yusuf
Published: August 2019

Efficient photopolymerization activated by nonharmful near-infrared (NIR) light is important for various biological applications. Here we propose a NIR light free-radical photoinitiator (PI) fabricated by incorporating oxime-ester coumarin functionality on the surface of upconversion nanoparticles (UCNPs). The coumarin groups of PI absorb the light emitted from the UCNP core, whereas the oxime ester groups undergo cleavage to form radicals. Upon irradiation at 980 nm, the mobile radicals, formed in a manner similar to that of dandelion seed release, initiate both free-radical and thiol-ene photopolymerizations. The superior efficiency of dandelion-like PIs assisted photopolymerizations can be attributed to the reduction of energy loss and increased local PI concentration due to Förster resonance energy transfer process and confinement effect, respectively. Moreover, the proposed PI system can initiate polymerization under low-power NIR laser and reduces the thermal side effects. The possibility of its potential use in deep curing applications was also demonstrated.
Packaging materials with desired mechanical and barrier properties and full chemical recyclability
Authors: Sangroniz Ainara , Zhu Jian-Bo , Tang Xiaoyan , Etxeberria Agustin , Chen Eugene Y.-X. , Sardon Haritz
Published: August 2019

Plastics have become indispensable in modern life and the material of choice in packaging applications, but they have also caused increasing plastic waste accumulation in oceans and landfills. Although there have been continuous efforts to develop biodegradable plastics, the mechanical and/or transport properties of these materials still need to be significantly improved to be suitable for replacing conventional plastic packaging materials. Here we report a class of biorenewable and degradable plastics, based on copolymers of γ-butyrolactone and its ring-fused derivative, with competitive permeability and elongation at break compared to commodity polymers and superior mechanical and transport properties to those of most promising biobased plastics. Importantly, these materials are designed with full chemical recyclability built into their performance with desired mechanical and barrier properties, thus representing a circular economy approach to plastic packaging materials.
Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
Authors: Kircher Martin , Xiong Chenling , Martin Beth , Schubach Max , Inoue Fumitaka , Bell Robert J. A. , Costello Joseph F. , Shendure Jay , Ahituv Nadav
Published: August 2019

The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we perform saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitutions and deletions. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
A consensus S. cerevisiae metabolic model Yeast8 and its ecosystem for comprehensively probing cellular metabolism
Authors: Lu Hongzhong , Li Feiran , Sánchez Benjamín J. , Zhu Zhengming , Li Gang , Domenzain Iván , Marcišauskas Simonas , Anton Petre Mihail , Lappa Dimitra , Lieven Christian , Beber Moritz Emanuel , Sonnenschein Nikolaus , Kerkhoven Eduard J. , Nielsen Jens
Published: August 2019

Genome-scale metabolic models (GEMs) represent extensive knowledgebases that provide a platform for model simulations and integrative analysis of omics data. This study introduces Yeast8 and an associated ecosystem of models that represent a comprehensive computational resource for performing simulations of the metabolism ofSaccharomyces cerevisiae––an important model organism and widely used cell-factory. Yeast8 tracks community development with version control, setting a standard for how GEMs can be continuously updated in a simple and reproducible way. We use Yeast8 to develop the derived models panYeast8 and coreYeast8, which in turn enable the reconstruction of GEMs for 1,011 different yeast strains. Through integration with enzyme constraints (ecYeast8) and protein 3D structures (proYeast8DB), Yeast8 further facilitates the exploration of yeast metabolism at a multi-scale level, enabling prediction of how single nucleotide variations translate to phenotypic traits.
Brain-targeted drug delivery by manipulating protein corona functions
Authors: Zhang Zui , Guan Juan , Jiang Zhuxuan , Yang Yang , Liu Jican , Hua Wei , Mao Ying , Li Cheng , Lu Weiyue , Qian Jun , Zhan Changyou
Published: August 2019

Protein corona presents a major obstacle to bench-to-bedside translation of targeted drug delivery systems, severely affecting targeting yields and directing unfavorable biodistribution. Corona-mediated targeting provides a new impetus for specific drug delivery by precisely manipulating interaction modes of functional plasma proteins on nano-surface. Here bio-inspired liposomes (SP-sLip) were developed by modifying liposomal surface with a short nontoxic peptide derived from Aβ1-42 that specifically interacts with the lipid-binding domain of exchangeable apolipoproteins. SP-sLip absorb plasma apolipoproteins A1, E and J, consequently exposing receptor-binding domain of apolipoproteins to achieve brain-targeted delivery. Doxorubicin loaded SP-sLip (SP-sLip/DOX) show significant enhancement of brain distribution and anti-brain cancer effect in comparison to doxorubicin loaded plain liposomes. SP-sLip preserve functions of the absorbed human plasma ApoE, and the corona-mediated targeting strategy works in SP modified PLGA nanoparticles. The present study may pave a new avenue to facilitate clinical translation of targeted drug delivery systems.
Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy
Authors: Ruzzo Annamaria , Graziano Francesco , Galli Francesca , Galli Fabio , Rulli Eliana , Lonardi Sara , Ronzoni Monica , Massidda Bruno , Zagonel Vittorina , Pella Nicoletta , Mucciarini Claudia , Labianca Roberto , Ionta Maria Teresa , Bagaloni Irene , Veltri Enzo , Sozzi Pietro , Barni Sandro , Ricci Vincenzo , Foltran Luisa , Nicolini Mario , Biondi Edoardo , Bramati Annalisa , Turci Daniele , Lazzarelli Silvia , Verusio Claudio , Bergamo Francesca , Sobrero Alberto , Frontini Luciano , Magnani Mauro
Published: August 2019

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/−), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.
Correlation between early dynamics in circulating tumour DNA and outcome from FOLFIRI treatment in metastatic colorectal cancer
Authors: Lyskjær Iben , Kronborg Camilla Skovhus , Rasmussen Mads Heilskov , Sørensen Boe Sandahl , Demuth Christina , Rosenkilde Mona , Johansen Amanda Frydendahl Boll , Knudsen Michael , Vang Søren , Krag Søren Rasmus Palmelund , Spindler Karen-Lise Garm , Andersen Claus Lindbjerg
Published: August 2019

Chemotherapy resistance remains a challenge in the clinical management of metastatic colorectal cancer (mCRC). Here, early changes in cell-free circulating tumour DNA (ctDNA) levels were explored as a marker of therapeutic efficacy. Twenty-four mCRC patients were enrolled and treated with FOLFIRI based first-line therapy. Blood samples collected pre-treatment, at day 7, 14, 21, 60 and at progression were analysed for cell-free DNA (cfDNA) and ctDNA levels using digital droplet PCR. A subset of samples were additionally analysed by targeted sequencing. Patients with high pre-treatment ctDNA or cfDNA levels (≥75th centile) had significantly shorter progression free survival (PFS) than patients with lower levels. Despite an overall decline in ctDNA levels from pre-treatment to first CT-scan, serial analysis identified seven patients with temporary increases in ctDNA consistent with growth of resistant cells. These patients had shorter PFS and shorter overall survival. Targeted sequencing analyses of cfDNA revealed dramatic changes in the clonal composition in response to treatment. Our study suggests that increasing ctDNA levels during the first cycles of first-line FOLFIRI treatment is a predictor of incipient progressive disease and poorer survival. Thus, we demonstrate the importance of monitoring ctDNA levels as early as one week after treatment onset to enable early detection of treatment failure.
Comparison of Two-Talker Attention Decoding from EEG with Nonlinear Neural Networks and Linear Methods
Authors: Ciccarelli Gregory , Nolan Michael , Perricone Joseph , Calamia Paul T. , Haro Stephanie , O’Sullivan James , Mesgarani Nima , Quatieri Thomas F. , Smalt Christopher J.
Published: August 2019

Auditory attention decoding (AAD) through a brain-computer interface has had a flowering of developments since it was first introduced by Mesgarani and Chang (2012) using electrocorticograph recordings. AAD has been pursued for its potential application to hearing-aid design in which an attention-guided algorithm selects, from multiple competing acoustic sources, which should be enhanced for the listener and which should be suppressed. Traditionally, researchers have separated the AAD problem into two stages: reconstruction of a representation of the attended audio from neural signals, followed by determining the similarity between the candidate audio streams and the reconstruction. Here, we compare the traditional two-stage approach with a novel neural-network architecture that subsumes the explicit similarity step. We compare this new architecture against linear and non-linear (neural-network) baselines using both wet and dry electroencephalogram (EEG) systems. Our results indicate that the new architecture outperforms the baseline linear stimulus-reconstruction method, improving decoding accuracy from 66% to 81% using wet EEG and from 59% to 87% for dry EEG. Also of note was the finding that the dry EEG system can deliver comparable or even better results than the wet, despite the latter having one third as many EEG channels as the former. The 11-subject, wet-electrode AAD dataset for two competing, co-located talkers, the 11-subject, dry-electrode AAD dataset, and our software are available for further validation, experimentation, and modification.
Kefir peptides alleviate particulate matter <4 μm (PM4.0)-induced pulmonary inflammation by inhibiting the NF-κB pathway using luciferase transgenic mice
Authors: Chen Hsiao-Ling , Hung Kuan-Fei , Yen Chih-Ching , Laio Chun-Huei , Wang Jiun-Long , Lan Ying-Wei , Chong Kowit-Yu , Fan Hueng-Chuen , Chen Chuan-Mu
Published: August 2019

Kefir peptides, generated by kefir grain fermentation of milk proteins, showed positive antioxidant effects, lowered blood pressure and modulated the immune response. In this study, kefir peptide was evaluated regarding their anti-inflammatory effects on particulate matter <4 μm (PM4.0)-induced lung inflammation in NF-κB-luciferase+/+ transgenic mice. The lungs of mice under 20 mg/kg or 10 mg/kg PM4.0 treatments, both increased significantly the generation of reactive oxygen species (ROS) and inflammatory cytokines; increased the protein expression levels of p-NF-κB, NLRP3, caspase-1, IL-1β, TNF-α, IL-6, IL-4 and α-SMA. Thus, we choose the 10 mg/kg of PM4.0 for animal trials; the mice were assigned to four treatment groups, including control group (saline treatment), PM4.0 + Mock group (only PM4.0 administration), PM4.0 + KL group (PM4.0 + 150 mg/kg low-dose kefir peptide) and PM4.0 + KH group (PM4.0 + 500 mg/kg high-dose kefir peptide). Data showed that treatment with both doses of kefir peptides decreased the PM4.0-induced inflammatory cell infiltration and the expression of the inflammatory mediators IL-lβ, IL-4 and TNF-α in lung tissue by inactivating NF-κB signaling. The oral administrations of kefir peptides decrease the PM4.0-induced lung inflammation process through the inhibition of NF-κB pathway in transgenic luciferase mice, proposing a new clinical application to particulate matter air pollution-induced pulmonary inflammation.
Incidence, prevalence, and outcome of primary biliary cholangitis in a nationwide Swedish population-based cohort
Authors: Marschall Hanns-Ulrich , Henriksson Ida , Lindberg Sara , Söderdahl Fabian , Thuresson Marcus , Wahlin Staffan , Ludvigsson Jonas F.
Published: August 2019

Available epidemiological data on primary biliary cholangitis (PBC) in Sweden originate from regional studies in the 1980s and may not reflect modern day PBC. We aimed to estimate incidence and prevalence, survival and death causes, and gender differences in PBC. We used international classification of disease (ICD) codes to identify patients with PBC in inpatient and outpatient registries 1987–2014 who were then linked to the Swedish cause of death, cancer and prescribed drug registries. Each PBC patient was matched with 10 reference individuals from the general population. In sensitivity analyses, we examined PBC patients identified through clinical patient records from Karolinska, Sahlgrenska and Örebro University Hospitals. We identified 5,350 adults with PBC. Prevalence of PBC increased steadily from 5.0 (1987) to 34.6 (2014) per 100,000 inhabitants whereas the yearly incidence rate was relatively constant with a median of 2.6 per 100,000 person-years, with a female:male gender ratio of 4:1. Compared to reference individuals, PBC individuals aged 15–39 years at diagnosis had a substantially higher risk of death (Hazard Ratio [HR] 12.7, 95% Confidence Interval [CI] 8.3–19.5) than those diagnosed between 40–59 (HR 4.1, 95% CI 3.7–4.5) and >60 (HR 3.7, 95% CI 3.5–3.9) years of age. Relative risks of mortality were highest in men. In conclusion, we found that recorded prevalence of PBC in Sweden has increased substantially during the last 30 years although incidence has been stable. Patients diagnosed in young adulthood were at a 12.7-fold increased risk of death, and male PBC patients had worse prognosis.
Stimulation or Cancellation of Ca2+ Influx by Bipolar Nanosecond Pulsed Electric Fields in Adrenal Chromaffin Cells Can Be Achieved by Tuning Pulse Waveform
Authors: Bagalkot Tarique R. , Leblanc Normand , Craviso Gale L.
Published: August 2019

Exposing adrenal chromaffin cells to single 150 to 400 ns electric pulses triggers a rise in intracellular Ca2+ ([Ca2+]i) that is due to Ca2+ influx through voltage-gated Ca2+ channels (VGCC) and plasma membrane electropores. Immediate delivery of a second pulse of the opposite polarity in which the duration and amplitude were the same as the first pulse (a symmetrical bipolar pulse) or greater than the first pulse (an asymmetrical bipolar pulse) had a stimulatory effect, evoking larger Ca2+ responses than the corresponding unipolar pulse. Progressively decreasing the amplitude of the opposite polarity pulse while also increasing its duration converted stimulation to attenuation, which reached a maximum of 43% when the positive phase was 150 ns at 3.1 kV/cm, and the negative phase was 800 ns at 0.2 kV/cm. When VGCCs were blocked, Ca2+ responses evoked by asymmetrical and even symmetrical bipolar pulses were significantly reduced relative to those evoked by the corresponding unipolar pulse under the same conditions, indicating that attenuation involved mainly the portion of Ca2+ influx attributable to membrane electropermeabilization. Thus, by tuning the shape of the bipolar pulse, Ca2+ entry into chromaffin cells through electropores could be attenuated while preserving Ca2+ influx through VGCCs.
Mating of escaped domestic pigs with wild boar and possibility of their offspring migration after the Fukushima Daiichi Nuclear Power Plant accident
Authors: Anderson Donovan , Toma Rio , Negishi Yuki , Okuda Kei , Ishiniwa Hiroko , Hinton Thomas G. , Nanba Kenji , Tamate Hidetoshi B. , Kaneko Shingo
Published: August 2019

The 2011 Tohoku earthquake drastically changed human activities in some regions of Fukushima Prefecture, Japan. The subsequent tsunami damage and radioactive pollution from the Fukushima Daiichi nuclear power plant resulted in the evacuation of humans, and abandonment of agricultural lands, allowing population expansion of wildlife into areas formally inhabited by domesticated livestock. Unintentional escape of domesticated pigs into wildlife inhabited environments also occurred. In this study, we tested the possibility of introgression between wild boar and domesticated pigs in Fukushima and neighboring prefectures. We analyzed mitochondrial DNA sequences of 338 wild boar collected from populations in the Tohoku region between 2006 and 2018. Although most boar exhibited Asian boar mitochondrial haplotypes, 18 boar, phenotypically identified as wild boar, had a European domesticated pig haplotype. Frequencies of this haplotype have remained stable since first detection in 2015. This result infers ongoing genetic pollution in wild boar populations from released domesticated pigs. In 2018, this haplotype was detected outside of evacuated areas, suggesting migration and successful adaptation. The natural and anthropocentric disasters at Fukushima gave us the rare opportunity to study introgression processes of domestic genes into populations of wild boar. The present findings suggest a need for additional genetic monitoring to document the dispersal of domestic genes within wild boar stock.