bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular vesicles: nature's nanoparticles for improving gene transfer with adeno‐associated virus vectors
Authors: György Bence , Maguire Casey A. 
Published: August 2017

Gene therapy, the ability to treat a disease at the level of nucleic acid, has journeyed from science fiction, to hard lessons learned from early clinical trials, to improved technologies with efficacy in patients for several diseases. Adeno‐associated virus (AAV) vectors are currently a leader for direct in vivo gene therapy. To date, AAV is safe in patients, with clinical benefit in trials to treat blindness, hemophilia, and a lipid disorder, with many more trials underway. Despite this remarkable progress, barriers exist for AAV vectors to be effective gene transfer vehicles in all organ/cell targets, as well as patient subpopulations. Extracellular vesicles (EVs, e.g., exosomes, microvesicles) are natural lipid particles released by many cell types. They have been reported to mediate cell to cell communication via transferred contents including proteins, nucleic acids, and metabolites. These properties of EV attracted our attention to help solve certain gene transfer issues encountered by AAV vectors. We made the initial discovery that a subpopulation of AAV vectors isolated from media directly interacted with EVs [referred to as exosome‐associated AAV (exo‐AAV)]. In following reports, we have demonstrated that exo‐AAV has advantages over the conventional AAV vector in areas such as anti‐AAV antibody evasion and transduction of cells of the eye and cochlea in preclinical models. The work of others using EVs as therapeutics as well as our continued development of the exo‐AAV platform may advance the field towards useful clinical applications.This article is categorized under:

Therapeutic Approaches and Drug Discovery > Emerging Technologies
Biology-Inspired Nanomaterials > Lipid‐Based Structures
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease
Effectiveness of a bounty program for reducing wild pig densities
Authors: Ditchkoff Stephen S. , Holtfreter Robert W. , Williams Brian L. 
Published: August 2017

ABSTRACTBounty programs have been historically implemented as a means of controlling invasive or pest species. Although bounty programs are generally considered to be ineffective, they are still proposed as management tools in situations where other management strategies have been unsuccessful. The wild pig (Sus scrofa) is an invasive large mammal in North America and most management strategies have proven to be ineffective at reducing or eliminating its populations, resulting in population expansion in recent decades. Fort Benning Army Infantry Training Center, Georgia, USA, had been inhabited by wild pigs since the mid‐1900s. In response to increasing negative impacts on flora, fauna, and military training activities and equipment, Fort Benning began offering a bounty on pigs in June 2007 to reduce the population and eventually eradicate wild pigs from the installation. To gauge the effectiveness of the program, we evaluated the population response of wild pigs within 2 study areas on the installation from June 2007 to February 2008. During the study, 1,138 pigs were harvested throughout the installation at a total cost (bounties paid and administration) of US$57,296. Surveys indicated that pig density and occupancy rates increased 23–130% and 12–19%, respectively, during the course of the bounty program. Additionally, sounder size and number of juveniles per adult female increased 144–233% and 191–219%, respectively. These data suggest that the wild pig population was increasing during the period when the bounty program was in effect. We hypothesize that this was due to increased food availability and reproduction associated with baiting wild pigs during the program, and because efforts of program participants were focused on eliminating the segment of the pig population that would maximize return on effort and “trophy” quality of animals rather than on the segment of the population that would most greatly influence population growth. © 2017 The Wildlife Society.
Vitamin B6 is essential for serine de novo biosynthesis
Authors: Ramos Rúben J. , Pras‐Raves Mia L. , Gerrits Johan , van der Ham Maria , Willemsen Marcel , Prinsen Hubertus , Burgering Boudewijn , Jans Judith J. , Verhoeven‐Duif Nanda M. 
Published: August 2017

AbstractPyridoxal 5′‐phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor in numerous enzyme reactions. PLP deficiency in brain, either genetic or acquired, results in severe drug‐resistant seizures that respond to vitamin B6 supplementation. The pathogenesis of vitamin B6 deficiency is largely unknown. To shed more light on the metabolic consequences of vitamin B6 deficiency in brain, we performed untargeted metabolomics in vitamin B6‐deprived Neuro‐2a cells. Significant alterations were observed in a range of metabolites. The most surprising observation was a decrease of serine and glycine, two amino acids that are known to be elevated in the plasma of vitamin B6 deficient patients. To investigate the cause of the low concentrations of serine and glycine, a metabolic flux analysis on serine biosynthesis was performed. The metabolic flux results showed that the de novo synthesis of serine was significantly reduced in vitamin B6‐deprived cells. In addition, formation of glycine and 5‐methyltetrahydrofolate was decreased. Thus, vitamin B6 is essential for serine de novo biosynthesis in neuronal cells, and serine de novo synthesis is critical to maintain intracellular serine and glycine. These findings suggest that serine and glycine concentrations in brain may be deficient in patients with vitamin B6 responsive epilepsy. The low intracellular 5‐mTHF concentrations observed in vitro may explain the favourable but so far unexplained response of some patients with pyridoxine‐dependent epilepsy to folinic acid supplementation.
Finding the Good in Grief: What Augustine Knew that Meursault Could Not
Authors: CHOLBI MICHAEL 
Published: August 2017

ABSTRACT:Meursault, the protagonist of Camus's The Stranger, was unable to experience grief at his mother's death—and was in fact condemned for this inability. Should Meursault's inability to grieve be pitied, or should it be welcomed inasmuch as grief is a painful and highly distressing experience? With the assistance of Augustine's remarks on grief in his Confessions, I argue that Meursault's plight is to be pitied. The emotional pains of grief are genuine and cannot be recast either as masochistic pleasures or as instrumental costs to be borne in exchange for grief's benefits. These pains are instead experienced as good inasmuch as they are components of a complex valuable experience. More specifically, because we experience grief at the deaths of those with whom we stand in identity-constituting relationships, grief is both a powerful source of, and motivator for, substantial self-knowledge.
A problematic cnidarian (Cambroctoconus; Octocorallia?) from the Cambrian (Series 2–3) of Laurentia
Authors: Peel John S. 
Published: August 2017

AbstractThe problematic calcified cnidarianCambroctoconusis described from the Henson Gletscher Formation (Cambrian Series 2, Stage 4–Series 3, Stage 5) of North Greenland, representing the first record from Laurentia of a genus otherwise recently described from China, Kyrgyzstan, and Korea. Internal molds produced by penetrative phosphatization mirror the pervasive pore system of the calice walls and septa. The pore system is compared to the network of gastrodermal solenia that distributes nutrients between polyps and surrounding stolon tissues in present day octocorals. In conjunction with the octagonal form of the individual coralla and eight-fold symmetry of septa, the pore system promotes assignment ofCambroctoconusto the Octocorallia, a basal clade in cnidarian phylogeny. Octocorals (‘soft corals’) are diverse in present day seas, but have a poor fossil record despite the general development of distinctive calcareous spicules. New taxa: Order Cambroctoconida new;Cambroctoconus koorinew species.
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells
Authors: Ranjan Satish , Goihl Alexander , Kohli Shrey , Gadi Ihsan , Pierau Mandy , Shahzad Khurrum , Gupta Dheerendra , Bock Fabian , Wang Hongjie , Shaikh Haroon , Kähne Thilo , Reinhold Dirk , Bank Ute , Zenclussen Ana C. , Niemz Jana , Schnöder Tina M. , Brunner-Weinzierl Monika , Fischer Thomas , Kalinski Thomas , Schraven Burkhart , Luft Thomas , Huehn Jochen , Naumann Michael , Heidel Florian H. , Isermann Berend 
Published: August 2017

AbstractGraft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4+FOXP3+). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4−CD4+) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.
Antiskyrmions stabilized at interfaces by anisotropic Dzyaloshinskii-Moriya interactions
Authors: Hoffmann Markus , Zimmermann Bernd , Müller Gideon P. , Schürhoff Daniel , Kiselev Nikolai S. , Melcher Christof , Blügel Stefan 
Published: August 2017

AbstractChiral magnets are an emerging class of topological matter harboring localized and topologically protected vortex-like magnetic textures called skyrmions, which are currently under intense scrutiny as an entity for information storage and processing. Here, on the level of micromagnetics we rigorously show that chiral magnets can not only host skyrmions but also antiskyrmions as least energy configurations over all non-trivial homotopy classes. We derive practical criteria for their occurrence and coexistence with skyrmions that can be fulfilled by (110)-oriented interfaces depending on the electronic structure. Relating the electronic structure to an atomistic spin-lattice model by means of density functional calculations and minimizing the energy on a mesoscopic scale by applying spin-relaxation methods, we propose a double layer of Fe grown on a W(110) substrate as a practical example. We conjecture that ultra-thin magnetic films grown on semiconductor or heavy metal substrates with C2v
symmetry are prototype classes of materials hosting magnetic antiskyrmions.
Brassinosteroid signaling-dependent root responses to prolonged elevated ambient temperature
Authors: Martins Sara , Montiel-Jorda Alvaro , Cayrel Anne , Huguet Stéphanie , Roux Christine Paysant-Le , Ljung Karin , Vert Grégory 
Published: August 2017

AbstractDue to their sessile nature, plants have to cope with and adjust to their fluctuating environment. Temperature elevation stimulates the growth of Arabidopsis aerial parts. This process is mediated by increased biosynthesis of the growth-promoting hormone auxin. How plant roots respond to elevated ambient temperature is however still elusive. Here we present strong evidence that temperature elevation impinges on brassinosteroid hormone signaling to alter root growth. We show that elevated temperature leads to increased root elongation, independently of auxin or factors known to drive temperature-mediated shoot growth. We further demonstrate that brassinosteroid signaling regulates root responses to elevated ambient temperature. Increased growth temperature specifically impacts on the level of the brassinosteroid receptor BRI1 to downregulate brassinosteroid signaling and mediate root elongation. Our results establish that BRI1 integrates temperature and brassinosteroid signaling to regulate root growth upon long-term changes in environmental conditions associated with global warming.
In situ atomic-scale imaging of the metal/oxide interfacial transformation
Authors: Zou Lianfeng , Li Jonathan , Zakharov Dmitri , Stach Eric A. , Zhou Guangwen 
Published: August 2017

AbstractDirectly probing structure dynamics at metal/oxide interfaces has been a major challenge due to their buried nature. Using environmental transmission electron microscopy, here we report observations of the in-place formation of Cu2O/Cu interfaces via the oxidation of Cu, and subsequently probe the atomic mechanisms by which interfacial transformation and grain rotation occur at the interfaces during reduction in an H2 gas environment. The Cu2O→Cu transformation is observed to occur initially along the Cu2O/Cu interface in a layer-by-layer manner. The accumulation of oxygen vacancies at the Cu2O/Cu interface drives the collapse of the Cu2O lattice near the interface region, which results in a tilted Cu2O/Cu interface with concomitant Cu2O island rotation. These results provide unprecedented microscopic detail regarding the redox reactions of supported oxides, which differs fundamentally from the reduction of bulk or isolated oxides that requires the formation of new interfaces between the parent oxide and the reduced phase.
Single molecule high-throughput footprinting of small and large DNA ligands
Authors: Manosas Maria , Camunas-Soler Joan , Croquette Vincent , Ritort Felix 
Published: August 2017

AbstractMost DNA processes are governed by molecular interactions that take place in a sequence-specific manner. Determining the sequence selectivity of DNA ligands is still a challenge, particularly for small drugs where labeling or sequencing methods do not perform well. Here, we present a fast and accurate method based on parallelized single molecule magnetic tweezers to detect the sequence selectivity and characterize the thermodynamics and kinetics of binding in a single assay. Mechanical manipulation of DNA hairpins with an engineered sequence is used to detect ligand binding as blocking events during DNA unzipping, allowing determination of ligand selectivity both for small drugs and large proteins with nearly base-pair resolution in an unbiased fashion. The assay allows investigation of subtle details such as the effect of flanking sequences or binding cooperativity. Unzipping assays on hairpin substrates with an optimized flat free energy landscape containing all binding motifs allows determination of the ligand mechanical footprint, recognition site, and binding orientation.
Visualizing atomic-scale redox dynamics in vanadium oxide-based catalysts
Authors: Ek Martin , Ramasse Quentin M. , Arnarson Logi , Georg Moses Poul , Helveg Stig 
Published: August 2017

AbstractSurface redox processes involving oxygen atom exchange are fundamental in catalytic reactions mediated by metal oxides. These processes are often difficult to uncover due to changes in the surface stoichiometry and atomic arrangement. Here we employ high-resolution transmission electron microscopy to study vanadium oxide supported on titanium dioxide, which is of relevance as a catalyst in, e.g., nitrogen oxide emission abatement for environmental protection. The observations reveal a reversible transformation of the vanadium oxide surface between an ordered and disordered state, concomitant with a reversible change in the vanadium oxidation state, when alternating between oxidizing and reducing conditions. The transformation depends on the anatase titanium dioxide surface termination and the vanadium oxide layer thickness, suggesting that the properties of vanadium oxide are sensitive to the supporting oxide. These atomic-resolution observations offer a basis for rationalizing previous reports on shape-sensitive catalytic properties.
Predicting hair cortisol levels with hair pigmentation genes: a possible hair pigmentation bias
Authors: Neumann Alexander , Noppe Gerard , Liu Fan , Kayser Manfred , Verhulst Frank C. , Jaddoe Vincent W. V. , van Rossum Elisabeth F. C. , Tiemeier Henning 
Published: August 2017

AbstractCortisol concentrations in hair are used to create hormone profiles spanning months. This method allows assessment of chronic cortisol exposure, but might be biased by hair pigmentation: dark hair was previously related to higher concentrations. It is unclear whether this association arises from local effects, such as increased hormone extractability, or whether the association represents systemic differences arising from population stratification. We tested the hypothesis that hair pigmentation gene variants are associated with varying cortisol levels independent of genetic ancestry. Hormone concentrations and genotype were measured in 1674 children from the Generation R cohort at age 6. We computed a polygenic score of hair color based on 9 single nucleotide polymorphisms. This score was used to predict hair cortisol concentrations, adjusted for genetic ancestry, sex, age and corticosteroid use. A 1-standard deviation (SD) higher polygenic score (darker hair) was associated with 0.08 SD higher cortisol levels (SE = 0.03, p = 0.002). This suggests that variation in hair cortisol concentrations is partly explained by local hair effects. In multi-ancestry studies this hair pigmentation bias can reduce power and confound results. Researchers should therefore consider adjusting analyses by reported hair color, by polygenic scores, or by both.
Groundwater nitrate response to sustainable nitrogen management
Authors: Hansen Birgitte , Thorling Lærke , Schullehner Jörg , Termansen Mette , Dalgaard Tommy 
Published: August 2017

AbstractThroughout the world, nitrogen (N) losses from intensive agricultural production may end up as undesirably high concentrations of nitrate in groundwater with a long-term impact on groundwater quality. This has human and environmental health consequences, due to the use of groundwater as a drinking water resource, and causes eutrophication of groundwater-dependent ecosystems such as wetlands, rivers and near-coastal areas. At national scale, the measured nitrate concentrations and trends in Danish oxic groundwater in the last 70 years correlate well with the annual agricultural N surpluses. We also show that the N use efficiency of agriculture is related to the groundwater nitrate concentrations. We demonstrate an inverted U-shape of annual nitrate concentrations as a function of economic growth from 1948 to 2014. Our analyses evidence a clear trend of a reversal at the beginning of the 1980s towards a more sustainable agricultural N management. This appears to be primarily driven by societal demand for groundwater protection linked to economic prosperity and an increased environmental awareness. However, the environmental and human health thresholds are still exceeded in many locations. Groundwater protection is of fundamental global importance, and this calls for further development of environmentally and economically sustainable N management in agriculture worldwide.
Dynamic local connectivity uncovers altered brain synchrony during propofol sedation
Authors: Bharath Rose Dawn , Panda Rajanikant , Saini Jitender , Sriganesh Kamath , Rao G. S. Umamaheswara 
Published: August 2017

AbstractHuman consciousness is considered a result of the synchronous “humming” of multiple dynamic networks. We performed a dynamic functional connectivity analysis using resting state functional magnetic resonance imaging (rsfMRI) in 14 patients before and during a propofol infusion to characterize the sedation-induced alterations in consciousness. A sliding 36-second window was used to derive 59 time points of whole brain integrated local connectivity measurements. Significant changes in the connectivity strength (Z Corr) at various time points were used to measure the connectivity fluctuations during awake and sedated states. Compared with the awake state, sedation was associated with reduced cortical connectivity fluctuations in several areas connected to the default mode network and around the perirolandic cortex with a significantly decreased correlation of connectivity between their anatomical homologues. In addition, sedation was associated with increased connectivity fluctuations in the frequency range of 0.027 to 0.063 Hz in several deep nuclear regions, including the cerebellum, thalamus, basal ganglia and insula. These findings advance our understanding of sedation-induced altered consciousness by visualizing the altered dynamics in several cortical and subcortical regions and support the concept of defining consciousness as a dynamic and integrated network.
Expression of long non-coding RNA MFI2-AS1 is a strong predictor of recurrence in sporadic localized clear-cell renal cell carcinoma
Authors: Flippot Ronan , Mouawad Roger , Spano Jean-Philippe , Rouprêt Morgan , Compérat Eva , Bitker Marc-Olivier , Parra Jérôme , Vaessen Christophe , Allanic Frederick , Manach Quentin , Tannir Nizar M. , Khayat David , Su Xiaoping , Malouf Gabriel G. 
Published: August 2017

AbstractPrediction of recurrence is a challenge for the development of adjuvant treatments in clear-cell renal cell carcinoma (ccRCC). In these tumors, expression of long non-coding RNAs (lncRNAs) are deregulated and closely associated with prognosis. Thus, we aimed to predict ccRCC recurrence risk using lncRNA expression. We identified prognostic lncRNAs in a training set of 351 localized ccRCCs from The Cancer Genome Atlas and validated lncRNA-based recurrence classification in an independent cohort of 167 localized ccRCCs. We identified lncRNA MFI2-AS1 as best candidate in the training set. In the validation cohort, MFI2-AS1 expression was independently associated with shorter disease-free survival (Hazard Ratio (HR) for relapse 3.5, p = 0.0001). Combined with Leibovich classification, MFI2-AS1 status improved prediction of recurrence (C-index 0.70) compared to MFI2-AS1 alone (0.67) and Leibovich classification alone (0.66). In patients with aggressive tumors (Leibovich ≥5), MFI2-AS1 expression was associated with dramatically increased risk of relapse (HR 12.16, p < 0.0001) compared to patients with undetectable MFI2-AS1 who had favorable outcomes. Compared to normal samples, MFI2-AS1 was upregulated in tumor tissue, and higher expression was associated with metastatic dissemination. Overall, MFI2-AS1 status improves patient stratification in localized ccRCC, which supports further integration of lncRNAs in molecular cancer classifications.
Energy-free machine learning force field for aluminum
Authors: Kruglov Ivan , Sergeev Oleg , Yanilkin Alexey , Oganov Artem R. 
Published: August 2017

AbstractWe used the machine learning technique of Liet al. (PRL 114, 2015) for molecular dynamics simulations. Atomic configurations were described by feature matrix based on internal vectors, and linear regression was used as a learning technique. We implemented this approach in the LAMMPS code. The method was applied to crystalline and liquid aluminum and uranium at different temperatures and densities, and showed the highest accuracy among different published potentials. Phonon density of states, entropy and melting temperature of aluminum were calculated using this machine learning potential. The results are in excellent agreement with experimental data and results of full ab initio calculations.