bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleosomal embedding reshapes the dynamics of abasic sites
Authors: Bignon Emmanuelle , Claerbout Victor E. P. , Jiang Tao , Morell Christophe , Gillet Natacha , Dumont Elise 
Published: October 2020

AbstractApurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. The impact of losing a nucleobase on the conformation and dynamics of B-DNA is well characterized. Yet AP sites seem to present an entirely different chemistry in nucleosomal DNA, with lifetimes reduced up to 100-fold, and the much increased formation of covalent DNA-protein cross-links leading to strand breaks, refractory to repair. We report microsecond range, all-atom molecular dynamics simulations that capture the conformational dynamics of AP sites and their tetrahydrofuran analogs at two symmetrical positions within a nucleosome core particle, starting from a recent crystal structure. Different behaviours between the deoxyribo-based and tetrahydrofuran-type abasic sites are evidenced. The two solvent-exposed lesion sites present contrasted extrahelicities, revealing the crucial role of the position of a defect around the histone core. Our all-atom simulations also identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNA-protein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation.
Wild-type huntingtin regulates human macrophage function
Authors: O’Regan Grace C. , Farag Sahar H. , Ostroff Gary R. , Tabrizi Sarah J. , Andre Ralph 
Published: October 2020

AbstractThe huntingtin (HTT) protein in its mutant form is the cause of the inherited neurodegenerative disorder, Huntington’s disease. Beyond its effects in the central nervous system, disease-associated mutant HTT causes aberrant phenotypes in myeloid-lineage innate immune system cells, namely monocytes and macrophages. Whether the wild-type form of the protein, however, has a role in normal human macrophage function has not been determined. Here, the effects of lowering the expression of wild-type (wt)HTT on the function of primary monocyte-derived macrophages from healthy, non-disease human subjects were examined. This demonstrated a previously undescribed role for wtHTT in maintaining normal macrophage health and function. Lowered wtHTT expression was associated, for instance, with a diminished release of induced cytokines, elevated phagocytosis and increased vulnerability to cellular stress. These may well occur by mechanisms different to that associated with the mutant form of the protein, given an absence of any effect on the intracellular signalling pathway predominantly associated with macrophage dysfunction in Huntington’s disease.
First on-line detection of radioactive fission isotopes produced by laser-accelerated protons
Authors: Boller Pascal , Zylstra Alex , Neumayer Paul , Bernstein Lee , Brabetz Christian , Despotopulos John , Glorius Jan , Hellmund Johannes , Henry Eugene A. , Hornung Johannes , Jeet Justin , Khuyagbaatar Jadambaa , Lens Lotte , Roeder Simon , Stoehlker Thomas , Yakushev Alexander , Litvinov Yuri A. , Shaughnessy Dawn , Bagnoud Vincent , Kuehl Thomas , Schneider Dieter H. G. 
Published: October 2020

AbstractThe on-going developments in laser acceleration of protons and light ions, as well as the production of strong bursts of neutrons and multi-$$\hbox {MeV}$$
MeV
photons by secondary processes now provide a basis for novel high-flux nuclear physics experiments. While the maximum energy of protons resulting from Target Normal Sheath Acceleration is presently still limited to around $$100 \, \hbox {MeV}$$

100

MeV

, the generated proton peak flux within the short laser-accelerated bunches can already today exceed the values achievable at the most advanced conventional accelerators by orders of magnitude. This paper consists of two parts covering the scientific motivation and relevance of such experiments and a first proof-of-principle demonstration. In the presented experiment pulses of $$200 \, \hbox {J}$$

200

J

at $$\approx \, 500 \, \hbox {fs}$$

≈

500

fs

duration from the PHELIX laser produced more than $$10^{12}$$

10
12

protons with energies above $$15 \, \hbox {MeV}$$

15

MeV

in a bunch of sub-nanosecond duration. They were used to induce fission in foil targets made of natural uranium. To make use of the nonpareil flux, these targets have to be very close to the laser acceleration source, since the particle density within the bunch is strongly affected by Coulomb explosion and the velocity differences between ions of different energy. The main challenge for nuclear detection with high-purity germanium detectors is given by the strong electromagnetic pulse caused by the laser-matter interaction close to the laser acceleration source. This was mitigated by utilizing fast transport of the fission products by a gas flow to a carbon filter, where the $$\upgamma$$
γ
-rays were registered. The identified nuclides include those that have half-lives down to $$39 \, \hbox {s}$$

39

s

. These results demonstrate the capability to produce, extract, and detect short-lived reaction products under the demanding experimental condition imposed by the high-power laser interaction. The approach promotes research towards relevant nuclear astrophysical studies at conditions currently only accessible at nuclear high energy density laser facilities.
Statistical models for identifying frequent hitters in high throughput screening
Authors: Goodwin Samuel , Shahtahmassebi Golnaz , Hanley Quentin S. 
Published: October 2020

AbstractHigh throughput screening (HTS) interrogates compound libraries to find those that are “active” in an assay. To better understand compound behavior in HTS, we assessed an existing binomial survivor function (BSF) model of “frequent hitters” using 872 publicly available HTS data sets. We found large numbers of “infrequent hitters” using this model leading us to reject the BSF for identifying “frequent hitters.” As alternatives, we investigated generalized logistic, gamma, and negative binomial distributions as models for compound behavior. The gamma model reduced the proportion of both frequent and infrequent hitters relative to the BSF. Within this data set, conclusions about individual compound behavior were limited by the number of times individual compounds were tested (1–1613 times) and disproportionate testing of some compounds. Specifically, most tests (78%) were on a 309,847-compound subset (17.6% of compounds) each tested ≥ 300 times. We concluded that the disproportionate retesting of some compounds represents compound repurposing at scale rather than drug discovery. The approach to drug discovery represented by these 872 data sets characterizes the assays well by challenging them with many compounds while each compound is characterized poorly with a single assay. Aggregating the testing information from each compound across the multiple screens yielded a continuum with no clear boundary between normal and frequent hitting compounds.
Petal abscission in fragrant roses is associated with large scale differential regulation of the abscission zone transcriptome
Authors: Singh Priya , Bharti Neeraj , Singh Amar Pal , Tripathi Siddharth Kaushal , Pandey Saurabh Prakash , Chauhan Abhishek Singh , Kulkarni Abhijeet , Sane Aniruddha P. 
Published: October 2020

AbstractFlowers of fragrant roses such as Rosa bourboniana are ethylene-sensitive and undergo rapid petal abscission while hybrid roses show reduced ethylene sensitivity and delayed abscission. To understand the molecular mechanism underlying these differences, a comparative transcriptome of petal abscission zones (AZ) of 0 h and 8 h ethylene-treated flowers from R. bourboniana was performed. Differential regulation of 3700 genes (1518 up, 2182 down) representing 8.5% of the AZ transcriptome was observed between 0 and 8 h ethylene-treated R. bourboniana petal AZ. Abscission was associated with large scale up-regulation of the ethylene pathway but prominent suppression of the JA, auxin and light-regulated pathways. Regulatory genes encoding kinases/phosphatases/F-box proteins and transcription factors formed the major group undergoing differential regulation besides genes for transporters, wall modification, defense and phenylpropanoid pathways. Further comparisons with ethylene-treated petals of R. bourboniana and 8 h ethylene-treated AZ (R. hybrida) identified a core set of 255 genes uniquely regulated by ethylene in R. bourboniana AZ. Almost 23% of these encoded regulatory proteins largely conserved with Arabidopsis AZ components. Most of these were up-regulated while an entire set of photosystem genes was prominently down-regulated. The studies provide important information on regulation of petal abscission in roses.
A genotyping method combining primer competition PCR with HRM analysis to identify point mutations in Duchenne animal models
Authors: Lasa-Fernandez Haizpea , Mosqueira-Martín Laura , Alzualde Ainhoa , Lasa-Elgarresta Jaione , Vallejo-Illarramendi Ainara 
Published: October 2020

AbstractDystrophin-null sapje zebrafish is an excellent model for better understanding the pathological mechanisms underlying Duchenne muscular dystrophy, and it has recently arisen as a powerful tool for high-throughput screening of therapeutic candidates for this disease. While dystrophic phenotype in sapje larvae can be easily detected by birefringence, zebrafish genotyping is necessary for drug screening experiments, where the potential rescue of larvae phenotype is the primary outcome. Genotyping is also desirable during colony husbandry since heterozygous progenitors need to be selected. Currently, sapje zebrafish are genotyped through techniques involving sequencing or multi-step PCR, which are often costly, tedious, or require special equipment. Here we report a simple, precise, cost-effective, and versatile PCR genotyping method based on primer competition. Genotypes can be resolved by standard agarose gel electrophoresis and high-resolution melt assay, the latter being especially useful for genotyping a large number of samples. Our approach has shown high sensitivity, specificity, and reproducibility in detecting the A/T point mutation in sapje zebrafish and the C/T mutation in the mdx mouse model of Duchenne. Hence, this method can be applied to other single nucleotide substitutions and may be further optimized to detect small insertions and deletions. Given its robust performance with crude DNA extracts, our strategy may be particularly well-suited for detecting single nucleotide variants in poor-quality samples such as ancient DNA or DNA from formalin-fixed, paraffin-embedded material.
Factors predicting final visual outcome in quiescent proliferative diabetic retinopathy
Authors: Kim Jinsoo , Park In Won , Kwon Soonil 
Published: October 2020

AbstractTo investigate factors reflecting visual outcome and macular perfusion in quiescent proliferative diabetic retinopathy (PDR) patients after panretinal photocoagulation (PRP). We included 118 patients with quiescent PDR who had completed PRP. All participants had standardized interview to determine ocular history, smoking status, cardiovascular risk factors, and history of diabetic mellitus (DM). Foveal avascular zone (FAZ) area, retinal vessel density (VD) and vessel length density (VLD) were measured using optical coherence tomography angiography. VD was negatively correlated with hypertension, diabetic foot, HbA1c, and time after PRP (β =  − 0.181, P = 0.046; β =  − 0.231, P = 0.020; β =  − 0.244, P = 0.010; β =  − 0.278, P = 0.029). FAZ area of superficial capillary plexus and deep capillary plexus (DCP) was positively correlated with DM duration and diabetic foot (β = 0.178, P = 0.047; β = 0.293, P = 0.002; β = 0.252, P = 0.045; β = 0.304, P = 0.002). Macular perfusion state in patients with quiescent PDR was associated with diabetic foot, DM duration, HbA1c, and time after PRP. Of note, diabetic foot showed the strongest correlation with macular perfusion among various systemic factors. VLD, especially in DCP was associated with poor visual outcome.
Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson’s disease
Authors: Gonzalez-Hunt C. P. , Thacker E. A. , Toste C. M. , Boularand S. , Deprets S. , Dubois L. , Sanders L. H. 
Published: October 2020

AbstractLeucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson’s disease (PD) and LRRK2 kinase inhibitors are currently being tested in early phase clinical trials. In order to ensure the highest chance of success, a biomarker-guided entry into clinical trials is key. LRRK2 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target engagement biomarkers for LRRK2 kinase inhibition. However, a pharmacodynamic biomarker to demonstrate that a biological response has occurred is lacking. We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent. Here, we have explored the possibility that measurement of mtDNA damage is a “surrogate” for LRRK2 kinase activity and consequently of kinase inhibitor activity. Mitochondrial DNA damage was robustly increased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls. Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage to healthy control levels was observed and correlated with measures of LRRK2 dephosphorylation. Taken together, assessment of mtDNA damage levels may be a sensitive measure of altered kinase activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.
Design and in vivo evaluation of a microparticulate depot formulation of buprenorphine for veterinary use
Authors: Schreiner Viktoria , Durst Mattea , Arras Margarete , Detampel Pascal , Jirkof Paulin , Huwyler Jörg 
Published: October 2020

AbstractBuprenorphine is a frequently used analgetic agent in veterinary medicine. A major drawback, however, is the short duration of action requiring several daily administrations. We therefore designed a poly-lactic-co-glycolic acid (PLGA) based microparticulate drug formulation for sustained parenteral drug release. Particles were designed to allow for a fast onset of action and a duration of the analgesic effect of at least two days in laboratory mice. Microparticles were produced using a solvent evaporation technique. Release rate was dependent on polymer type and particle size. Spherical particles used for subsequent animal studies had a mean size of 50 µm and contained 4.5% of buprenorphine. Drug release was characterized by an initial burst release of 30% followed by complete release over seven days. In vivo pharmacokinetic experiments in female C57BL/6 J mice confirmed prolonged exposure in plasma and brain tissue and correlated with the pharmacological effect in the hot plate assay or after minor abdominal surgery. No adverse side effects with respect to food and water intake, body weight, local tolerability, or nesting behavior were observed. Our formulation is an attractive alternative to established immediate release formulations. A use for prolonged pain management in laboratory animals is proposed.
A 1H-NMR approach to myocardial energetics
Authors: Heitzman Jackie A. , Dobratz Tyler C. , Fischer Kaleb D. , Townsend DeWayne 
Published: October 2020

AbstractUnderstanding the energetic state of the heart is essential for unraveling the central tenets of cardiac physiology. The heart uses a tremendous amount of energy and reductions in that energy supply can have lethal consequences. While ischemic events clearly result in significant metabolic perturbations, heart failure with both preserved and reduced ejection fraction display reductions in energetic status. To date, most cardiac energetics have been performed using 31P-NMR, which requires dedicated access to a specialized NMR spectrometer. This has limited the availability of this method to a handful of centers around the world. Here we present a method of assessing myocardial energetics in the isolated mouse heart using 1H-NMR spectrometers that are widely available in NMR core facilities. In addition, this methodology provides information on many other important metabolites within the heart, including unique metabolic differences between the hypoxic and ischemic hearts. Furthermore, we demonstrate the correlation between myocardial energetics and measures of contractile function in the mouse heart. These methods will allow a broader examination of myocardial energetics providing a valuable tool to aid in the understanding of the nature of these energetic deficits and to develop therapies directed at improving myocardial energetics in failing hearts.
Discovering spatial interaction patterns of near repeat crime by spatial association rules mining
Authors: He Zhanjun , Tao Liufeng , Xie Zhong , Xu Chong 
Published: October 2020

AbstractUrban crime incidents always exhibit a structure of spatio-temporal dependence. Exploration of the spatio-temporal interactions of crime incidents is critical to understanding the occurrence mechanism and spatial transmission characteristics of crime occurrences, therefore facilitating the determination of policing practices. Although previous researches have repeatedly demonstrated that the crime incidents are spatially clustered, the anisotropic characteristics of spatial interaction has not been fully considered and the detailed spatial transmission of crime incidents has rarely been explored. To better understand the spatio-temporal interaction patterns of crime occurrence, this study proposes a new spatial association mining approach to discover significant spatial transmission routes and related high flow regions. First, all near repeat crime pairs are identified based on spatio-temporal proximity. Then, these links between close pairs are simplified by spatial aggregation on spatial grids. Based on that, measures of the spatio-temporal interactions are defined and a spatial association pattern mining approach is developed to discover significant spatial interaction patterns. Finally, the relationship between significant spatial transmission patterns and road network structure is analyzed. The experimental results demonstrate that our approach is able to effectively discover spatial transmission patterns from massive crime incidents data. Our results are expected to provide effective guidance for crime pattern analysis and even crime prevention.
The impact of handling technique and handling frequency on laboratory mouse welfare is sex-specific
Authors: Sensini Federica , Inta Dragos , Palme Rupert , Brandwein Christiane , Pfeiffer Natascha , Riva Marco Andrea , Gass Peter , Mallien Anne Stephanie 
Published: October 2020

AbstractHandling is a well-known source of stress to laboratory animals and can affect variability of results and even compromise animal welfare. The conventional tail handling in mice has been shown to induce aversion and anxiety-like behaviour. Recent findings demonstrate that the use of alternative handling techniques, e.g. tunnel handling, can mitigate negative handling-induced effects. Here, we show that technique and frequency of handling influence affective behaviour and stress hormone release of subjects in a sex-dependent manner. While frequent tail handling led to a reduction of wellbeing-associated burrowing and increased despair-like behaviour in male mice, females seemed unaffected. Instead, they displayed a stress response to a low handling frequency, which was not detectable in males. This could suggest that in terms of refinement, the impact in handling could differ between the sexes. Independently from this observation, both sexes preferred to interact with the tunnel. Mice generally explored the tunnel more often than the tail-handling hands of the experimenter and showed more positively rated approaches, e.g. touching or climbing, and at the same time, less defensive burrowing, indicating a strong preference for the tunnel.
Monitoring elasmobranch assemblages in a data-poor country from the Eastern Tropical Pacific using baited remote underwater video stations
Authors: Espinoza Mario , Araya-Arce Tatiana , Chaves-Zamora Isaac , Chinchilla Isaac , Cambra Marta 
Published: October 2020

AbstractUnderstanding how threatened species are distributed in space and time can have direct applications to conservation planning. However, implementing standardized methods to monitor populations of wide-ranging species is often expensive and challenging. In this study, we used baited remote underwater video stations (BRUVS) to quantify elasmobranch abundance and distribution patterns across a gradient of protection in the Pacific waters of Costa Rica. Our BRUVS survey detected 29 species, which represents 54% of the entire elasmobranch diversity reported to date in shallow waters (< 60 m) of the Pacific of Costa Rica. Our data demonstrated that elasmobranchs benefit from no-take MPAs, yet large predators are relatively uncommon or absent from open-fishing sites. We showed that BRUVS are capable of providing fast and reliable estimates of the distribution and abundance of data-poor elasmobranch species over large spatial and temporal scales, and in doing so, they can provide critical information for detecting population-level changes in response to multiple threats such as overfishing, habitat degradation and climate change. Moreover, given that 66% of the species detected are threatened, a well-designed BRUVS survey may provide crucial population data for assessing the conservation status of elasmobranchs. These efforts led to the establishment of a national monitoring program focused on elasmobranchs and key marine megafauna that could guide monitoring efforts at a regional scale.
Removal of biogenic amines from wines by chemisorption on functionalized silica and effects on other wine components
Authors: Rodríguez-Bencomo Juan José , Rigou Peggy , Mattivi Fulvio , López Francisco , Mehdi Ahmad 
Published: October 2020

AbstractThe effectiveness of several functionalized silica materials (cation-exchange materials) for the removal of biogenic amines from wines, and the effects on other wine components and organoleptic characteristics were evaluated. Results have shown that mesoporous silica material bi-functionalized with phosphonic and sulfonic acids allowed the removal of histamine, putrescine, cadaverine, spermine and spermidine from wines, although the dose must be adapted for each wine according to the removal requirements and wine characteristics. A plus of the adsorbent developed is that it can be recovered and re-used for at least 3 treatments. Immediately following the treatments, a decrease in the levels of linear ethyl esters (ethyl hexanoate, ethyl octanoate and ethyl decanoate) was observed, although these levels were re-equilibrated after several days reducing this undesired side effect. A slight, but perceptible, effect on wine color was observed, probably due to the slight decrease in the pH of the wine produced by the treatments. On the basis of the sensory analysis that focused only on the aroma of the wines, the proposed technique would be more adequate for wines aged in barrels than for young wines.