bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Fe–O isotope correlation reveals magmatic origin of Kiruna-type apatite-iron-oxide ores
Authors: Troll Valentin R. , Weis Franz A. , Jonsson Erik , Andersson Ulf B. , Majidi Seyed Afshin , Högdahl Karin , Harris Chris , Millet Marc-Alban , Chinnasamy Sakthi Saravanan , Kooijman Ellen , Nilsson Katarina P.
Published: April 2019

Kiruna-type apatite-iron-oxide ores are key iron sources for modern industry, yet their origin remains controversial. Diverse ore-forming processes have been discussed, comprising low-temperature hydrothermal processes versus a high-temperature origin from magma or magmatic fluids. We present an extensive set of new and combined iron and oxygen isotope data from magnetite of Kiruna-type ores from Sweden, Chile and Iran, and compare them with new global reference data from layered intrusions, active volcanic provinces, and established low-temperature and hydrothermal iron ores. We show that approximately 80% of the magnetite from the investigated Kiruna-type ores exhibit δ56Fe and δ18O ratios that overlap with the volcanic and plutonic reference materials (> 800 °C), whereas ~20%, mainly vein-hosted and disseminated magnetite, match the low-temperature reference samples (≤400 °C). Thus, Kiruna-type ores are dominantly magmatic in origin, but may contain late-stage hydrothermal magnetite populations that can locally overprint primary high-temperature magmatic signatures.
Diel population and functional synchrony of microbial communities on coral reefs
Authors: Kelly Linda Wegley , Nelson Craig E. , Haas Andreas F. , Naliboff Douglas S. , Calhoun Sandi , Carlson Craig A. , Edwards Robert A. , Fox Michael D. , Hatay Mark , Johnson Maggie D. , Kelly Emily L. A. , Lim Yan Wei , Macherla Saichetana , Quinlan Zachary A. , Silva Genivaldo Gueiros Z. , Vermeij Mark J. A. , Zgliczynski Brian , Sandin Stuart A. , Smith Jennifer E. , Rohwer Forest
Published: April 2019

On coral reefs, microorganisms are essential for recycling nutrients to primary producers through the remineralization of benthic-derived organic matter. Diel investigations of reef processes are required to holistically understand the functional roles of microbial players in these ecosystems. Here we report a metagenomic analysis characterizing microbial communities in the water column overlying 16 remote forereef sites over a diel cycle. Our results show that microbial community composition is more dissimilar between day and night samples collected from the same site than between day or night samples collected across geographically distant reefs. Diel community differentiation is largely driven by the flux ofPsychrobactersp., which is two-orders of magnitude more abundant during the day. Nighttime communities are enriched with species ofRoseobacter,Halomonas, andAlteromonasencoding a greater variety of pathways for carbohydrate catabolism, further illustrating temporal patterns of energetic provisioning between different marine microbes. Dynamic diel fluctuations of microbial populations could also support the efficient trophic transfer of energy posited in coral reef food webs.
Dynamic control of enhancer activity drives stage-specific gene expression during flower morphogenesis
Authors: Yan Wenhao , Chen Dijun , Schumacher Julia , Durantini Diego , Engelhorn Julia , Chen Ming , Carles Cristel C. , Kaufmann Kerstin
Published: April 2019

Enhancers are critical for developmental stage-specific gene expression, but their dynamic regulation in plants remains poorly understood. Here we compare genome-wide localization of H3K27ac, chromatin accessibility and transcriptomic changes during flower development in Arabidopsis. H3K27ac prevalently marks promoter-proximal regions, suggesting that H3K27ac is not a hallmark for enhancers in Arabidopsis. We provide computational and experimental evidence to confirm that distal DNase І hypersensitive sites are predictive of enhancers. The predicted enhancers are highly stage-specific across flower development, significantly associated with SNPs for flowering-related phenotypes, and conserved across crucifer species. Through the integration of genome-wide transcription factor (TF) binding datasets, we find that floral master regulators and stage-specific TFs are largely enriched at developmentally dynamic enhancers. Finally, we show that enhancer clusters and intronic enhancers significantly associate with stage-specific gene regulation by floral master TFs. Our study provides insights into the functional flexibility of enhancers during plant development, as well as hints to annotate plant enhancers.
Altered steady state and activity-dependent de novo protein expression in fragile X syndrome
Authors: Bowling Heather , Bhattacharya Aditi , Zhang Guoan , Alam Danyal , Lebowitz Joseph Z. , Bohm-Levine Nathaniel , Lin Derek , Singha Priyangvada , Mamcarz Maggie , Puckett Rosemary , Zhou Lili , Aryal Sameer , Sharp Kevin , Kirshenbaum Kent , Berry-Kravis Elizabeth , Neubert Thomas A. , Klann Eric
Published: April 2019

Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.
Platanus-allee is a de novo haplotype assembler enabling a comprehensive access to divergent heterozygous regions
Authors: Kajitani Rei , Yoshimura Dai , Okuno Miki , Minakuchi Yohei , Kagoshima Hiroshi , Fujiyama Asao , Kubokawa Kaoru , Kohara Yuji , Toyoda Atsushi , Itoh Takehiko
Published: April 2019

The ultimate goal for diploid genome determination is to completely decode homologous chromosomes independently, and several phasing programs from consensus sequences have been developed. These methods work well for lowly heterozygous genomes, but the manifold species have high heterozygosity. Additionally, there are highly divergent regions (HDRs), where the haplotype sequences differ considerably. Because HDRs are likely to direct various interesting biological phenomena, many genomic analysis targets fall within these regions. However, they cannot be accessed by existing phasing methods, and we have to adopt costly traditional methods. Here, we develop a de novo haplotype assembler, Platanus-allee (http://platanus.bio.titech.ac.jp/platanus2), which initially constructs each haplotype sequence and then untangles the assembly graphs utilizing sequence links and synteny information. A comprehensive benchmark analysis reveals that Platanus-allee exhibits high recall and precision, particularly for HDRs. Using this approach, previously unknown HDRs are detected in the human genome, which may uncover novel aspects of genome variability.
Nanomechanical DNA resonators for sensing and structural analysis of DNA-ligand complexes
Authors: Stassi Stefano , Marini Monica , Allione Marco , Lopatin Sergei , Marson Domenico , Laurini Erik , Pricl Sabrina , Pirri Candido Fabrizio , Ricciardi Carlo , Di Fabrizio Enzo
Published: April 2019

The effect of direct or indirect binding of intercalant molecules on DNA structure is of fundamental importance in understanding the biological functioning of DNA. Here we report on self-suspended DNA nanobundles as ultrasensitive nanomechanical resonators for structural studies of DNA-ligand complexes. Such vibrating nanostructures represent the smallest mechanical resonator entirely composed of DNA. A correlative analysis between the mechanical and structural properties is exploited to study the intrinsic changes of double strand DNA, when interacting with different intercalant molecules (YOYO-1 and GelRed) and a chemotherapeutic drug (Cisplatin), at different concentrations. Possible implications of our findings are related to the study of interaction mechanism of a wide category of molecules with DNA, and to further applications in medicine, such as optimal titration of chemotherapeutic drugs and environmental studies for the detection of heavy metals in human serum.
Boosting oxygen evolution of single-atomic ruthenium through electronic coupling with cobalt-iron layered double hydroxides
Authors: Li Pengsong , Wang Maoyu , Duan Xinxuan , Zheng Lirong , Cheng Xiaopeng , Zhang Yuefei , Kuang Yun , Li Yaping , Ma Qing , Feng Zhenxing , Liu Wen , Sun Xiaoming
Published: April 2019

Single atom catalyst, which contains isolated metal atoms singly dispersed on supports, has great potential for achieving high activity and selectivity in hetero-catalysis and electrocatalysis. However, the activity and stability of single atoms and their interaction with support still remains a mystery. Here we show a stable single atomic ruthenium catalyst anchoring on the surface of cobalt iron layered double hydroxides, which possesses a strong electronic coupling between ruthenium and layered double hydroxides. With 0.45 wt.% ruthenium loading, the catalyst exhibits outstanding activity with overpotential 198 mV at the current density of 10 mA cm−2 and a small Tafel slope of 39 mV dec−1 for oxygen evolution reaction. By using operando X-ray absorption spectroscopy, it is disclosed that the isolated single atom ruthenium was kept under the oxidation states of 4+ even at high overpotential due to synergetic electron coupling, which endow exceptional electrocatalytic activity and stability simultaneously.
Plug-and-play metabolic transducers expand the chemical detection space of cell-free biosensors
Authors: Voyvodic Peter L. , Pandi Amir , Koch Mathilde , Conejero Ismael , Valjent Emmanuel , Courtet Philippe , Renard Eric , Faulon Jean-Loup , Bonnet Jerome
Published: April 2019

Cell-free transcription–translation systems have great potential for biosensing, yet the range of detectable chemicals is limited. Here we provide a workflow to expand the range of molecules detectable by cell-free biosensors through combining synthetic metabolic cascades with transcription factor-based networks. These hybrid cell-free biosensors have a fast response time, strong signal response, and a high dynamic range. In addition, they are capable of functioning in a variety of complex media, including commercial beverages and human urine, in which they can be used to detect clinically relevant concentrations of small molecules. This work provides a foundation to engineer modular cell-free biosensors tailored for many applications.
Ranking network mechanisms by how they fit diverse experiments and deciding on E. coli's ammonium transport and assimilation network
Authors: Maeda Kazuhiro , Westerhoff Hans V. , Kurata Hiroyuki , Boogerd Fred C.
Published: April 2019

The complex ammonium transport and assimilation network of E. coli involves the ammonium transporter AmtB, the regulatory proteins GlnK and GlnB, and the central N-assimilating enzymes together with their highly complex interactions. The engineering and modelling of such a complex network seem impossible because functioning depends critically on a gamut of data known at patchy accuracy. We developed a way out of this predicament, which employs: (i) a constrained optimization-based technology for the simultaneous fitting of models to heterogeneous experimental data sets gathered through diverse experimental set-ups, (ii) a ‘rubber band method’ to deal with different degrees of uncertainty, both in experimentally determined or estimated parameter values and in measured transient or steady-state variables (training data sets), (iii) integration of human expertise to decide on accuracies of both parameters and variables, (iv) massive computation employing a fast algorithm and a supercomputer, (v) an objective way of quantifying the plausibility of models, which makes it possible to decide which model is the best and how much better that model is than the others. We applied the new technology to the ammonium transport and assimilation network, integrating recent and older data of various accuracies, from different expert laboratories. The kinetic model objectively ranked best, has E. coli's AmtB as an active transporter of ammonia to be assimilated with GlnK minimizing the futile cycling that is an inevitable consequence of intracellular ammonium accumulation. It is 130 times better than a model with facilitated passive transport of ammonia.
Metric-guided regularisation parameter selection for statistical iterative reconstruction in computed tomography
Authors: Allner Sebastian , Gustschin Alex , Fehringer Andreas , Noël Peter B. , Pfeiffer Franz
Published: April 2019

As iterative reconstruction in Computed Tomography (CT) is an ill-posed problem, additional prior information has to be used to get a physically meaningful result (close to ground truth if available). However, the amount of influence of the regularisation prior is crucial to the outcome of the reconstruction. Therefore, we propose a scheme for tuning the strength of the prior via a certain image metric. In this work, the parameter is tuned for minimal histogram entropy in selected regions of the reconstruction as histogram entropy is a very basic approach to characterise the information content of data. We performed a sweep over different regularisation parameters showing that the histogram entropy is a suitable metric as it is well behaved over a wide range of parameters. The parameter determination is a feedback loop approach we applied to numerically simulated FORBILD phantom data and verified with an experimental measurement of a micro-CT device. The outcome is evaluated visually and quantitatively by means of root mean squared error (RMSE) and structural similarity (SSIM) for the simulation and visually for the measured sample (no ground truth available). The final reconstructed images exhibit noise-suppressed iterative reconstruction. For both datasets, the optimisation is robust where its initial value is concerned. The parameter tuning approach shows that the proposed metric-driven feedback loop is a promising tool for finding a suitable regularisation parameter in statistical iterative reconstruction.
Increased Plasma Levels of the TH2 chemokine CCL18 associated with low CD4+ T cell counts in HIV-1-infected Patients with a Suppressed Viral Load
Authors: Malhotra Prashant , Haslett Patrick , Sherry Barbara , Shepp David H. , Barber Paul , Abshier Jonathan , Roy Upal , Schmidtmayerova Helena
Published: April 2019

The chemokine (C-C motif) chemokine ligand 18 (CCL18) is a structural homolog of CCL3 primarily produced by monocyte-derived cells with an M2 phenotype. Elevated levels of CCL18 have been observed in several diseases associated with malignancies and chronic inflammation. The role of CCL18 in Human Immunodeficiency Virus (HIV-1) infection remains unknown. We analyzed expression levels of T helper cell-mediated (TH2) chemokines CCL18, CCL17, and CCL22 by ELISA in plasma collected from HIV-1-infected and healthy donors. In HIV-1-infected individuals, plasma viral loads were monitored by NucliSense HIV-1 QT assay and T cell counts and expression of the activation marker CD38 were determined by flow cytometry. Our data showed a significant increase in plasma levels of CCL18 in HIV-1-infected individuals compared to uninfected controls (p < 0.001) and a significant correlation between CCL18 levels and viral load in untreated patients. No significant difference of CCL18 levels was detected among the HIV-1-infected patients treated with combined antiretroviral therapy (cART) and HIV-1-untreated patients.CCL18 values are negatively correlated with CD4+CD38+ cell numbers and total CD4+ T cell counts in patients with a suppressed viral load. Notably, plasma levels of the TH2 chemokines CCL17 and CCL22 are also elevated during HIV-1 infection. However, no correlation of CCL17 and CCL22 production with CD4+ T cell counts was detected. Presented data shows that the chemokines, CCL17, CCL18, and CCL22 are increased during HIV-1 infection. However, only increased levels of CCL18, a marker of M2 macrophages, correlate with low CD4+ T cell counts in patients with suppressed viral load, raising the possibility that CCL18 and/or CCL18-producing cells may interfere with their reconstitution in HIV-1-infected patients on cART.
Predictive Big Data Analytics using the UK Biobank Data
Authors: Zhou Yiwang , Zhao Lu , Zhou Nina , Zhao Yi , Marino Simeone , Wang Tuo , Sun Hanbo , Toga Arthur W , Dinov Ivo D
Published: April 2019

The UK Biobank is a rich national health resource that provides enormous opportunities for international researchers to examine, model, and analyze census-like multisource healthcare data. The archive presents several challenges related to aggregation and harmonization of complex data elements, feature heterogeneity and salience, and health analytics. Using 7,614 imaging, clinical, and phenotypic features of 9,914 subjects we performed deep computed phenotyping using unsupervised clustering and derived two distinct sub-cohorts. Using parametric and nonparametric tests, we determined the top 20 most salient features contributing to the cluster separation. Our approach generated decision rules to predict the presence and progression of depression or other mental illnesses by jointly representing and modeling the significant clinical and demographic variables along with the derived salient neuroimaging features. We reported consistency and reliability measures of the derived computed phenotypes and the top salient imaging biomarkers that contributed to the unsupervised clustering. This clinical decision support system identified and utilized holistically the most critical biomarkers for predicting mental health, e.g., depression. External validation of this technique on different populations may lead to reducing healthcare expenses and improving the processes of diagnosis, forecasting, and tracking of normal and pathological aging.
Application of ESMACS binding free energy protocols to diverse datasets: Bromodomain-containing protein 4
Authors: Wright David W. , Wan Shunzhou , Meyer Christophe , van Vlijmen Herman , Tresadern Gary , Coveney Peter V.
Published: April 2019

As the application of computational methods in drug discovery pipelines becomes more widespread it is increasingly important to understand how reproducible their results are and how sensitive they are to choices made in simulation setup and analysis. Here we use ensemble simulation protocols, termed ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent), to investigate the sensitivity of the popular molecular mechanics Poisson-Boltzmann surface area (MMPBSA) methodology. Using the bromodomain-containing protein 4 (BRD4) system bound to a diverse set of ligands as our target, we show that robust rankings can be produced only through combining ensemble sampling with multiple trajectories and enhanced solvation via an explicit ligand hydration shell.
A Fundamental Micro Scale Study of the Roles of Associated Gas Content and Different Classes of Hydrocarbons on the Dominant Oil Recovery Mechanism by CWI
Authors: Seyyedi Mojtaba , Mahzari Pedram , Sohrabi Mehran
Published: April 2019

Various studies demonstrated new gaseous phase formation and oil swelling and viscosity reduction are the oil recovery mechanisms by carbonated water injection (CWI) with new gaseous phase formation being the major recovery mechanism for live oil systems. However, none of the previous studies investigated the influences of dissolved gas content of the oil and oil composition, on the new gaseous phase. This study attempts to provide insights on this area. Based on the results, during CWI as CO2 partitions into the oil the dissolved gas of the oil liberates, which leads to in-situ new gaseous phase formation. The dissolved gas content of the crude oil has a direct impact on the saturation and growth rate of the new gaseous phase. The new gaseous phase doesn’t form for oils that have an infinite capacity for dissolving CO2, such as light pure hydrocarbon components. Oils with limited capacity for dissolving CO2, such as heavy hydrocarbon components, are responsible for the formation of the new gaseous phase. Therefore for a live crude oil, the relatively heavier fractions of oil are responsible for triggering of the new gaseous phase and light to intermediate oil components control the further growth of the new gaseous phase.
Green barley mitigates cytotoxicity in human lymphocytes undergoing aggressive oxidative stress, via activation of both the Lyn/PI3K/Akt and MAPK/ERK pathways
Authors: Ruiz-Medina Blanca E. , Lerma Dennise , Hwang Michael , Ross Jeremy A. , Skouta Rachid , Aguilera Renato J. , Kirken Robert A. , Varela-Ramirez Armando , Robles-Escajeda Elisa
Published: April 2019

Oxidative stress plays a critical role in numerous diseases. Therefore, the pursuit of compounds with antioxidant activity remains critical. Green barley young leaves aqueous extract (GB) was tested for its capacity to ameliorate cellular oxidative stress, and its potential cytoprotective mechanism was partially elucidated. Through Folin-Ciocalteau and 1,1-diphenyl-2-picrylhydrazyl (DPPH) colorimetric assays, GB total phenolic content and free radical scavenging activity were found to be 59.91 ± 2.17 mg/L and 110.75 µg/ml (IC50), respectively. Using a live cell-based propidium iodide dye exclusion assay and flow cytometry, GB was found to display significant cytoprotection activity on three human lymphocytic cell lines exposed to an aggressive H2O2-induced oxidative stress. The molecular mechanism for GB cytoprotection activity was assessedviabead-based xMAP technology on the Luminex platform and western blot analysis. GB treatment resulted in activation of Lyn, Akt, and ERK1/2, suggesting that GB is able to mitigate the H2O2-induced oxidative stressviaactivation of both the Lyn/PI3K/Akt and ERK/MAPK pathways. Our findings support the notion that GB extract has the potential to be a valuable therapeutic agent and may serve to establish a strategy to discover potential compound(s) or biological extracts/mixtures to be incorporated as a treatment to prevent oxidative stress-related diseases.
The serial blocking effect: a testbed for the neural mechanisms of temporal-difference learning
Authors: Mahmud Ashraf , Petrov Petio , Esber Guillem R. , Iordanova Mihaela D.
Published: April 2019

Temporal-difference (TD) learning models afford the neuroscientist a theory-driven roadmap in the quest for the neural mechanisms of reinforcement learning. The application of these models to understanding the role of phasic midbrain dopaminergic responses in reward prediction learning constitutes one of the greatest success stories in behavioural and cognitive neuroscience. Critically, the classic learning paradigms associated with TD are poorly suited to cast light on its neural implementation, thus hampering progress. Here, we present a serial blocking paradigm in rodents that overcomes these limitations and allows for the simultaneous investigation of two cardinal TD tenets; namely, that learning depends on the computation of a prediction error, and that reinforcing value, whether intrinsic or acquired, propagates back to the onset of the earliest reliable predictor. The implications of this paradigm for the neural exploration of TD mechanisms are highlighted.
Histogram-based models on non-thin section chest CT predict invasiveness of primary lung adenocarcinoma subsolid nodules
Authors: Oikonomou Anastasia , Salazar Pascal , Zhang Yuchen , Hwang David M. , Petersen Alexander , Dmytriw Adam A. , Paul Narinder S. , Nguyen Elsie T.
Published: April 2019

109 pathologically proven subsolid nodules (SSN) were segmented by 2 readers on non-thin section chest CT with a lung nodule analysis software followed by extraction of CT attenuation histogram and geometric features. Functional data analysis of histograms provided data driven features (FPC1,2,3) used in further model building. Nodules were classified as pre-invasive (P1, atypical adenomatous hyperplasia and adenocarcinoma in situ), minimally invasive (P2) and invasive adenocarcinomas (P3). P1 and P2 were grouped together (T1) versus P3 (T2). Various combinations of features were compared in predictive models for binary nodule classification (T1/T2), using multiple logistic regression and non-linear classifiers. Area under ROC curve (AUC) was used as diagnostic performance criteria. Inter-reader variability was assessed using Cohen’s Kappa and intra-class coefficient (ICC). Three models predicting invasiveness of SSN were selected based on AUC. First model included 87.5 percentile of CT lesion attenuation (Q.875), interquartile range (IQR), volume and maximum/minimum diameter ratio (AUC:0.89, 95%CI:[0.75 1]). Second model included FPC1, volume and diameter ratio (AUC:0.91, 95%CI:[0.77 1]). Third model included FPC1, FPC2 and volume (AUC:0.89, 95%CI:[0.73 1]). Inter-reader variability was excellent (Kappa:0.95, ICC:0.98). Parsimonious models using histogram and geometric features differentiated invasive from minimally invasive/pre-invasive SSN with good predictive performance in non-thin section CT.
Intergeneric hybrids inform reproductive isolating barriers in the Antarctic icefish radiation
Authors: Desvignes Thomas , Le François Nathalie R. , Goetz Laura C. , Smith Sierra S. , Shusdock Kathleen A. , Parker Sandra K. , Postlethwait John H. , Detrich H. William
Published: April 2019

Interspecific hybridization or barriers to hybridization may have contributed to the diversification of Antarctic icefishes (Channichthyidae), but data supporting these hypotheses is scarce. To understand the potential for hybridization and to investigate reproductive isolating mechanisms among icefish species, we performedin vitrofertilization experiments using eggs from a female blackfin icefishChaenocephalus aceratusand sperm from a male of another genera, the ocellated icefishChionodraco rastrospinosus. Sequencing of genomic and mitochondrial DNA confirmed the intergeneric hybrid nature of resulting embryos which successfully developed and hatched as active larvae at about four and a half months during the Antarctic winter. This result demonstrates the compatibility of gametes of these two species and the viability of resulting zygotes and larvae. Due to logistic constraints and the slow developmental rate of icefishes, we could not test for long-term hybrid viability, fertility, fitness, or hybrid breakdown. Analysis of our fishing records and available literature, however, suggests that the strongest barriers to hybridization among parapatric icefish species are likely to be behavioral and characterized by assortative mating and species-specific courtship and nesting behaviors. This conclusion suggests that, in long-lived fish species with late sexual maturity and high energetic investment in reproduction like icefishes, pre-mating barriers are energetically more efficient than post-mating barriers to prevent hybridization.
Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid
Authors: Kakuda Keita , Ikenaka Kensuke , Araki Katsuya , So Masatomo , Aguirre César , Kajiyama Yuta , Konaka Kuni , Noi Kentaro , Baba Kousuke , Tsuda Hiroshi , Nagano Seiichi , Ohmichi Takuma , Nagai Yoshitaka , Tokuda Takahiko , El-Agnaf Omar M. A. , Ogi Hirotsugu , Goto Yuji , Mochizuki Hideki
Published: April 2019

α-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson’s disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson’s disease was higher than that of control patients. Notably, the lag time of patients with Parkinson’s disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF.
Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide
Authors: Koehn Liam M. , Dziegielewska Katarzyna M. , Møllgård Kjeld , Saudrais Elodie , Strazielle Nathalie , Ghersi-Egea Jean-Francois , Saunders Norman R. , Habgood Mark D.
Published: April 2019

Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.
Structural bases of peptidoglycan recognition by lysostaphin SH3b domain
Authors: Mitkowski Paweł , Jagielska Elżbieta , Nowak Elżbieta , Bujnicki Janusz M. , Stefaniak Filip , Niedziałek Dorota , Bochtler Matthias , Sabała Izabela
Published: April 2019

Staphylococcus simulans lysostaphin cleaves pentaglycine cross-bridges between stem peptides in the peptidoglycan of susceptible staphylococci, including S. aureus. This enzyme consists of an N-terminal catalytic domain and a cell wall binding domain (SH3b), which anchors the protein to peptidoglycan. Although structures of SH3bs from lysostaphin are available, the binding modes of peptidoglycan to these domains are still unclear. We have solved the crystal structure of the lysostaphin SH3b domain in complex with a pentaglycine peptide representing the peptidoglycan cross-bridge. The structure identifies a groove between β1 and β2 strands as the pentaglycine binding site. The structure suggests that pentaglycine specificity of the SH3b arises partially directly by steric exclusion of Cβ atoms in the ligand and partially indirectly due to the selection of main chain conformations that are easily accessible for glycine, but not other amino acid residues. We have revealed further interactions of SH3b with the stem peptides with the support of bioinformatics tools. Based on the structural data we have attempted engineering of the domain specificity and have investigated the relevance of the introduced substitutions on the domain binding and specificity, also in the contexts of the mature lysostaphin and of its bacteriolytic activity.
Relation between Baseline Total Serum Cortisol Level and Outcome in Pediatric Intensive Care Unit
Authors: Bekhit Osama E. , Mohamed Shereen A. , Yousef Remon M. , AbdelRasol Hoiyda A. , Khalaf Nirvana A. , Salah Fatma
Published: April 2019

Elevated cortisol level is an component of the stress response. However, some patients have low cortisol levels; a condition termed: critical illness-related corticosteroid insufficiency (CIRCI). Basal cortisol levels during PICU admission may be related to outcome. This prospective cohort study aimed to assess basal total serum cortisol levels and their relation to outcome in PICU. The study included 81 children over 6 months. Total serum cortisol was assessed using an early morning sample. The severity of illness was assessed using the PRISM-III score. Outcome measures included mechanical ventilation duration, use of inotropic support, length of stay, mortality. Comparison between patients’ subgroups according to total serum cortisol levels revealed significantly higher PRISM-III score in patients with total serum cortisol levels. In addition, those patients had a significantly higher mortality rate when compared with patients with low and normal total serum cortisol levels. Multivariate logistic regression analysis recognized high total serum cortisol level and PRISM-III score as significant predictors of mortality. We concluded that PRISM-III score and elevated total serum cortisol levels are significant predictors of mortality in the PICU. Although CIRCI is prevalent in this population, it wasn’t associated with an increased mortality rate.
Intrinsic molecular insights to enhancement of biogas production from kitchen refuse using alkaline-microwave pretreatment
Authors: Singh Puneet Kumar , Verma Suresh K. , Ojha Sanjay Kumar , Panda Pritam Kumar , Srichandan Haragobinda , Jha Ealisha , Mishra Snehasish
Published: April 2019

The current study analyzed and optimized the concentration of NaOH for alkaline pretreatment of kitchen refuse for biogas production. Also, the benefits of microwave assistance in enhanced biogasification of kitchen refuse were evaluated. The TS, VS and structural changes were compared using standard experimental techniques. Molecular dynamics was investigated for the molecular level changes leading to higher biogasification in NaOHmicrowave combined pretreatment. The methane and biogas yields were calculated to validate the benefits of microwave assistance in efficient biogasification. The NaOH-microwave combined pretreatment showed higher VS production. Microwave treatment degraded and removed lignin more efficiently. Molecular dynamics studies revealed the induction of configurational instability in lignin and cellulose molecules with variable temperatures. The methane and biogas production increased with 6% NaOH concentration, and decreased at higher NaOH concentration till 10%. Microwave assistance declined the required NaOH concentration further to 4%. Thus, as compared to 6% NaOH concentration required for an efficient pretreatment, the kitchen refuse was efficiently pretreated with 4% NaOH concentration when combined with a 30 min duration microwaving. The experimental and computational data provided a detailed analysis proposing an optimized, novel and promising method to pretreat kitchen refuse for efficient and enhanced biogas production.
An in vivo wound healing model for the characterization of the angiogenic process and its modulation by pharmacological interventions
Authors: Schneider Martin Karl , Ioanas Horea-Ioan , Xandry Jael , Rudin Markus
Published: April 2019

Angiogenesis during wound healing is essential for tissue repair and also affected during cancer treatment by anti-angiogenic drugs. Here, we introduce a minimally invasive wound healing model in the mouse ear to assess angiogenesis with high spatiotemporal resolution in a longitudinal manner in vivo using two-photon microscopy in mice expressing GCaMP2 in arterial endothelial cells. The development of vascular sprouts occurred in a highly orchestrated manner within a time window of 8 days following wounding. Novel sprouts developed exclusively from the distal stump of the transsected arteries, growing towards the proximal arterial stump. This was in line with the incidence of Ca2+ transients in the arterial endothelial cells, most probably a result of VEGF stimulation, which were more numerous on the distal part. Functional analysis revealed perfusion across the wound site via arterial sprouts developed between days 6 and 8 following the incision. At day 8, proximal and distal arteries were structurally and functionally connected, though only 2/3 of all sprouts detected were actually perfused. Treatment with the FDA approved drug, sunitinib, the preclinical drug AZD4547, as well as with the combination of the two agents had significant effects on both structural and functional readouts of neo-angiogenesis. The simplicity and high reproducibility of the model makes it an attractive tool for elucidating migratory activity, phenotype and functionality of endothelial cells during angiogenesis and for evaluating specific anti-angiogenic drug interventions.
Tuning of mRNA stability through altering 3′-UTR sequences generates distinct output expression in a synthetic circuit driven by p53 oscillations
Authors: Koh Woo Seuk , Porter Joshua R. , Batchelor Eric
Published: April 2019

Synthetic biological circuits that can generate outputs with distinct expression dynamics are useful for a variety of biomedical and industrial applications. We present a method to control output dynamics by altering output mRNA decay rates. Using oscillatory expression of the transcription factor p53 as the circuit regulator, we use two approaches for controlling target gene transcript degradation rates based on the output gene’s 3′-untranslated region (3′-UTR): introduction of copies of destabilizing AU-rich elements into the 3′-UTR or swapping in naturally occurring 3′-UTRs conferring different transcript stabilities. As a proof of principle, we apply both methods to control the expression dynamics of a fluorescent protein and visualize the circuit output dynamics in single living cells. We then use the naturally occurring 3′-UTR approach to restore apoptosis in a tunable manner in a cancer cell line deficient for caspase-3 expression. Our method can be readily adapted to regulate multiple outputs each with different expression dynamics under the control of a single naturally occurring or synthetically constructed biological oscillator.
The molecular genetics of hand preference revisited
Authors: de Kovel Carolien G. F. , Francks Clyde
Published: April 2019

Hand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.
Optical coherence tomography angiography for noninvasive evaluation of angiogenesis in a limb ischemia mouse model
Authors: Wang Liwei , Chen Zuoguan , Li Yongjun , Yang Jing , Li Yuejie
Published: April 2019

We developed an optical coherence tomography angiography technique by improving the speckle contrast algorithm and the imaging process. This technique, which can achieve angiogenesis imaging in vivo without increasing trauma, was used to evaluate the microvasculature in limb ischemia mice. Sixteen left hindlimb ischemia mice were randomly allocated into CuSO4 and saline groups. Within 7 days after treatment, limb ischemic damage, temperature and histological staining were assessed by traditional methods. In addition, angiogenesis was evaluated using an optical coherence tomography angiography system in vivo. All results were compared. After 7 days of treatment, both the ischemic tissue damage score and temperature ratio of the CuSO4 group were significantly higher than those of the control group (all P < 0.05). The number of CD31-positive endothelial cells in the CuSO4 group (0.1836 ± 0.0153) was significantly greater than that in the saline control group (0.0436 ± 0.0069) (P < 0.001). Optical coherence tomography angiography showed that the vessel area density of mice in the CuSO4 group (0.2566 ± 0.0060) was significantly greater than that of mice in the control group (0.2079 ± 0.0202) (P = 0.027). Optical coherence tomography angiography represents a practical and effective method for observing angiogenesis in the mouse hindlimb in vivo without increasing trauma.
HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen
Authors: Zamora Ruben , Barclay Derek , Yin Jinling , Alonso Estella M. , Leonis Mike A. , Mi Qi , Billiar Timothy R. , Simmons Richard L. , Squires Robert H. , Vodovotz Yoram
Published: April 2019

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1–2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2–3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.
A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation
Authors: Walker Stephen J. , Langefeld Carl D. , Zimmerman Kip , Schwartz Marshall Z. , Krigsman Arthur
Published: April 2019

In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.
Approaches for measuring the surface areas of metal oxide electrocatalysts for determining their intrinsic electrocatalytic activity
Authors: Wei Chao , Sun Shengnan , Mandler Daniel , Wang Xun , Qiao Shi Zhang , Xu Zhichuan J.
Published: April 2019

A summary and analysis of approaches for measuring the surface areas of metal oxide electrocatalysts for evaluating their intrinsic electrocatalytic activity.
Quantifying low-energy ICP-MS isotope deposition
Authors: Liezers Martin , Dion Michael P. , Eiden Gregory C. , Thomas May-Lin P.
Published: April 2019

Mass spectrometry (MS) offers an alternative approach to chemical or chromatographic separations to selectively isolate and collect individual isotopes of an element for analytical purposes.
Elucidating the electronic structure of CuWO4 thin films for enhanced photoelectrochemical water splitting
Authors: Tian C. M. , Jiang M. , Tang D. , Qiao L. , Xiao H. Y. , Oropeza F. E. , Hofmann J. P. , Hensen E. J. M. , Tadich A. , Li W. , Qi D. C. , Zhang K. H. L.
Published: April 2019

CuWO4 is an n-type oxide semiconductor with a bandgap of 2.2 eV which exhibits great potential for photoelectrochemical (PEC) conversion of solar energy into chemical fuels.
Evaluation and regulation of the corrosion resistance of macroporous titanium scaffolds with bioactive surface films for biomedical applications
Authors: Zhou Xingyu , Fu Xi , Chen Hongjie , Xiao Zhanwen , Min Li , Zhou Yong , Zhu Xiangdong , Zhang Kai , Tu Chongqi , Zhang Xingdong
Published: April 2019

A three-layer bioactive film on porous titanium was constructed and evaluated for its corrosion resistance via electrochemical analysis.
Analysis of neurochemicals by capillary electrophoresis in athletes' urine and a pilot study of their changes responding to sport fatigue
Authors: Ma Shuai , Xu Zhongqi , Ren Jie
Published: April 2019

Neurochemicals may play an important role in metabolism and sport fatigue.