bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Earthquakes and Fluids on the Metamorphism of the Lower Continental Crust
Authors: Jamtveit Bjørn , Petley‐Ragan Arianne , Incel Sarah , Dunkel Kristina G. , Aupart Claire , Austrheim Håkon , Corfu Fernando , Menegon Luca , Renard François
Published: July 2019

Rock rheology and density have first‐order effects on the lithosphere's response to plate tectonic forces at plate boundaries. Changes in these rock properties are controlled by metamorphic transformation processes that are critically dependent on the presence of fluids. At the onset of a continental collision, the lower crust is in most cases dry and strong. However, if exposed to internally produced or externally supplied fluids, the thickened crust will react and be converted into a mechanically weaker lithology by fluid‐driven metamorphic reactions. Fluid introduction is often associated with deep crustal earthquakes. Microstructural evidence, suggest that in strong highly stressed rocks, seismic slip may be initiated by brittle deformation and that wall‐rock damage caused by dynamic ruptures plays a very important role in allowing fluids to enter into contact with dry and highly reactive lower crustal rocks. The resulting metamorphism produces weaker rocks which subsequently deform by viscous creep. Volumes of weak rocks contained in a highly stressed environment of strong rocks may experience significant excursions toward higher pressure without any associated burial. Slow and highly localized creep processes in a velocity strengthening regime may produce mylonitic shear zones along faults initially characterized by earthquake‐generated frictional melting and wall rock damage. However, stress pulses from earthquakes in the shallower brittle regime may kick start new episodes of seismic slip at velocity weakening conditions. These processes indicate that the evolution of the lower crust during continental collisions is controlled by the transient interplay between brittle deformation, fluid‐rock interactions, and creep flow.
Developments in the Continuing Search for New Mineral Deposits
Authors: Decrée Sophie , Robb Laurence
Published: July 2019

New developments in the science of ore genesis and exploration could address the challenges of finding new mineral deposits for our increasingly materialistic world.
Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress
Authors: Wang Qi , Wei Song , Zhou Haoming , Shen Gefenqiang , Gan Xiaojie , Zhou Shun , Qiu Jiannan , Shi Chenyu , Lu Ling
Published: July 2019

Although diabetes mellitus/hyperglycemia is a risk factor for acute liver injury, the underlying mechanism remains largely unknown. Liver-resident macrophages (Kupffer cells, KCs) and oxidative stress play critical roles in the pathogenesis of toxin-induced liver injury. Here, we evaluated the role of oxidative stress in regulating KC polarization against acetaminophen (APAP)-mediated acute liver injury in a streptozotocin-induced hyperglycemic murine model. Compared to the controls, hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation. KCs obtained from hyperglycemic mice secreted higher levels of the proinflammatory factors, such as TNF-α and IL-6, lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced oxidative stress was revealed by increased levels of reactive oxygen species (ROS) in KCs from hyperglycemic mice post APAP treatment. In addition, ROS inhibitor NAC resulted in a significant decrease of ROS production in hyperglycemic KCs from mice posttreated with APAP. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia promoted M1 polarization, but inhibited M2 polarization of KCs obtained from APAP-exposed livers, as evidenced by increased MCP-1 and inducible NO synthase (iNOS) gene induction but decreased Arg-1 and CD206 gene induction accompanied by increased STAT1 activation and decreased STAT6 activation. NAC restored Arg-1, CD206 gene induction, and STAT6 activation. To explore the mechanism how hyperglycemia regulates KCs polarization against APAP-induced acute liver injury, we examined the AMPK/PI3K/AKT signaling pathway and found decreased AMPK activation and increased AKT activation in liver and KCs from hyperglycemic mice post APAP treatment. AMPK activation by its agonist AICAR or PI3K inhibition by its antagonist LY294002 inhibited ROS production in KCs from hyperglycemic mice post APAP treatment and significantly attenuated APAP-induced liver injury in the hyperglycemic mice, compared to the control mice. Our results demonstrated that hyperglycemia exacerbated APAP-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress.
Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART
Authors: Bachmann Nadine , von Siebenthal Chantal , Vongrad Valentina , Turk Teja , Neumann Kathrin , Beerenwinkel Niko , Bogojeska Jasmina , Fellay Jaques , Roth Volker , Kok Yik Lim , Thorball Christian W. , Borghesi Alessandro , Parbhoo Sonali , Wieser Mario , Böni Jürg , Perreau Matthieu , Klimkait Thomas , Yerly Sabine , Battegay Manuel , Rauch Andri , Hoffmann Matthias , Bernasconi Enos , Cavassini Matthias , Kouyos Roger D. , Günthard Huldrych F. , Metzner Karin J. ,   the Swiss HIV Cohort Study, Anagnostopoulos Alexia , Battegay Manuel , Bernasconi Enos , Böni Jürg , Braun Dominique L. , Bucher Heiner C. , Calmy Alexandra , Cavassini Matthias , Ciuffi Angela , Dollenmaier Günter , Egger Matthias , Elzi Luigia , Fehr Jan , Fellay Jacques , Furrer Hansjakob , Fux Christoph A. , Günthard Huldrych F. , Haerry David , Hasse Barbara , Hirsch Hans H. , Hoffmann Matthias , Hösli Irene , Huber Michael , Kahlert Christian , Kaiser Laurent , Keiser Olivia , Klimkait Thomas , Kouyos Roger D. , Kovari Helen , Ledergerber Bruno , Martinetti Gladys , Tejada Begona Martinez de , Marzolini Catia , Metzner Karin J. , Müller Nicolas , Nicca Dunja , Paioni Paolo , Pantaleo Guiseppe , Perreau Matthieu , Rauch Andri , Rudin Christoph , Scherrer Alexandra U. , Schmid Patrick , Speck Roberto , Stöckle Marcel , Tarr Philip , Trkola Alexandra , Vernazza Pietro , Wandeler Gilles , Weber Rainer , Yerly Sabine
Published: July 2019

The HIV-1 reservoir is the major hurdle to a cure. We here evaluate viral and host characteristics associated with reservoir size and long-term dynamics in 1,057 individuals on suppressive antiretroviral therapy for a median of 5.4 years. At the population level, the reservoir decreases with diminishing differences over time, but increases in 26.6% of individuals. Viral blips and low-level viremia are significantly associated with slower reservoir decay. Initiation of ART within the first year of infection, pretreatment viral load, and ethnicity affect reservoir size, but less so long-term dynamics. Viral blips and low-level viremia are thus relevant for reservoir and cure studies.
RNA structure drives interaction with proteins
Authors: Sanchez de Groot Natalia , Armaos Alexandros , Graña-Montes Ricardo , Alriquet Marion , Calloni Giulia , Vabulas R. Martin , Tartaglia Gian Gaetano
Published: July 2019

The combination of high-throughput sequencing and in vivo crosslinking approaches leads to the progressive uncovering of the complex interdependence between cellular transcriptome and proteome. Yet, the molecular determinants governing interactions in protein-RNA networks are not well understood. Here we investigated the relationship between the structure of an RNA and its ability to interact with proteins. Analysing in silico, in vitro and in vivo experiments, we find that the amount of double-stranded regions in an RNA correlates with the number of protein contacts. This relationship —which we call structure-driven protein interactivity— allows classification of RNA types, plays a role in gene regulation and could have implications for the formation of phase-separated ribonucleoprotein assemblies. We validate our hypothesis by showing that a highly structured RNA can rearrange the composition of a protein aggregate. We report that the tendency of proteins to phase-separate is reduced by interactions with specific RNAs.
ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response
Authors: Adeyemo Adebowale A. , Zaghloul Norann A. , Chen Guanjie , Doumatey Ayo P. , Leitch Carmen C. , Hostelley Timothy L. , Nesmith Jessica E. , Zhou Jie , Bentley Amy R. , Shriner Daniel , Fasanmade Olufemi , Okafor Godfrey , Eghan Benjamin , Agyenim-Boateng Kofi , Chandrasekharappa Settara , Adeleye Jokotade , Balogun William , Owusu Samuel , Amoah Albert , Acheampong Joseph , Johnson Thomas , Oli Johnnie , Adebamowo Clement ,   South Africa Zulu Type 2 Diabetes Case-Control Study, Chen Ji , Sun Meng , Pirie Fraser , Carstensen Tommy , Pomilla Cristina , Young Elizabeth H. , Sandhu Manjinder , Morris Andrew P. , Barroso Inês , McCarthy Mark I. , Mahajan Anubha , Wheeler Eleanor , Motala Ayesha A. , Collins Francis , Dunston Georgia , Rotimi Charles N.
Published: July 2019

Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10−9). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.
β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer
Authors: Tocci Piera , Cianfrocca Roberta , Di Castro Valeriana , Rosanò Laura , Sacconi Andrea , Donzelli Sara , Bonfiglio Silvia , Bucci Gabriele , Vizza Enrico , Ferrandina Gabriella , Scambia Giovanni , Tonon Giovanni , Blandino Giovanni , Bagnato Anna
Published: July 2019

The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that β-arrestin1 (β-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows β-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, β-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through β-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the β-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/β-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.
Ancient recycled lower crust in the mantle source of recent Italian magmatism
Authors: Koornneef Janne M. , Nikogosian Igor , van Bergen Manfred J. , Vroon Pieter Z. , Davies Gareth R.
Published: July 2019

Recycling of Earth’s crust through subduction and delamination contributes to mantle heterogeneity. Melt inclusions in early crystallised magmatic minerals record greater geochemical variability than host lavas and more fully reflect the heterogeneity of magma sources. To date, use of multiple isotope systems on small (< 300 μm) melt inclusions was hampered by analytical limitations. Here we report the first coupled Sr-Nd-Pb isotope data on individual melt inclusions from potassium-rich lavas from neighbouring Quaternary volcanoes in central Italy and infer the presence of a previously unidentified ancient lower crustal component in the mantle. We suggest derivation from Variscan or older basement included in the upper mantle by either delamination, sediment recycling, subduction erosion and/or slab detachment processes during Cenozoic subduction and collision of the western Mediterranean. The capability to determine isotope ratios in individual melt inclusions permits the detection of distinctive mantle contaminants and can provide insights into how geodynamic processes affect subduction recycling.
Northward drift of the Azores plume in the Earth’s mantle
Authors: Arnould Maëlis , Ganne Jérôme , Coltice Nicolas , Feng Xiaojun
Published: July 2019

Mantle plume fixity has long been a cornerstone assumption to reconstruct past tectonic plate motions. However, precise geochronological and paleomagnetic data along Pacific continuous hotspot tracks have revealed substantial drift of the Hawaiian plume. The question remains for evidence of drift for other mantle plumes. Here, we use plume-derived basalts from the Mid-Atlantic ridge to confirm that the upper-mantle thermal anomaly associated with the Azores plume is asymmetric, spreading over ~2,000 km southwards and ~600 km northwards. Using for the first time a 3D-spherical mantle convection where plumes, ridges and plates interact in a fully dynamic way, we suggest that the extent, shape and asymmetry of this anomaly is a consequence of the Azores plume moving northwards by 1–2 cm/yr during the past 85 Ma, independently from other Atlantic plumes. Our findings suggest redefining the Azores hotspot track and open the way for identifying how plumes drift within the mantle.
Comprehensive evaluation and characterisation of short read general-purpose structural variant calling software
Authors: Cameron Daniel L. , Di Stefano Leon , Papenfuss Anthony T.
Published: July 2019

In recent years, many software packages for identifying structural variants (SVs) using whole-genome sequencing data have been released. When published, a new method is commonly compared with those already available, but this tends to be selective and incomplete. The lack of comprehensive benchmarking of methods presents challenges for users in selecting methods and for developers in understanding algorithm behaviours and limitations. Here we report the comprehensive evaluation of 10 SV callers, selected following a rigorous process and spanning the breadth of detection approaches, using high-quality reference cell lines, as well as simulations. Due to the nature of available truth sets, our focus is on general-purpose rather than somatic callers. We characterise the impact on performance of event size and type, sequencing characteristics, and genomic context, and analyse the efficacy of ensemble calling and calibration of variant quality scores. Finally, we provide recommendations for both users and methods developers.
Dynamical nonlinear memory capacitance in biomimetic membranes
Authors: Najem Joseph S. , Hasan Md Sakib , Williams R. Stanley , Weiss Ryan J. , Rose Garrett S. , Taylor Graham J. , Sarles Stephen A. , Collier C. Patrick
Published: July 2019

Two-terminal memory elements, or memelements, capable of co-locating signal processing and memory via history-dependent reconfigurability at the nanoscale are vital for next-generation computing materials striving to match the brain’s efficiency and flexible cognitive capabilities. While memory resistors, or memristors, have been widely reported, other types of memelements remain underexplored or undiscovered. Here we report the first example of a volatile, voltage-controlled memcapacitor in which capacitive memory arises from reversible and hysteretic geometrical changes in a lipid bilayer that mimics the composition and structure of biomembranes. We demonstrate that the nonlinear dynamics and memory are governed by two implicitly-coupled, voltage-dependent state variables—membrane radius and thickness. Further, our system is capable of tuneable signal processing and learning via synapse-like, short-term capacitive plasticity. These findings will accelerate the development of low-energy, biomolecular neuromorphic memelements, which, in turn, could also serve as models to study capacitive memory and signal processing in neuronal membranes.
Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice
Authors: Oza Megha , Becker William , Gummadidala Phani M. , Dias Travis , Omebeyinje Mayomi H. , Chen Li , Mitra Chandrani , Jesmin Rubaiya , Chakraborty Paramita , Sajish Mathew , Hofseth Lorne J. , Banerjee Koyeli , Wang Qian , Moeller Peter D. R. , Nagarkatti Mitzi , Nagarkatti Prakash , Chanda Anindya
Published: July 2019

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound in Cannabis, which is studied extensively for its medicinal value. A central gap in the science is the underlying mechanisms surrounding THC’s therapeutic effects and the role of gut metabolite profiles. Using a mass-spectrometry based metabolomics, we show here that intraperitoneal injection of THC in C57BL/6 mice modulates metabolic profiles that have previously been identified as integral to health. Specifically, we investigated the effects of acute (single THC injection denoted here as ‘1X’) and short -term (five THC injections on alternate days denoted as ‘5X’) THC administration on fecal and intestinal tissue metabolite profiles. Results are consistent with the hypothesis that THC administration alters host metabolism by targeting two prominent lipid metabolism pathways: glycerophospholipid metabolism and fatty acid biosynthesis.
A direct comparison of interphase FISH versus low-coverage single cell sequencing to detect aneuploidy reveals respective strengths and weaknesses
Authors: Andriani Grasiella A. , Maggi Elaine , Piqué Daniel , Zimmerman Samuel E. , Lee Moonsook , Quispe-Tintaya Wilber , Maslov Alexander , Campisi Judith , Vijg Jan , Mar Jessica C. , Montagna Cristina
Published: July 2019

Aneuploidy has been reported to occur at remarkably high levels in normal somatic tissues using Fluorescence In Situ Hybridization (FISH). Recently, these reports were contradicted by single-cell low-coverage whole genome sequencing (scL-WGS) analyses, which showed aneuploidy frequencies at least an order of magnitude lower. To explain these seemingly contradictory findings, we used both techniques to analyze artificially generated mock aneuploid cells and cells with natural random aneuploidy. Our data indicate that while FISH tended to over-report aneuploidies, a modified 2-probe approach can accurately detect low levels of aneuploidy. Further, scL-WGS tends to underestimate aneuploidy levels, especially in a polyploid background.
Accurate Detection of Dobutamine-induced Haemodynamic Changes by Kino-Cardiography: A Randomised Double-Blind Placebo-Controlled Validation Study
Authors: Hossein Amin , Mirica Daniela Corina , Rabineau Jérémy , Rio José Ignacio Del , Morra Sofia , Gorlier Damien , Nonclercq Antoine , van de Borne Philippe , Migeotte Pierre-François
Published: July 2019

Non-invasive remote detection of cardiac and blood displacements is an important topic in cardiac telemedicine. Here we propose kino-cardiography (KCG), a non-invasive technique based on measurement of body vibrations produced by myocardial contraction and blood flow through the cardiac chambers and major vessels. KCG is based on ballistocardiography and measures 12 degrees-of-freedom (DOF) of body motion. We tested the hypothesis that KCG reliably assesses dobutamine-induced haemodynamic changes in healthy subjects. Using a randomized double-blinded placebo-controlled crossover study design, dobutamine and placebo were infused to 34 volunteers (25 ± 2 years, BMI 22 ± 2 kg/m², 18 females). Baseline recordings were followed by 3 sessions of increasing doses of dobutamine (5, 10, 20 μg/kg.min) or saline solution. During each session, stroke volume (SV) and cardiac output (CO) were determined by echocardiography and followed by a 90 s KCG recording. Measured linear accelerations and angular velocities were used to compute total Kinetic energy (iK) and power (Pmax). KCG sorted dobutamine infusion vs. placebo with 96.9% accuracy. Increases in SV and CO were correlated to iK (r = +0.71 and r = +0.8, respectively, p < 0.0001). Kino-cardiography, with 12-DOF, allows detecting dobutamine-induced haemodynamic changes with a high accuracy and present a major improvement over single axis ballistocardiography or seismocardiography.
Gains and losses of metabolic function inferred from a phylotranscriptomic analysis of algae
Authors: Goh Falicia Qi Yun , Jeyakani Justin , Tipthara Phornpimon , Cazenave-Gassiot Amaury , Ghosh Rajoshi , Bogard Nicholas , Yeo Zhenxuan , Wong Gane Ka-Shu , Melkonian Michael , Wenk Markus R. , Clarke Neil D.
Published: July 2019

Hidden Markov models representing 167 protein sequence families were used to infer the presence or absence of homologs within the transcriptomes of 183 algal species/strains. Statistical analyses of the distribution of HMM hits across major clades of algae, or at branch points on the phylogenetic tree of 98 chlorophytes, confirmed and extended known cases of metabolic loss and gain, most notably the loss of the mevalonate pathway for terpenoid synthesis in green algae but not, as we show here, in the streptophyte algae. Evidence for novel events was found as well, most remarkably in the recurrent and coordinated gain or loss of enzymes for the glyoxylate shunt. We find, as well, a curious pattern of retention (or re-gain) of HMG-CoA synthase in chlorophytes that have otherwise lost the mevalonate pathway, suggesting a novel, co-opted function for this enzyme in select lineages. Finally, we find striking, phylogenetically linked distributions of coding sequences for three pathways that synthesize the major membrane lipid phosphatidylcholine, and a complementary phylogenetic distribution pattern for the non-phospholipid DGTS (diacyl-glyceryl-trimethylhomoserine). Mass spectrometric analysis of lipids from 25 species was used to validate the inference of DGTS synthesis from sequence data.
Molecular basis of the scalp-ear-nipple syndrome unraveled by the characterization of disease-causing KCTD1 mutants
Authors: Smaldone Giovanni , Balasco Nicole , Pirone Luciano , Caruso Daniela , Di Gaetano Sonia , Pedone Emilia Maria , Vitagliano Luigi
Published: July 2019

The scalp-ear-nipple (SEN) syndrome is an autosomal-dominant disorder characterized by cutis aplasia of the scalp and malformations of breast, external ears, digits, and nails. Genetic analyses have shown that the disease is caused by missense mutations of the KCTD1 protein, although the functional/structural basis of SEN insurgence is hitherto unknown. With the aim of unravelling the molecular basis of the SEN syndrome associated with KCTD1 mutations we here expressed and characterized several disease causing mutants. A preliminary dissection of the protein provides insights into the role that individual domains play in KCTD1 stability. The characterization of SEN-causing mutants indicates that, although the mutation sites are located in distant regions of the BTB domain or of the pre-BTB region, all of them are unable to interact with the transcription factor AP-2α, a well-known KCTD1 biological partner. Notably, all mutations, including the one located in the pre-BTB region, produce a significant destabilization of the protein. The structural role of the pre-BTB region in KCTD1 and other proteins of the family is corroborated by its sequence conservation in orthologs and paralogs. Interestingly, SEN-causing mutations also favor the tendency of KCTD1 to adopt structural states that are characterized by the ability to bind the β-amyloid fluorescent dye thioflavin T. The formation of aggregation-prone species may have important implications for the disease etiology. Collectively, these findings provide an intriguing picture of the functional and structural alterations induced by KCTD1 mutations that ultimately lead to disease.
Machine Learning Approaches for Automated Lesion Detection in Microwave Breast Imaging Clinical Data
Authors: Rana Soumya Prakash , Dey Maitreyee , Tiberi Gianluigi , Sani Lorenzo , Vispa Alessandro , Raspa Giovanni , Duranti Michele , Ghavami Mohammad , Dudley Sandra
Published: July 2019

Breast lesion detection employing state of the art microwave systems provide a safe, non-ionizing technique that can differentiate healthy and non-healthy tissues by exploiting their dielectric properties. In this paper, a microwave apparatus for breast lesion detection is used to accumulate clinical data from subjects undergoing breast examinations at the Department of Diagnostic Imaging, Perugia Hospital, Perugia, Italy. This paper presents the first ever clinical demonstration and comparison of a microwave ultra-wideband (UWB) device augmented by machine learning with subjects who are simultaneously undergoing conventional breast examinations. Non-ionizing microwave signals are transmitted through the breast tissue and the scattering parameters (S-parameter) are received via a dedicated moving transmitting and receiving antenna set-up. The output of a parallel radiologist study for the same subjects, performed using conventional techniques, is taken to pre-process microwave data and create suitable data for the machine intelligence system. These data are used to train and investigate several suitable supervised machine learning algorithms nearest neighbour (NN), multi-layer perceptron (MLP) neural network, and support vector machine (SVM) to create an intelligent classification system towards supporting clinicians to recognise breasts with lesions. The results are rigorously analysed, validated through statistical measurements, and found the quadratic kernel of SVM can classify the breast data with 98% accuracy.
Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity - implications for mechanistic pharmacokinetics modeling
Authors: Okyar Alper , Kumar Swati A. , Filipski Elisabeth , Piccolo Enza , Ozturk Narin , Xandri-Monje Helena , Pala Zeliha , Abraham Kristin , Gomes Ana Rita Gato de Jesus , Orman Mehmet N. , Li Xiao-Mei , Dallmann Robert , Lévi Francis , Ballesta Annabelle
Published: July 2019

P-glycoprotein (P-gp) largely influences the pharmacokinetics (PK) and toxicities of xenobiotics in a patient-specific manner so that personalized drug scheduling may lead to significant patient’s benefit. This systems pharmacology study investigated P-gp activity in mice according to organ, sex, feeding status, and circadian time. Sex-specific circadian changes were found in P-gp ileum mRNA and protein levels, circadian amplitudes being larger in females as compared to males. Plasma, ileum and liver concentrations of talinolol, a pure P-gp substrate, significantly differed according to sex, feeding and circadian timing. A physiologically-based PK model was designed to recapitulate these datasets. Estimated mesors (rhythm-adjusted mean) of ileum and hepatic P-gp activity were higher in males as compared to females. Circadian amplitudes were consistently higher in females and circadian maxima varied by up to 10 h with respect to sex. Fasting increased P-gp activity mesor and dampened its rhythm. Ex-vivo bioluminescence recordings of ileum mucosae from transgenic mice revealed endogenous circadian rhythms of P-gp protein expression with a shorter period, larger amplitude, and phase delay in females as compared to males. Importantly, this study provided model structure and parameter estimates to refine PK models of any P-gp substrate to account for sex, feeding and circadian rhythms.
Compatibility of Maximum Inorganic and Organic Calcium and Phosphate Content in Neonatal Parenteral Solutions
Authors: Watrobska-Swietlikowska Dorota
Published: July 2019

The purpose of the study was to determine the maximum safe concentration of calcium and phosphate in neonatal parenteral nutrition (PN) solutions when various combinations of inorganic and organic salts are applied. Twelve PN solutions for neonatal use were aseptically prepared. Increasing concentrations of inorganic and organic calcium and phosphate were added to the standard formulas. Each admixture was separately tested according to the following conditions; after mixing, at 37 °C for 24 hr, and the maximum safe combination of calcium and phosphate were stored at 4 °C for 30 days and followed by 24 hr at 37 °C. Visual inspections and microscopic observation of undiluted PN solutions as well as the membrane filter after filtration of the PN solution, pH evaluation, and absorbance were examined. The safe maximum concentration of organic and inorganic calcium and phosphate were proposed individually for each composition of parenteral nutrition solutions. Surprisingly, organic calcium with organic phosphate showed precipitation but over the therapeutic range. The protective effect of amino acid was observed and higher concentrations of calcium and phosphate were free of precipitation. This work is valuable in daily practice as it allows an increase in the limits of calcium and phosphate in PN solutions for infants.
Analysis of serum adiponectin and leptin in patients with acute exacerbation of idiopathic pulmonary fibrosis
Authors: Enomoto Noriyuki , Oyama Yoshiyuki , Yasui Hideki , Karayama Masato , Hozumi Hironao , Suzuki Yuzo , Kono Masato , Furuhashi Kazuki , Fujisawa Tomoyuki , Inui Naoki , Nakamura Yutaro , Suda Takafumi
Published: July 2019

Weight loss progresses with the progression of idiopathic pulmonary fibrosis (IPF), and acute exacerbation of IPF (AE-IPF) frequently occurs in its advanced stage. Adiponectin and leptin are adipokines produced from adipose tissue, and are related to thinness and obesity, respectively. Additionally, these adipokines are implicated in the regulation of inflammation and fibrosis centering on peroxisome proliferator-activated receptor γ (PPARγ). However, the relationship between adiponectin/leptin and AE-IPF remains poorly known. We conducted this study to evaluate levels of serum adiponectin/leptin, and to elucidate the clinical importance of adiponectin and leptin in patients with AE-IPF. Thirty-two patients (39 episodes) who were diagnosed with AE-IPF at our hospital from 1997 to 2016 were retrospectively studied. Serum adiponectin and leptin concentrations were measured with enzyme-linked immunosorbent assay. Patients with AE-IPF showed higher levels of serum adiponectin and leptin than those at initial diagnosis of IPF (p = 0.007 and p = 0.027, respectively). Serum adiponectin/leptin (A/L) ratio was negatively correlated with body mass index at AE-IPF (r = −0.456, p = 0.003) and PaO2 before AE-IPF (r = −0.498, p = 0.034), and positively correlated with C-reactive protein at AE-IPF (r = 0.316, p = 0.049). Patients with higher A/L ratios had worse survival than those with lower A/L ratios (log-rank, p = 0.026). Further, in multivariate analysis, serum A/L ratio was a significant prognostic factor in patients with AE-IPF (HR 2.60, p = 0.042). In conclusion, the higher adiponectin/leptin ratio may be associated with a poor prognosis in patients with AE-IPF.
Multistep Protein Unfolding Scenarios from the Rupture of a Complex Metal Cluster Cd3S9
Authors: Yuan Guodong , Ma Qun , Wu Tao , Wang Mengdi , Li Xi , Zuo Jinglin , Zheng Peng
Published: July 2019

Protein (un)folding is a complex and essential process. With the rapid development of single-molecule techniques, we can detect multiple and transient proteins (un)folding pathways/intermediates. However, the observation of multiple multistep (>2) unfolding scenarios for a single protein domain remains limited. Here, we chose metalloprotein with relatively stable and multiple metal-ligand coordination bonds as a system for such a purpose. Using AFM-based single-molecule force spectroscopy (SMFS), we successfully demonstrated the complex and multistep protein unfolding scenarios of the β-domain of a human protein metallothionein-3 (MT). MT is a protein of ~60 amino acids (aa) in length with 20 cysteines for various metal binding, and the β-domain (βMT) is of ~30 aa with an M3S9 metal cluster. We detected four different types of three-step protein unfolding scenarios from the Cd-βMT, which can be possibly explained by the rupture of Cd-S bonds in the complex Cd3S9 metal cluster. In addition, complex unfolding scenarios with four rupture peaks were observed. The Cd-S bonds ruptured in both single bond and multiple bonds modes. Our results provide not only evidence for multistep protein unfolding phenomena but also reveal unique properties of metalloprotein system using single-molecule AFM.
Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers
Authors: Tapial Sandra , Olmedillas-López Susana , Rueda Daniel , Arriba María , García Juan L. , Vivas Alfredo , Pérez Jessica , Pena-Couso Laura , Olivera Rocío , Rodríguez Yolanda , García-Arranz Mariano , García-Olmo Damián , González-Sarmiento Rogelio , Urioste Miguel , Goel Ajay , Perea José
Published: July 2019

Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a “unique” CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.
Severity of dental caries and risk of coronary heart disease in middle-aged men and women: a population-based cohort study of Korean adults, 2002–2013
Authors: Kim Kyuwoong , Choi Seulggie , Chang Jooyoung , Kim Sung Min , Kim Seon Jip , Kim Ryan Jin-Young , Cho Hyun-Jae , Park Sang Min
Published: July 2019

We aimed to evaluate the risk of coronary heart disease (CHD) according to dental caries status in middle-aged patients using a population-based cohort database containing medical/dental claims, health examination, and death records in the Republic of Korea. A total of 234,597 patients were identified in the database who were without history of cardiovascular disease, including 104,638 patients without dental caries, 41,696 with incipient/moderate stage dental caries, and 88,262 advanced/severe dental caries. We used Cox proportional hazards model adjusted for sociodemographic, lifestyle, and medical characteristics to compute hazard ratio (HR) and 95% confidence intervals (95% CI) for CHD according to severity of dental caries. During 1,491,190 person-years of follow-up, there were a total of 6,015 CHD events. After adjustment for potential confounders, patients in the highest quartile of outpatient visits for advanced/severe stage dental caries was associated with an increase in CHD risk (HR = 1.13; 95% CI: 1.04–1.22) as compared with patients without dental caries. When the analysis was restricted to the patients with advanced/severe dental caries, dose-response relationship between number of outpatient visits for dental caries and risk of CHD was observed (Ptrend: <0.001). Prevention and control of dental caries might be worth promoting in clinical practice to prevent CHD.
Transcriptomic analysis of mouse cochleae suffering from gentamicin damage reveals the signalling pathways involved in hair cell regeneration
Authors: Bai Huanju , Jiang Lingling , Wang Xi , Gao Xue , Bing Jie , Xi Chao , Wang Weiqian , Zhang Meiguang , Zhang Xinwen , Han Zhongming , Xu Jincao , Zeng Shaoju
Published: July 2019

There is a strong capacity for hair cell regeneration after damage in the inner ear of non-mammals. However, mammalian hair cells are substantially unable to regenerate. To obtain insights into the mechanism of this difference, we analyzed the transcriptomic changes in the mouse cochleae suffered from gentamicin damage and compared them with those in the chick cochleae suffered from the same damage. The results indicated that 2,230 genes had significantly differential expression between the gentamicin- and saline-treated mouse cochleae. Some of the differentially expressed genes were grouped into 265 signaling pathways, including the Notch, Wnt (Wingless and INT-1), Bmp (bone morphogenetic protein), FGF (fibroblast growth factor) and Shh (sonic hedgehog) pathways. Using pharmacological inhibitors or agonists of these pathways, the effects of these pathways on hair cell regeneration were further studied. The results indicated that Bmp alone and its coregulation with the Notch or Wnt signaling pathways increased the numbers of generated cells from transdifferentiation or proliferation in the mouse cochlea after damage, in addition to the reported coregulation of Notch and Wnt. Thus, this work indicates a new signaling pathway (Bmp) and its synergetic coregulation in mammalian hair cell regeneration, providing potential therapeutic targets to increase mammalian hair cell regeneration.
Application of trilobal capillary-channeled polymer (C-CP) fibers for reversed phase liquid chromatography and ESI-MS for the determination of proteins in different biological matrices
Authors: Youmans Katherine B. , Wang Lei , Marcus R. Kenneth
Published: July 2019

Protein mixtures in biological matrices can be directly analyzed by RP-LC on trilobal C-CP fiber columns coupled with ESI-MS.
Alkyl triphenylphosphonium surfactants as nucleic acid carriers: complexation efficacy toward DNA decamers, interaction with lipid bilayers and cytotoxicity studies
Authors: Zakharova Lucia Ya. , Kaupova Guzalia I. , Gabdrakhmanov Dinar R. , Gaynanova Gulnara A. , Ermakova Elena A. , Mukhitov Alexander R. , Galkina Irina V. , Cheresiz Sergey V. , Pokrovsky Andrey G. , Skvortsova Polina V. , Gogolev Yuri V. , Zuev Yuriy F.
Published: July 2019

Herein, for the first time the complexation ability of a homological series of triphenylphosphonium surfactants (TPPB-n) toward DNA decamers has been explored.
Microwave assisted synthesis of heterometallic 3d–4f M4Ln complexes
Authors: Rosado Piquer L. , Dey S. , Castilla-Amorós L. , Teat S. J. , Cirera J. , Rajaraman G. , Sañudo E. C.
Published: July 2019

We describe the solvent-free microwave assisted synthesis and magnetic properties of a series of 3d–4f complexes of formula [M4Ln(OH)2(chp)4(SALOH)5(H2O)(MeCN)(Solv)] (Solv = MeOH, MeCN, H2O, M = Ni(ii), Co(ii); Ln = La, Gd, Dy, Tb).
Anthocyanin-rich extract from black rice (Oryza sativa L. Japonica) ameliorates diabetic osteoporosis in rats
Authors: Qi Shanshan , He Jia , Han Hao , Zheng Hongxing , Jiang Hai , Hu Ching Yuan , Zhang Zhijian , Li Xinsheng
Published: July 2019

Diabetic osteoporosis (DOP) is a systemic endocrine-metabolic osteopathy which has the characteristics of bone mineral density (BMD) reduction and bone microstructural destruction.
Maternal quercetin intake during lactation attenuates renal inflammation and modulates autophagy flux in high-fructose-diet-fed female rat offspring exposed to maternal malnutrition
Authors: Sato Shin , Norikura Toshio , Mukai Yuuka
Published: July 2019

Quercetin intake during lactation causes long-term alterations in inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring exposed to maternal normal- or low-protein diets.
Mechanistic studies on the N-heterocyclic carbene-catalyzed reaction of isatin-derived enals with hydrazones
Authors: Gao Jinxin , Wang Yang
Published: July 2019

The detailed mechanism and origin of stereoselectivity of the NHC-catalyzed annulation reaction were investigated.
A unique spiro-β-triazinedione-γ-hydantoin type alkaloid with antiviral activity against tobacco mosaic virus from Streptomyces gamaensis
Authors: Guo Xiaowei , Wang Jidong , Su Can , Liu Chongxi , Ma Xiao-Yan , Yu Zhiyin , Li Jiansong , Wang Xiangjing , Xiang Wensheng , Huang Sheng-Xiong
Published: July 2019

Chemical investigation of a soil actinomycete strain Streptomyces gamaensis NEAU-Gz11 led to the isolation of three alkaloids 1–3 with antiviral activity.
C(sp3)–H hydroxylation of fluorenes, oxindoles and benzofuranones with a Mg(NO3)2–HP(O)Ph2 oxidation system
Authors: Hu Chen , Hong Gang , Nahide Pradip D. , He Yuchen , Zhou Chen , Kozlowski Marisa C. , Wang Limin
Published: July 2019

A novel oxidation system in which magnesium nitrate is used as an oxidant in the presence of diphenylphosphine oxide permits the C(sp3)–H hydroxylation of fluorenes, oxindoles, and benzofuranones.
Monitoring NAD(P)H by an ultrasensitive fluorescent probe to reveal reductive stress induced by natural antioxidants in HepG2 cells under hypoxia
Authors: Pan Xiaohong , Zhao Yuehui , Cheng Tingting , Zheng Aishan , Ge Anbin , Zang Lixin , Xu Kehua , Tang Bo
Published: July 2019

An ultrasensitive fluorescent probe for monitoring NAD(P)H and revealing reductive stress induced by natural antioxidants in HepG2 cells under hypoxia.
Carbon beads with a well-defined pore structure derived from ion-exchange resin beads
Authors: He Ping , Haw Kok-Giap , Yan Shichen , Tang Lingxue , Fang Qianrong , Qiu Shilun , Valtchev Valentin
Published: July 2019

Carbon beads with a well-defined micropore structure and excellent CO2 capture ability were obtained by carbonization of K-exchanged cation exchange resin precursors.
A general strategy to prepare high-quality inorganic charge-transporting layers for efficient and stable all-layer-inorganic perovskite solar cells
Authors: Zhang Shasha , Chen Weitao , Wu Shaohang , Chen Rui , Huang Yuqian , Yang Zhichun , Li Jiangyu , Han Liyuan , Chen Wei
Published: July 2019

A general strategy for fabrication of high-quality inorganic CTLs on top of an inorganic perovskite to achieve high efficiency and stability.
Immobilization of highly active bimetallic PdAu nanoparticles onto nanocarbons for dehydrogenation of formic acid
Authors: Hong Wei , Kitta Mitsunori , Tsumori Nobuko , Himeda Yuichiro , Autrey Tom , Xu Qiang
Published: July 2019

An approach for the immobilization of PdAu nanoparticles onto commercial carbons as catalysts toward dehydrogenation of formic acid is developed.
A two-dimensional halogenated thiophene side-chain strategy for balancing Voc and Jsc and improving efficiency of non-fullerene small molecule acceptor-based organic solar cells
Authors: Yuan Gui-Zhou , Fan Haijun , Wan Shi-Sheng , Jiang Zhao , Liu Yan-Qiang , Liu Kai-Kai , Bai Hai-Rui , Zhu Xiaozhang , Wang Jin-Liang
Published: July 2019

A PCE of 12.36% is achieved through a two-dimensional halogenated thiophene side-chain strategy, which is the highest value for NF-SMAs with a fluorinated fused central core in binary organic solar cells.
Peculiar motions of the gas at the centre of the barred galaxy UGC 4056
Authors: Zinchenko I. A. , Pilyugin L. S. , Sakhibov F. , Grebel E. K. , Just A. , Berczik P. , Nefedyev Y. A. , Vílchez J. M. , Shulga V. M.
Published: July 2019

We derive the circular velocity curves of the gaseous and stellar discs of UGC 4056, a giant barred galaxy with an active galactic nucleus (AGN). We analyse UGC 4056 using the 2D spectroscopy obtained within the framework of the Mapping Nearby Galaxies at APO (MaNGA) survey. Using images and the colour index g − r from the Sloan Digital Sky Survey (SDSS), we determined the tilt of the galaxy, which allows us to conclude that the galaxy rotates clockwise with trailing spiral arms. We found that the gas motion at the central part of the UGC 4056 shows peculiar features. The rotation velocity of the gaseous disc shows a bump within around three kiloparsecs while the rotation velocity of the stellar disc falls smoothly to zero with decreasing galactocentric distance. We demonstrate that the peculiar radial velocities in the central part of the galaxy may be caused by the inflow of the gas towards the nucleus of the galaxy. The unusual motion of the gas takes place at the region with the AGN-like radiation and can be explained by the gas response to the bar potential.
Warped diffusive radio halo around the quiescent spiral edge-on galaxy NGC 4565
Authors: Heesen V. , Whitler L. , Schmidt P. , Miskolczi A. , Sridhar S. S. , Horellou C. , Beck R. , Gürkan G. , Scannapieco E. , Brüggen M. , Heald G. H. , Krause M. , Paladino R. , Nikiel-Wroczyński B. , Wilber A. , Dettmar R.-J.
Published: July 2019

Context. Cosmic rays play a pivotal role in launching galactic winds, particularly in quiescently star-forming galaxies where the hot gas alone is not sufficient to drive a wind. Except for the Milky Way, not much is known about the transport of cosmic rays in galaxies.

Aims. In this Letter, we present low-frequency observations of the nearby edge-on spiral galaxy NGC 4565 using the LOw-Frequency ARray (LOFAR). With our deep 144 MHz observations, we obtain a clean estimate of the emission originating from old cosmic-ray electrons (CRe), which is almost free from contamination by thermal emission.

Methods. We measured vertical profiles of the non-thermal radio continuum emission that we fitted with Gaussian and exponential functions. The different profile shapes correspond to 1D cosmic-ray transport models of pure diffusion and advection, respectively.

Results. We detect a warp in the radio continuum that is reminiscent of the previously known H I warp. Because the warp is not seen at GHz-frequencies in the radio continuum, its minimum age must be about 100 Myr. The warp also explains the slight flaring of the thick radio disc that can otherwise be well described by a Gaussian profile with an FWHM of 65 arcsec (3.7 kpc).

Conclusions. The diffusive radio halo together with the extra-planar X-ray emission may be remnants of enhanced star-forming activity in the past where the galaxy had a galactic wind, as GHz-observations indicate only a weak outflow in the last 40 Myr. NGC 4565 could be in transition from an outflow- to an inflow-dominated phase.