bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCε signaling pathway
Authors: Benoist Lauriane , Chadet Stéphanie , Genet Thibaud , Lefort Claudie , Heraud Audrey , Danila Maria D. , Muntean Danina M. , Baron Christophe , Angoulvant Denis , Babuty Dominique , Bourguignon Thierry , Ivanes Fabrice 
Published: August 2019

AbstractSterile inflammation is a key determinant of myocardial reperfusion injuries. It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts’ response to ischemia/reperfusion in vitro and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia/reperfusion. We subjected human AC16 cardiomyocytes to 5 h hypoxia/1 h reoxygenation (H/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. In vitro H/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H2O2-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKCε signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia/reperfusion outcomes in acute myocardial infarction and cardiac transplantation.
Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein
Authors: Schaeffer Céline , Izzi Claudia , Vettori Andrea , Pasqualetto Elena , Cittaro Davide , Lazarevic Dejan , Caridi Gianluca , Gnutti Barbara , Mazza Cinzia , Jovine Luca , Scolari Francesco , Rampoldi Luca 
Published: August 2019

AbstractAutosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD-REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD-REN, a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD-REN, and possibly more generally in ADTKD.
Geometric principles of second messenger dynamics in dendritic spines
Authors: Cugno Andrea , Bartol Thomas M. , Sejnowski Terrence J. , Iyengar Ravi , Rangamani Padmini 
Published: August 2019

AbstractDendritic spines are small, bulbous protrusions along dendrites in neurons and play a critical role in synaptic transmission. Dendritic spines come in a variety of shapes that depend on their developmental state. Additionally, roughly 14–19% of mature spines have a specialized endoplasmic reticulum called the spine apparatus. How does the shape of a postsynaptic spine and its internal organization affect the spatio-temporal dynamics of short timescale signaling? Answers to this question are central to our understanding the initiation of synaptic transmission, learning, and memory formation. In this work, we investigated the effect of spine and spine apparatus size and shape on the spatio-temporal dynamics of second messengers using mathematical modeling using reaction-diffusion equations in idealized geometries (ellipsoids, spheres, and mushroom-shaped). Our analyses and simulations showed that in the short timescale, spine size and shape coupled with the spine apparatus geometries govern the spatiotemporal dynamics of second messengers. We show that the curvature of the geometries gives rise to pseudo-harmonic functions, which predict the locations of maximum and minimum concentrations along the spine head. Furthermore, we showed that the lifetime of the concentration gradient can be fine-tuned by localization of fluxes on the spine head and varying the relative curvatures and distances between the spine apparatus and the spine head. Thus, we have identified several key geometric determinants of how the spine head and spine apparatus may regulate the short timescale chemical dynamics of small molecules that control synaptic plasticity.
Sources of mercury in deep-sea sediments of the Mediterranean Sea as revealed by mercury stable isotopes
Authors: Ogrinc Nives , Hintelmann Holger , Kotnik Jože , Horvat Milena , Pirrone Nicola 
Published: August 2019

AbstractMercury (Hg) and its stable isotope composition were used to determine the sources of Hg in deep-sea sediments of the Mediterranean Sea. Surface and down-core sediment δ202Hg values varied widely between −2.30 and +0.78‰, showed consistently positive values for mass independent fractionation of odd Hg isotopes (with average values of Δ199Hg = +0.10 ± 0.04‰ and Δ201Hg = +0.04 ± 0.02‰) and near-zero Δ200Hg values, indicating either multiple Hg sources or a combination of different Hg isotope fractionating processes before and after sediment deposition. Both mass-dependent and mass-independent fractionation processes influence the isotopic composition of Hg in the Mediterranean Sea. Positive Δ199Hg values are likely the result of enhanced Hg2+ photoreduction in the Mediterranean water column before incorporation of Hg into sediments, while mass-dependent fractionation decreases δ202Hg values due to kinetic isotope fractionation during deposition and mobilization. An isotope mixing model based on mass-dependent and mass-independent fractionation (δ202Hg and Δ199Hg) suggests at least three primary Hg sources of atmospheric deposition in the surface sediments: urban, industrial and global precipitation-derived. Industry is the main source of Hg in Algerian and Western Basin surface sediments and at two sites in the Adriatic Sea, while the urban contribution is most prominent at the Strait of Otranto (MS3) and in Adriatic surface sediments. The contribution from precipitation ranged from 10% in Algerian to 37% in W Basin sediments. Overall, results suggest that atmospheric Hg deposition to Mediterranean surface sediments is dominated by gaseous elemental mercury (58 ± 11%) rather than wet deposition.
Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
Authors: Khan Reas S. , Baumann Bailey , Dine Kimberly , Song Ying , Dunaief Joshua L. , Kim Sangwon F. , Shindler Kenneth S. 
Published: August 2019

AbstractDysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.
CYLD dysregulation in pathogenesis of sporadic inclusion body myositis
Authors: Yamashita Satoshi , Matsuo Yoshimasa , Tawara Nozomu , Hara Kentaro , Yamamoto Masanori , Nishikami Tomo , Kawakami Kensuke , Zhang Xiao , Zhang Ziwei , Doki Tsukasa , Ando Yukio 
Published: August 2019

AbstractSporadic inclusion body myositis (sIBM) is the most commonly acquired myopathy in middle-aged and elderly people. The muscle histology is characterized by both inflammation and degeneration, including sarcoplasmic aggregation of TDP-43. Cylindromatosis (CYLD) is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and negatively regulates signal transduction pathways, such as NF-κB signalling pathways. We examined localization of CYLD as well as phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in muscle tissues of sIBM patients and muscle-specific wild-type TDP-43 transgenic (TDP-43 TG) mice. We investigated whether overexpression of CYLD can affect muscle toxicity in the cell models treated by endoplasmic reticulum (ER) stress inducers tunicamycin and thapsigargin. CYLD expressed with phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in the nuclear and perinuclear regions of muscle fibres of wild-type TDP-43 TG mice and the degenerative myofibres of sIBM patients with rimmed vacuoles and endomysial cellular infiltration. Although expression levels of CYLD decreased and cell viability was reduced in cells treated with ER stress inducers, wild-type CYLD, but not the catalytic mutant, substantially improved cell viability based on the deubiquitinase activity. Dysregulation of CYLD may reinforce myodegeneration in the pathophysiology of sIBM by attenuating autophagic clearance of protein aggregates. Regulating CYLD in muscle fibres might serve as a novel therapeutic strategy for sIBM treatment.
Unraveling structural and compositional information in 3D FinFET electronic devices
Authors: Trombini Henrique , Marmitt Gabriel Guterres , Alencar Igor , Baptista Daniel Lorscheitter , Reboh Shay , Mazen Frédéric , Pinheiro Rafael Bortolin , Sanchez Dario Ferreira , Senna Carlos Alberto , Archanjo Bráulio Soares , Achete Carlos Alberto , Grande Pedro Luis 
Published: August 2019

AbstractNon-planar Fin Field Effect Transistors (FinFET) are already present in modern devices. The evolution from the well-established 2D planar technology to the design of 3D nanostructures rose new fabrication processes, but a technique capable of full characterization, particularly their dopant distribution, in a representative (high statistics) way is still lacking. Here we propose a methodology based on Medium Energy Ion Scattering (MEIS) to address this query, allowing structural and compositional quantification of advanced 3D FinFET devices with nanometer spatial resolution. When ions are backscattered, their energy losses unfold the chemistry of the different 3D compounds present in the structure. The FinFET periodicity generates oscillatory features as a function of backscattered ion energy and, in fact, these features allow a complete description of the device dimensions. Additionally, each measurement is performed over more than thousand structures, being highly representative in a statistical meaning. Finally, independent measurements using electron microscopy corroborate the proposed methodology.
3D multiscale-imaging of processing-induced defects formed during sintering of hierarchical powder packings
Authors: Okuma Gaku , Watanabe Shuhei , Shinobe Kan , Nishiyama Norimasa , Takeuchi Akihisa , Uesugi Kentaro , Tanaka Satoshi , Wakai Fumihiro 
Published: August 2019

AbstractThe characterization of the processing-induced defects is an essential step for developing defect-free processing, which is important to the assurance of structural reliability of brittle ceramics. The multiscale X-ray computed tomography, consisting of micro-CT as a wide-field and low-resolution system and nano-CT as a narrow-field and high-resolution system, is suitable for observing crack-like defects with small length and with very small crack opening displacement. Here we applied this powerful imaging tool in order to reveal the complicated three-dimensional morphology of defects evolved during sintering of alumina. The hierarchical packing structure of granules was the origin of several types of strength-limiting defects, which could not be eliminated due to the differential sintering of heterogeneous microstructures. This imaging technique of internal defects provides a link between the processing and the fracture strength for the development of structural materials.
Identification of methotrexate as a heterochromatin-promoting drug
Authors: Loyola Andre C. , Zhang Lin , Shang Robin , Dutta Pranabananda , Li Jinghong , Li Willis X. 
Published: August 2019

AbstractHeterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics.
SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines
Authors: Ehrenhöfer-Wölfer Katharina , Puchner Teresa , Schwarz Cornelia , Rippka Janine , Blaha-Ostermann Silvia , Strobl Ursula , Hörmann Alexandra , Bader Gerd , Kornigg Stefan , Zahn Stephan , Sommergruber Wolfgang , Schweifer Norbert , Zichner Thomas , Schlattl Andreas , Neumüller Ralph A. , Shi Junwei , Vakoc Christopher R. , Kögl Manfred , Petronczki Mark , Kraut Norbert , Pearson Mark A. , Wöhrle Simon 
Published: August 2019

AbstractSMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screening, we identify SMARCA4 as a novel dependency in SMARCA2-deficient esophageal squamous cell carcinoma (ESCC) models, reciprocal to the known synthetic lethal interaction. Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4. Dependency on SMARCA4 is linked to its ATPase activity, but not to bromodomain function. We highlight the relevance of SMARCA4 as a drug target in esophageal cancer using an engineered ESCC cell model harboring a SMARCA4 allele amenable to targeted proteolysis and identify SMARCA4-dependent cell models with low or absent SMARCA2 expression from additional tumor types. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and suggest that pharmacological inhibition of SMARCA4 represents a novel therapeutic opportunity for SMARCA2-deficient cancers.
A pyramid MOT with integrated optical cavities as a cold atom platform for an optical lattice clock
Authors: Bowden William , Hobson Richard , Hill Ian R. , Vianello Alvise , Schioppo Marco , Silva Alissa , Margolis Helen S. , Baird Patrick E. G. , Gill Patrick 
Published: August 2019

AbstractWe realize a two-stage, hexagonal pyramid magneto-optical trap (MOT) with strontium, and demonstrate loading of cold atoms into cavity-enhanced 1D and 2D optical lattice traps, all within a single compact assembly of in-vacuum optics. We show that the device is suitable for high-performance quantum technologies, focusing especially on its intended application as a strontium optical lattice clock. We prepare 2 × 104 spin-polarized atoms of 87Sr in the optical lattice within 500 ms; we observe a vacuum-limited lifetime of atoms in the lattice of 27 s; and we measure a background DC electric field of 12 V m−1 from stray charges, corresponding to a fractional frequency shift of (−1.2 ± 0.8) × 10−18 to the strontium clock transition. When used in combination with careful management of the blackbody radiation environment, the device shows potential as a platform for realizing a compact, robust, transportable optical lattice clock with systematic uncertainty at the 10−18 level.
PD-1 of Sigmodon hispidus: Gene identification, characterization and preliminary evaluation of expression in inactivated RSV vaccine-induced enhanced respiratory disease
Authors: Muralidharan Abenaya , Larocque Louise , Russell Marsha , Creskey Marybeth , Li Changgui , Chen Wangxue , Van Domselaar Gary , Cao Jingxin , Cyr Terry , Rosu-Myles Michael , Wang Lisheng , Li Xuguang 
Published: August 2019

AbstractSigmodon hispidus or cotton rat is an excellent animal model for studying human infections of respiratory viruses including respiratory syncytial virus (RSV), which is the leading cause of hospitalization in infants and causes high rates of infection in the elderly and immunocompromised patient populations. Despite several decades of research, no vaccine has been licensed whereas inactivated vaccines have been shown to induce severe adverse reaction in a clinical trial, with other forms of RSV vaccine also found to induce enhanced disease in preclinical animal studies. While arguably the cotton rat is the best small animal model for evaluation of RSV vaccines and antivirals, many important genes of the immune system remain to be isolated. Programmed cell death-1 (PD-1) plays an integral role in regulating many aspects of immunity by inducing suppressive signals. In this study, we report the isolation of mRNA encoding the cotton rat PD-1 (crPD-1) and characterization of the PD-1 protein. crPD-1 bound to its cognate ligand on dendritic cells and effectively suppressed cytokine secretion. Moreover, using the newly acquired gene sequence, we observed a decreased level of crPD-1 levels in cotton rats with enhanced respiratory disease induced by inactivated RSV vaccine, unraveling a new facet of vaccine-induced disease.
Imaging of sacroiliac joints in patients with acromegaly
Authors: Ugur Kader , Karatas Ahmet , Oz Burak , Artas Hakan , Aydin Suleyman , Koca Suleyman Serdar 
Published: August 2019

AbstractAcromegaly can lead to structural alterations of joints and bones. Patients with acromegaly may, therefore, have musculoskeletal complaints. In this study, sacroiliac joints are investigated in patients with acromegaly. 33 patients with acromegaly were enrolled. Sacroiliac joints were examined by X-ray and magnetic resonance imaging (MRI). In acromegaly, sacroiliac joints were abnormal in 36% of the patients by X-ray and 12.1% by MRI. When current axial spondylarthritis (SpA) classification criteria were taken into account, 6.1% of acromegaly patients could be classified as non-radiographic axial SpA and 2% as radiographic axial SpA. Sacroiliac joints are frequently affected in acromegaly and thus this disorder mimics the features of AS and SpA. Acromegaly should be kept in mind in the differential diagnosis of AS and SpA.
Dual-responsive (pH/temperature) Pluronic F-127 hydrogel drug delivery system for textile-based transdermal therapy
Authors: Chatterjee Sudipta , Hui Patrick Chi-leung , Kan Chi-wai , Wang Wenyi 
Published: August 2019

AbstractA dual-responsive hydrogel (pH/temperature) was developed from a thermos-responsive polymer, pluronic F-127 (PF127), and pH-responsive polymers, N,N,N-trimethyl chitosan (TMC) and polyethylene glycolated hyaluronic acid (PEG-HA). Gallic acid, the principal component of the traditional Chinese drug Cortex Moutan was loaded into the hydrogel (PF127/TMC/PEG-HA) for possible application in textile-based transdermal therapy as Cortex Moutan has been proven to be an effective drug for the treatment of atopic dermatitis (AD). TMC and PEG-HA were synthesized, characterized (1H-NMR and FTIR), and added to the formulations to enhance drug release from the hydrogels, and increase the drug targeting of the carriers. The thermo-responsive properties of the hydrogel were assessed by dynamic viscosity analysis and the tube inversion method, and the pH-responsiveness of the formulation was determined by changing the pH of the external media. Rheology study of the hydrogels showed that complex viscosity and storage/loss moduli for PF127/TMC/PEG-HA hydrogel formulation are higher than PF127 hydrogel. The microstructure analysis by reflection SAXS indicated similar type of frozen inhomogeneity of hydrogel formulations. Various characterizations such as FTIR, SEM, TEM, zeta potential, and degradation of the hydrogel formulation indicated that the PF127/TMC/PEG-HA hydrogel showed better physico-chemical properties and morphology than did the PF127 hydrogel, and drug release was also higher for the PF127/TMC/PEG-HA hydrogel than for PF127. The drug release from hydrogels followed more closely first-order rate model than other rate models.