bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart
Authors: Hesketh Louise M. , Wilder Catherine D. E. , Ranadive Niraja N. , Lytra Georgia , Qazimi Patrisia , Munro Jade S. , Ahdi Nakita , Curtis Michael J. 
Published: May 2020

AbstractThe ‘translational therapeutic index’ (TTI) is a drug’s ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. Our aim was to evaluate a novel integrated approach for generating a TTI for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine’s beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine’s TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the TTI further, it cannot increase it. Our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine’s TTI defining the gold standard that would need to be bettered.
Fast response of complementary electrochromic device based on WO3/NiO electrodes
Authors: Chen Po-Wen , Chang Chen-Te , Ko Tien-Fu , Hsu Sheng-Chuan , Li Ke-Ding , Wu Jin-Yu 
Published: May 2020

AbstractNanoporous structures have proven as an effective way for enhanced electrochromic performance by providing a large surface area can get fast ion/electron transfer path, leading to larger optical modulation and fast response time. Herein, for the first time, application of vacuum cathodic arc plasma (CAP) deposition technology to the synthesis of WO3/NiO electrode films on ITO glass for use in fabricating complementary electrochromic devices (ECDs) with a ITO/WO3/LiClO4-Perchlorate solution/NiO/ITO structure. Our objective was to optimize electrochromic performance through the creation of electrodes with a nanoporous structure. We also examined the influence of WO3 film thickness on the electrochemical and optical characteristics in terms of surface charge capacity and diffusion coefficients. The resulting 200-nm-thick WO3 films achieved ion diffusion coefficients of (7.35 × 10−10 (oxidation) and 4.92 × 10−10 cm2/s (reduction)). The complementary charge capacity ratio of WO3 (200 nm thickness)/NiO (60 nm thickness) has impressive reversibility of 98%. A demonstration ECD device (3 × 4 cm2) achieved optical modulation (ΔT) of 46% and switching times of 3.1 sec (coloration) and 4.6 sec (bleaching) at a wavelength of 633 nm. In terms of durability, the proposed ECD achieved ΔT of 43% after 2500 cycles; i.e., 93% of the initial device.
Trails of ants converge or diverge through lens-shaped impediments, resembling principles of optics
Authors: Choi Jibeom , Lim Hangah , Song Woncheol , Cho Han , Kim Ho-Young , Lee Sang-im , Jablonski Piotr G. 
Published: May 2020

AbstractAnalogies across disciplines often indicate the existence of universal principles such as optimization, while the underlying proximate mechanisms may differ. It was reported recently that trails of ants refract at the border of substrates, on which walking speeds differ. This phenomenon is analogous to the travel-time-minimizing routes of light refracting at the borders between different media. Here, we further demonstrate that ant tracks converge or diverge across lens-shaped impediments similar to light rays through concave or convex optical lenses. The results suggest that the optical principle of travel time reduction may apply to ants. We propose a simple mathematical model that assumes nonlinear positive feedback in pheromone accumulation. It provides a possible explanation of the observed similarity between ant behavior and optics, and it is the first quantitative theoretical demonstration that pheromone-based proximate mechanisms of trail formation may produce this similarity. However, the future detailed empirical observations of ant behavior on impediment edges during the process of pheromone trail formation are needed in order to evaluate alternative explanations for this similarity.
Correctors modify the bicarbonate permeability of F508del-CFTR
Authors: Fiore Michele , Picco Cristiana , Moran Oscar 
Published: May 2020

AbstractOne of the most common mutations in Cystic Fibrosis (CF) patients is the deletion of the amino acid phenylalanine at position 508. This mutation causes both the protein trafficking defect and an early degradation. Over time, small molecules, called correctors, capable of increasing the amount of mutated channel in the plasma membrane and causing an increase in its transport activity have been developed. This study shows that incubating in vitro cells permanently transfected with the mutated channel with the correctors VX809, VX661 and Corr4a, and the combination of VX809 and Corr4a, a recovery of anion transport activity is observed. Interestingly, the permeability of bicarbonate increases in the cells containing corrected p.F508del CFTR channels is greater than the increase of the halide permeability. These different increases of the permeability of bicarbonate and halides are consistent with the concept that the structural conformation of the pore of the corrector-rescued p.F508del channels would be different than the normal wild type CFTR protein.
Molecular Basis of Differential Stability and Temperature Sensitivity of ZIKA versus Dengue Virus Protein Shells
Authors: Pindi Chinmai , Chirasani Venkat R. , Rahman Mohammad Homaidur , Ahsan Mohd , Revanasiddappa Prasanna D. , Senapati Sanjib 
Published: May 2020

AbstractRapid spread of ZIKA virus (ZIKV) and its association with severe birth defects have raised worldwide concern. Recent studies have shown that ZIKV retains its infectivity and remains structurally stable at temperatures up to 40 °C, unlike dengue and other flaviviruses. In spite of recent cryo-EM structures that showed similar architecture of ZIKA and dengue virus (DENV) E protein shells, little is known that makes ZIKV so temperature insensitive. Here, we attempt to unravel the molecular basis of greater thermal stability of ZIKV over DENV2 by executing atomistic molecular dynamics (MD) simulations on the viral E protein shells at 37 °C. Our results suggest that ZIKA E protein shell retains its structural integrity through stronger inter-raft communications facilitated by a series of electrostatic and H-bonding interactions among multiple inter-raft residues. In comparison, the DENV2 E protein shell surface was loosly packed that exhibited holes at all 3-fold vertices, in close agreement with another EM structure solved at 37 °C. The residue-level information obtained from our study could pave way for designing small molecule inhibitors and specific antibodies to inhibit ZIKV E protein assembly and membrane fusion.
PPARδ-mediated mitochondrial rewiring of osteoblasts determines bone mass
Authors: Müller Dorothea I. H. , Stoll Cornelia , Palumbo-Zerr Katrin , Böhm Christina , Krishnacoumar Brenda , Ipseiz Natacha , Taubmann Jule , Zimmermann Max , Böttcher Martin , Mougiakakos Dimitrios , Tuckermann Jan , Djouad Farida , Schett Georg , Scholtysek Carina , Krönke Gerhard 
Published: May 2020

AbstractBone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover.
Switching of Sox9 expression during musculoskeletal system development
Authors: Nagakura Ryotaro , Yamamoto Masahito , Jeong Juhee , Hinata Nobuyuki , Katori Yukio , Chang Wei-Jen , Abe Shinichi 
Published: May 2020

AbstractThe musculoskeletal system, which comprises muscles, tendons, and bones, is an efficient tissue complex that coordinates body movement and maintains structural stability. The process of its construction into a single functional and complex organization is unclear. SRY-box containing gene 9 (Sox9) is expressed initially in pluripotent cells and subsequently in ectodermal, endodermal, and mesodermal derivatives. This study investigated how Sox9 controls the development of each component of the musculoskeletal system. Sox9 was expressed in MTJ, tendon, and bone progenitor cells at E13 and in bone at E16. We detected Sox9 expression in muscle progenitor cells using double-transgenic mice and myoblastic cell lines. However, we found no Sox9 expression in developed muscle. A decrease in Sox9 expression in muscle-associated connective tissues, tendons, and bones led to hypoplasia of the cartilage and its attachment to tendons and muscle. These results showed that switching on Sox9 expression in each component (muscle, tendon, and bone) is essential for the development of the musculoskeletal system. Sox9 is expressed in not only tendon and bone progenitor cells but also muscle progenitor cells, and it controls musculoskeletal system development.
Long-term changes and effect of pterygium size on corneal topographic irregularity after recurrent pterygium surgery
Authors: Ono Takashi , Mori Yosai , Nejima Ryohei , Lee Jinhee , Abe Kentaro , Nagata Yuji , Iwasaki Takuya , Aihara Makoto , Miyata Kazunori 
Published: May 2020

AbstractThis retrospective observational study compared long-term topographic changes after recurrent- and primary-pterygium surgery depending on pterygium size. Patients who underwent recurrent-pterygium excision between 2002–2013 and age, sex, and pterygium size-matched controls who underwent primary-pterygium surgery were included (33 eyes of 33 patients in each group). Pterygium size was graded per advancing edge position: <1/3 of corneal diameter (grade 1), outside the pupil (grade 2), and within the pupillary area (grade 3). Surface asymmetry index (SAI), surface regularity index (SRI) in corneal topography, and uncorrected and best-spectacle-corrected visual acuity were compared before and 1, 3, 6, and 12 months postoperatively. Three, 17, and 13 eyes had grades 1, 2, and 3, respectively. In grade 2, the SAI and SRI were respectively significantly larger at all observation points (p = 0.01, 0.03, 0.02, 0.02, and 0.004) and before and 6 and 12 months postoperatively (p = 0.02, 0.04, and 0.03) in recurrent pterygium. In grade 3, the SAI was significantly larger before and 1, 3, and 12 months postoperatively (p = 0.04, 0.01, 0.01, and 0.02) and the SRI was significantly larger before and 12 months postoperatively (p < 0.001, 0.02) in recurrent pterygium. Corneal irregularity persisted 12 months after recurrent-pterygium surgery compared with that in same-size primary pterygium.
CO-Reductive and O2-Oxidative Annealing Assisted Surface Restructure and Corresponding Formic Acid Oxidation Performance of PdPt and PdRuPt Nanocatalysts
Authors: Bhalothia Dinesh , Huang Tzu-Hsi , Chou Pai-Hung , Chen Po-Chun , Wang Kuan-Wen , Chen Tsan-Yao 
Published: May 2020

AbstractFormic acid oxidation reaction (FAOR) at anode counterpart incurs at substantial high overpotential, limiting the power output efficiency of direct formic acid fuel cells (DFAFCs). Despite intense research, the lack of high-performance nanocatalysts (NCs) for FAOR remains a challenge in realizing DFAFC technologies. To surmount the overpotential losses, it is desirable to have NCs to trigger the FAOR as close to the reversible conditions (i.e. with over-potential loss as close to zero as possible). Herein, Pd-based binary and ternary NCs consisting of PdPt and PdRuPt have been synthesized via the polyol reduction method on the carbon support. As prepared PdPt and PdRuPt NCs were further subjected to heat treatment (annealed) in CO (namely PdPt-CO and PdRuPt-CO) and O2 (namely PdPt-O2 and PdRuPt-O2) atmosphere at 473 K temperature. By cross-referencing results of electron microscopy and X-ray spectroscopy together with electrochemical analysis, the effects of heat treatment under CO-reductive and O2-oxidative conditions towards FAOR were schematically elucidated. Of special relevance, the mass activity (MA) of PdPt-CO, PdPt-O2, PdRuPt-CO, and PdRuPt-O2 NCs is 1.7/2.0, 1.3/2.2, 1.1/5.5, and 0.9/4.7 Amg−1 in the anodic/cathodic scan, respectively, which is 2~4-folds improved comparative to of as-prepared PdPt (1.0/1.9 Amg−1 in anodic/cathodic scan, respectively) and PdRuPt (0.9/1.4 Amg−1 in anodic/cathodic scan, respectively) NCs. Meanwhile, after chronoamperometric (CA) stability test up to 2000 s, PdPt-CO (72 mAmg−1) and PdRuPt-CO (213 mAmg−1) NCs exhibit higher MA compared to as-prepared PdPt (54 mAmg−1) and PdRuPt (62 mAmg−1) NCs, which is attributed to the increase of surface Pt composition, especially for PdRuPt-CO NC. Besides, the stability of PdPt-O2 (15 mAmg−1) and PdRuPt-O2 (22 mAmg−1) NCs is deteriorated as compared to that of as-prepared NCs due to severe oxidation in O2 atmosphere. Of utmost importance, we developed a ternary PdRuPt catalyst with ultra-low Pt content (~2 wt.%) and significantly improved FAOR performance than pure Pt catalysts. Moreover, we demonstrated that the FAOR performance can be further enhanced by more than 30% via a unique CO annealing treatment.
The aryl hydrocarbon receptor pathway controls matrix metalloproteinase-1 and collagen levels in human orbital fibroblasts
Authors: Roztocil Elisa , Hammond Christine L. , Gonzalez Mithra O. , Feldon Steven E. , Woeller Collynn F. 
Published: May 2020

AbstractThyroid eye disease (TED) affects 25–50% of patients with Graves’ Disease. In TED, collagen accumulation leads to an expansion of the extracellular matrix (ECM) which causes destructive tissue remodeling. The purpose of this study was to investigate the therapeutic potential of activating the aryl hydrocarbon receptor (AHR) to limit ECM accumulation in vitro. The ability of AHR to control expression of matrix metalloproteinase-1 (MMP1) was analyzed. MMP1 degrades collagen to prevent excessive ECM. Human orbital fibroblasts (OFs) were treated with the pro-scarring cytokine, transforming growth factor beta (TGFβ) to induce collagen production. The AHR ligand, 6-formylindolo[3,2b]carbazole (FICZ) was used to activate the AHR pathway in OFs. MMP1 protein and mRNA levels were analyzed by immunosorbent assay, Western blotting and quantitative PCR. MMP1 activity was detected using collagen zymography. AHR and its transcriptional binding partner, ARNT were depleted using siRNA to determine their role in activating expression of MMP1. FICZ induced MMP1 mRNA, protein expression and activity. MMP1 expression led to a reduction in collagen 1A1 levels. Furthermore, FICZ-induced MMP1 expression required both AHR and ARNT, demonstrating that the AHR-ARNT transcriptional complex is necessary for expression of MMP1 in OFs. These data show that activation of the AHR by FICZ increases MMP1 expression while leading to a decrease in collagen levels. Taken together, these studies suggest that AHR activation could be a promising target to block excessive collagen accumulation and destructive tissue remodeling that occurs in fibrotic diseases such as TED.
Pulse Reshaping in Double-zero-index Photonic Crystals with Dirac-like-cone Dispersion
Authors: Xu Tao , Zhu Dejun , Hang Zhi Hong 
Published: May 2020

AbstractTriply-degenerate Dirac-like cone at the Brillouin zone center attracts much research interest in recent years. Whether the linear dispersion in such a Dirac-like cone reflects the same physics to Dirac cones at the Brillouin zone boundaries is still under investigation. In this manuscript, through microwave experiments and numerical simulations, we observe intriguing pulse reshaping phenomena in double-zero-index photonic crystals, which cannot be fully understood from their close-to-zero effective parameters. A reshaped pulse, with frequency components close to the Dirac frequency filtered, is propagating at a constant group velocity while part of these filtered frequencies appears at a much later time. In time domain measurements, we find a way to separate the effect between the linear dispersion and the extra flat band in Dirac-like cone to have a better understanding of the underneath physics. We succeed in obtaining the group velocity inside a double-zero-index photonic crystal and good consistence can be found between experiments, numerical simulations and band diagram calculations.
Caffeoyl–Pro–His amide relieve DNCB-Induced Atopic Dermatitis-Like phenotypes in BALB/c mice
Authors: Jang Sunhyae , Ohn Jungyoon , Kim Ji Won , Kang So Min , Jeon Dasom , Heo Chan Yeong , Lee Yoon-Sik , Kwon Ohsang , Kim Kyu Han 
Published: May 2020

AbstractThe main factors involved in the pathogenesis of atopic dermatitis (AD) are skin barrier abnormality, allergy/immunology, and pruritus. Considering how oxidative stress influences these factors, antioxidant agents may be effective candidates in the treatment of AD. To evaluate the effect of Caffeoyl–Pro–His amide (CA-PH), an antioxidant agent, on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like phenotypes in BALB/c mice. Topical sensitization and challenge by DNCB were performed on the dorsal skin of BALB/c mice to induce AD-like cutaneous lesions, phenotypes, and immunologic response. CA-PH was applied topically for 2 weeks to assess its effects on DNCB-induced AD-like phenotypes. As a result, CA-PH relieved DNCB-induced AD-like phenotypes quantified by dermatitis severity score, scratching duration, and trans-epidermal water loss. Histopathological analysis showed that CA-PH decreased epidermal thickening, the number of mast cells, and eosinophil infiltration in dermis. Immunohistochemical staining revealed that CA-PH recovered skin barrier-related proteins: filaggrin, involucrin, and loricrin. As for the immunologic aspects, CA-PH treatment lowered mRNA or protein levels of interleukin (IL)-4, IL-6, IL-17a, IL-1b, IL-31, and IL-33 levels and thymic stromal lymphopoietin (TSLP) levels in cutaneous tissue, reducing the DNCB-induced serum IgE level elevation. In conclusion, topical CA-PH may be a therapeutic option for the treatment of AD.
Generation and characterization of HLA-universal platelets derived from induced pluripotent stem cells
Authors: Norbnop Phatchara , Ingrungruanglert Praewphan , Israsena Nipan , Suphapeetiporn Kanya , Shotelersuk Vorasuk 
Published: May 2020

AbstractPlatelet demand has increased around the world. However, the inadequacy of donors, the risk of transfusion-transmitted infections and associated reactions, and the refractory nature of platelet transfusions are among the limitations of allogeneic platelet transfusions. To alleviate these problems, we propose generating platelets in a laboratory that do not induce alloimmunity to human leukocyte antigen (HLA) class I, which is a major cause of immune reaction in platelet transfusion refractoriness. Induced pluripotent stem cells (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) of a healthy Thai woman. We then knocked out the β2-microglobulin (β2m) gene in the cells using paired CRISPR/Cas9 nickases and sequentially differentiated the cells into haematopoietic stem cells (HSCs), megakaryocytes (MKs) and platelets. Silencing of HLA class I expression was observed on the cell surface of β2m-knockout iPSCs, iPSC-derived HSCs, MKs and platelets. The HLA-universal iPSC-derived platelets were shown to be activated, and they aggregated after stimulation. In addition, our in vivo platelet survival experiments demonstrated that human platelets were detectable at 2 and 24 hours after injecting the β2m-KO MKs. In summary, we successfully generated functional iPSC-derived platelets in vitro without HLA class I expression by knocking out the β2m gene using paired CRISPR/Cas9 nickases.
Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis
Authors: Chen Meihong , Zhou Yilu , Xu Hong , Hill Charlotte , Ewing Rob M. , He Deming , Zhang Xiaoling , Wang Yihua 
Published: May 2020

AbstractBackground: Endometriosis is a frequently occurring disease in women, which seriously affects their quality of life. However, its etiology and pathogenesis are still unclear. Methods: To identify key genes/pathways involved in the pathogenesis of endometriosis, we recruited 3 raw microarray datasets (GSE11691, GSE7305, and GSE12768) from Gene Expression Omnibus database (GEO), which contain endometriosis tissues and normal endometrial tissues. We then performed in-depth bioinformatic analysis to determine differentially expressed genes (DEGs), followed by gene ontology (GO), Hallmark pathway enrichment and protein-protein interaction (PPI) network analysis. The findings were further validated by immunohistochemistry (IHC) staining in endometrial tissues from endometriosis or control patients. Results: We identified 186 DEGs, of which 118 were up-regulated and 68 were down-regulated. The most enriched DEGs in GO functional analysis were mainly associated with cell adhesion, inflammatory response, and extracellular exosome. We found that epithelial-mesenchymal transition (EMT) ranked first in the Hallmark pathway enrichment. EMT may potentially be induced by inflammatory cytokines such as CXCL12. IHC confirmed the down-regulation of E-cadherin (CDH1) and up-regulation of CXCL12 in endometriosis tissues. Conclusions: Utilizing bioinformatics and patient samples, we provide evidence of EMT in endometriosis. Elucidating the role of EMT will improve the understanding of the molecular mechanisms involved in the development of endometriosis.