bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced generation of human induced pluripotent stem cells by ectopic expression of Connexin 45
Authors: Ke Qiong , Li Li , Yao Xin , Lai Xingqiang , Cai Bing , Chen Hong , Chen Rui , Zhai Zhichen , Huang Lihua , Li Kai , Hu Anbin , Mao Frank Fuxiang , Xiang Andy Peng , Tao Liang , Li Weiqiang
Published: March 2017

Somatic cells can be successfully reprogrammed into pluripotent stem cells by the ectopic expression of defined transcriptional factors. However, improved efficiency and better understanding the molecular mechanism underlying reprogramming are still required. In the present study, a scrape loading/dye transfer assay showed that human induced pluripotent stem cells (hiPSCs) contained functional gap junctions partially contributed by Connexin 45 (CX45). We then found CX45 was expressed in human embryonic stem cells (hESCs) and human dermal fibroblasts (hDFs) derived hiPSCs. Then we showed that CX45 was dramatically upregulated during the reprogramming process. Most importantly, the ectopic expression of CX45 significantly enhanced the reprogramming efficiency together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC - OSKM), whereas knockdown of endogenous CX45 expression significantly blocked cellular reprogramming and reduced the efficiency. Our further study demonstrated that CX45 overexpression or knockdown modulated the cell proliferation rate which was associated with the reprogramming efficiency. In conclusion, our data highlighted the critical role of CX45 in reprogramming and may increase the cell division rate and result in an accelerated kinetics of iPSCs production.
Removal of Diethylhexyl Phthalate from Hands by Handwashing: Evidence from Experimental N-of-1 and Crossover Designs
Authors: Lin Pi-I. D. , Wu Chia-Fang , Kou Hwang-Shang , Huang Tzu-Ying , Shiea Jentaie , Wu Ming-Tsang
Published: March 2017

Phthalate exposure through skin is often neglected due to the small quantity and limited dermal absorption rate. However, free phthalate can be ingested by hand-to-mouth action or by contact with food. To evaluate the effectiveness in removing phthalate exposure on hand, we compare here the removal efficiency of di-(2-ethylhexyl)phthalate (DEHP) on hands by handwashing with soap-and-water versus water-only. In two three-day N-of-1 trials, residual DEHP was measured in a single female adult who washed exposed hands with soap-and-water or water-only. Subsequently, a crossover study was performed by randomly assigning another 28 subjects equally to wash with soap-and-water or with water-only, and then each one received the other treatment 24 hrs later. In the N-of-1 trials, mean DEHP removal rates range from 95.9% (SD = 0.1%) to 97.0% (SD = 2.5%) for soap-and-water handwashes, and 1.8% (SD = 0.1%) to 7.0% (SD = 0.3%) (n = 3) for water-only. In the crossover study, mean removal rate was 94.6% (SD = 6.5%) for handwashing with soap-and-water (n = 28) and 8.7% (SD = 5.7%) for water-only (n = 28). We concluded that handwashing with soap-and-water removes 80% more DEHP than handwashing with water alone, and may be a cost-effective way of removing other endocrine disruptors from hands.
Hydration of Proton-conducting BaCe0.9Y0.1O3−δ by Decoupled Mass Transport
Authors: Lim Dae-Kwang , Im Ha-Ni , Song Sun-Ju , Yoo Han-Ill
Published: March 2017

Mass relaxation profile of a perovskite-type oxide, BaCe0.9Y0.1O3−δ, was studied to understand decoupled diffusion of oxygen and hydrogen species during hydration/dehydration. The mass relaxation measurements are performed by thermogravimetric analysis (TGA) under various humidity conditions (Dry, −3.0 ≤ log(pH2O/atm) ≤ −1.6) at a constant oxygen partial pressure (log(pO2/atm) = −1.00 ± 0.01). The decoupled ions participated in hydration/dehydration reactions were proven to be at different ratios from the result introduced by the 8R
m
function. The enthalpy and entropy of non-stoichiometric hydration reaction, which considers each ratio of charge-carrier species, were −144.7 ± 3.7 kJ/mol and −147.8 ± 3.2 J/mol · K, respectively.
Surface chemistry of rare-earth oxide surfaces at ambient conditions: reactions with water and hydrocarbons
Authors: Külah Elçin , Marot Laurent , Steiner Roland , Romanyuk Andriy , Jung Thomas A. , Wäckerlin Aneliia , Meyer Ernst
Published: March 2017

Rare-earth (RE) oxide surfaces are of significant importance for catalysis and were recently reported to possess intrinsic hydrophobicity. The surface chemistry of these oxides in the low temperature regime, however, remains to a large extent unexplored. The reactions occurring at RE surfaces at room temperature (RT) in real air environment, in particular, in presence of polycyclic aromatic hydrocarbons (PAHs), were not addressed until now. Discovering these reactions would shed light onto intermediate steps occurring in automotive exhaust catalysts before reaching the final high operational temperature and full conversion of organics. Here we first address physical properties of the RE oxide, nitride and fluoride surfaces modified by exposure to ambient air and then we report a room temperature reaction between PAH and RE oxide surfaces, exemplified by tetracene (C18H12) on a Gd2O3. Our study evidences a novel effect – oxidation of higher hydrocarbons at significantly lower temperatures (~300 K) than previously reported (>500 K). The evolution of the surface chemical composition of RE compounds in ambient air is investigated and correlated with the surface wetting. Our surprising results reveal the complex behavior of RE surfaces and motivate follow-up studies of reactions between PAH and catalytic surfaces at the single molecule level.
Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis
Authors: Fowler Tristan W. , Acevedo Claire , Mazur Courtney M. , Hall-Glenn Faith , Fields Aaron J. , Bale Hrishikesh A. , Ritchie Robert O. , Lotz Jeffrey C. , Vail Thomas P. , Alliston Tamara
Published: March 2017

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.
Neoadjuvant Chemotherapy Creates Surgery Opportunities For Inoperable Locally Advanced Breast Cancer
Authors: Wang Minghao , Hou Lingmi , Chen Maoshan , Zhou Yan , Liang Yueyang , Wang Shushu , Jiang Jun , Zhang Yi
Published: March 2017

Neoadjuvant chemotherapy (NAC), the systematic chemotherapy given to patients with locally advanced and inoperable breast caner, has been proven to be of great clinical values. Many scientific reports confirmed NAC could effectively eliminate sub-clinical disseminated lesions of tumor, and improve long-term and disease-free survival rate of patients with locally advanced breast cancer (LABC); however, up to now, LABC is still a serious clinical issue given improved screening and early diagnosis. This study, with main focus on inoperable LABC, investigated the values of NAC in converting inoperable LABC into operable status and assessed the prognosis. Sixty-one patients with inoperable LABC were initially treated with neoadjuvant chemotherapy; their local conditions were improved to operable status. Radical surgery was exerted on 49 patients. Original chemotherapy was performed after surgery, followed by local radiotherapy. And endocrine therapy was optional according to the hormone receptor status. The quality of life for most patients with skin diabrosis was obviously improved because their local conditions were under control. For all recruited cases, the survival duration and life quality were significantly improved in patients who finished both NAC and surgery compared to those who did not. Further more, this study demonstrates improved prognostic consequences.
Quantum Locality in Game Strategy
Authors: Melo-Luna Carlos A. , Susa Cristian E. , Ducuara Andrés F. , Barreiro Astrid , Reina John H.
Published: March 2017

Game theory is a well established branch of mathematics whose formalism has a vast range of applications from the social sciences, biology, to economics. Motivated by quantum information science, there has been a leap in the formulation of novel game strategies that lead to new (quantum Nash) equilibrium points whereby players in some classical games are always outperformed if sharing and processing joint information ruled by the laws of quantum physics is allowed. We show that, for a bipartite non zero-sum game, input local quantum correlations, and separable states in particular, suffice to achieve an advantage over any strategy that uses classical resources, thus dispensing with quantum nonlocality, entanglement, or even discord between the players’ input states. This highlights the remarkable key role played by pure quantum coherence at powering some protocols. Finally, we propose an experiment that uses separable states and basic photon interferometry to demonstrate the locally-correlated quantum advantage.
Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma
Authors: Jalbert Llewellyn E. , Elkhaled Adam , Phillips Joanna J. , Neill Evan , Williams Aurelia , Crane Jason C. , Olson Marram P. , Molinaro Annette M. , Berger Mitchel S. , Kurhanewicz John , Ronen Sabrina M. , Chang Susan M. , Nelson Sarah J.
Published: March 2017

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.
Duration of untreated bipolar disorder: a multicenter study
Authors: Zhang Ling , Yu Xin , Fang Yi-Ru , Ungvari Gabor S. , Ng Chee H. , Chiu Helen F. K. , Li Hui-Chun , Yang Hai-Chen , Tan Qing-Rong , Xu Xiu-Feng , Wang Gang , Xiang Yu-Tao
Published: March 2017

Little is known about the demographic and clinical differences between short and long duration of untreated bipolar disorder (DUB) in Chinese patients. This study examined the demographic and clinical features of short (≤2 years) and long DUB (>2 years) in China. A consecutively recruited sample of 555 patients with bipolar disorder (BD) was examined in 7 psychiatric hospitals and general hospital psychiatric units across China. Patients’ demographic and clinical characteristics were collected using a standardized protocol and data collection procedure. The mean DUB was 3.2 ± 6.0 years; long DUB accounted for 31.0% of the sample. Multivariate analyses revealed that longer duration of illness, diagnosis of BD type II, and earlier misdiagnosis of BD for major depressive disorder or schizophrenia were independently associated with long DUB. The mean DUB in Chinese BD patients was shorter than the reported figures from Western countries. The long-term impact of DUB on the outcome of BD is warranted.
Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry
Authors: Lagrutta Armando , Regan Christopher P. , Zeng Haoyu , Imredy John P. , Koeplinger Kenneth , Morissette Pierre , Liu Liping , Wollenberg Gordon , Brynczka Christopher , Lebrón José , DeGeorge Joseph , Sannajust Frederick
Published: March 2017

Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not. Stereochemical selectivity on emerging bradycardia was confirmed in vivo. Diastereomer pairs entered cells equally well, and there was no difference in intracellular accumulation of L-ala,SP metabolites ± amiodarone, but no D-ala,RP metabolites were detected. Cathepsin A (CatA) inhibitors attenuated L-ala,SP prodrug metabolite formation, yet exacerbated L-ala,SP + amiodarone effects, implicating the prodrugs in these effects. Experiments indicate that pharmacological effects and metabolic conversion to UTP analog are L-ala,SP prodrug-dependent in cardiomyocytes.
Long-term effectiveness of irreversible electroporation in a murine model of colorectal liver metastasis
Authors: Sánchez-Velázquez P. , Castellví Q. , Villanueva A. , Iglesias M. , Quesada R. , Pañella C. , Cáceres M. , Dorcaratto D. , Andaluz A. , Moll X. , Burdío J. M. , Grande L. , Ivorra A. , Burdío F.
Published: March 2017

Irreversible electroporation (IRE) has recently gained in popularity as an ablative technique, however little is known about its oncological long-term outcomes. To determine the long-time survival of animals treated with a high dose of IRE and which histological changes it induces in tumoral tissue, IRE ablation was performed in forty-six athymic-nude mice with KM12C tumors implanted in the liver by applying electric current with different voltages (2000 V/cm, 1000 V/cm). The tumors were allowed to continue to grow until the animals reached the end-point criteria. Histology was harvested and the extent of tumor necrosis was semi-quantitatively assessed. IRE treatment with the 2000 V/cm protocol significantly prolonged median mouse survival from 74.3 ± 6.9 days in the sham group to 112.5 ± 15.2 days in the 2000 V/cm group. No differences were observed between the mean survival of the 1000 V/cm and the sham group (83.2 ± 16.4 days, p = 0.62). Histology revealed 63.05% ± 23.12 of tumor necrosis in animals of the 2000 V/cm group as compared to 17.50% ± 2.50 in the 1000 V/cm group and 25.6% ± 22.1 in the Sham group (p = 0.001). IRE prolonged the survival of animals treated with the highest electric field (2000 V/cm). The animals in this group showed significantly higher rate of tumoral necrosis.
Partial Reprogramming of Pluripotent Stem Cell-Derived Cardiomyocytes into Neurons
Authors: Chuang Wenpo , Sharma Arun , Shukla Praveen , Li Guang , Mall Moritz , Rajarajan Kuppusamy , Abilez Oscar J. , Hamaguchi Ryoko , Wu Joseph C. , Wernig Marius , Wu Sean M.
Published: March 2017

Direct reprogramming of somatic cells has been demonstrated, however, it is unknown whether electrophysiologically-active somatic cells derived from separate germ layers can be interconverted. We demonstrate that partial direct reprogramming of mesoderm-derived cardiomyocytes into neurons is feasible, generating cells exhibiting structural and electrophysiological properties of both cardiomyocytes and neurons. Human and mouse pluripotent stem cell-derived CMs (PSC-CMs) were transduced with the neurogenic transcription factors Brn2, Ascl1, Myt1l and NeuroD. We found that CMs adopted neuronal morphologies as early as day 3 post-transduction while still retaining a CM gene expression profile. At week 1 post-transduction, we found that reprogrammed CMs expressed neuronal markers such as Tuj1, Map2, and NCAM. At week 3 post-transduction, mature neuronal markers such as vGlut and synapsin were observed. With single-cell qPCR, we temporally examined CM gene expression and observed increased expression of neuronal markers Dcx, Map2, and Tubb3. Patch-clamp analysis confirmed the neuron-like electrophysiological profile of reprogrammed CMs. This study demonstrates that PSC-CMs are amenable to partial neuronal conversion, yielding a population of cells exhibiting features of both neurons and CMs.
Non-occupational physical activity during pregnancy and the risk of preterm birth: a meta-analysis of observational and interventional studies
Authors: Wen Ju , Xun Pengcheng , Chen Cheng , Quan Minghui , Wang Ru , Liu Yu , He Ka
Published: March 2017

A meta-analysis was conducted to evaluate the association between non-occupational physical activity (PA) during pregnancy and the risk of preterm birth (PTB). By searching PubMed and EMBASE from inception to August 20, 2016, 25 observational studies (18 cohorts and 7 case-controls) and 12 interventional studies were identified. Comparing the highest to the lowest category of leisure-time PA during pregnancy, the pooled relative risk (RR) of PTB was 0.83 [95% confidence interval (CI) = 0.74–0.93] for cohort studies and 0.60 (95% CI = 0.43–0.84) for case-control studies. No overall significant association was found between domestic or commuting PA and the risk of PTB. In addition, PA intervention did not indicate significant beneficial effect on the risk of PTB. Evidence from the observational studies suggested that leisure-time, but not domestic or commuting, PA during pregnancy was inversely associated with the risk of PTB. The findings were not supported by small-scale and short-term interventional studies. Further research with objective measurement on leisure-time PA is warranted.
Synthesis of Norbornene Derived Helical Copolymer by Simple Molecular Marriage Approach to Produce Smart Nanocarrier
Authors: Mane Shivshankar R. , Sathyan Ashlin , Shunmugam Raja
Published: March 2017

A novel library of norbornene derived helical copolymer has been synthesized through the coupling of two homopolymers via Molecular Marriage Approach. The helicity is governed by the non-covalent interactions like hydrogen bonding, π-π stacking and the influence of hydrophobic and hydrophilic motifs. The detailed characterization of the copolymer (Copoly 1) has been provided and the super structures are confirmed through dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The observed size of the aggregates was about 200 nm. The density functional theory (DFT) is favorably supported for the formation of proposed structure of Copoly 1. Circular dichroism (CD) measurement has confirmed the one handed helical structure of the copolymer. Reservoir capability of this pH responsive polymer (Copoly 1) to encapsulate anti-cancer drug doxorubicin (DOX) warrants its potential applications in the field of bio-medical sciences.
Elaboration and controlling excited state double proton transfer mechanism of 2,5-bis(benzoxazol-2-yl)thiophene-3,4-diol
Authors: Zhao Jinfeng , Zheng Yujun
Published: March 2017

In the present work, we theoretically illuminate the excited state double proton transfer (ESDPT) process about a novel synthesized system 2,5-bis(benzoxazol-2-yl)thiophene-3,4-diol (BBTD). Minor changes of both structure and charge redistribution deriving from photoexcitation result in obviously different excited state dynamical process. Exploration about our constructed S1-state potential energy surface (PES) indicates a stepwise ESDPT mechanism for BBTD. In addition, we present a new mechanism about regulating and controlling stepwise ESDPT process via external electric field.
Pollen-mediated gene flow from glyphosate-resistant common waterhemp (Amaranthus rudis Sauer): consequences for the dispersal of resistance genes
Authors: Sarangi Debalin , Tyre Andrew J. , Patterson Eric L. , Gaines Todd A. , Irmak Suat , Knezevic Stevan Z. , Lindquist John L. , Jhala Amit J.
Published: March 2017

Gene flow is an important component in evolutionary biology; however, the role of gene flow in dispersal of herbicide-resistant alleles among weed populations is poorly understood. Field experiments were conducted at the University of Nebraska-Lincoln to quantify pollen-mediated gene flow (PMGF) from glyphosate-resistant (GR) to -susceptible (GS) common waterhemp using a concentric donor-receptor design. More than 130,000 common waterhemp plants were screened and 26,199 plants were confirmed resistant to glyphosate. Frequency of gene flow from all distances, directions, and years was estimated with a double exponential decay model using Generalized Nonlinear Model (packagegnm) in R. PMGF declined by 50% at <3 m distance from the pollen source, whereas 90% reduction was found at 88 m (maximum) depending on the direction of the pollen-receptor blocks. Amplification of the target site gene, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), was identified as the mechanism of glyphosate resistance in parent biotype. TheEPSPSgene amplification was heritable in common waterhemp and can be transferred via PMGF, and also correlated with glyphosate resistance in pseudo-F2progeny. This is the first report of PMGF in GR common waterhemp and the results are critical in explaining the rapid dispersal of GR common waterhemp in Midwestern United States.
Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
Authors: Backman Samuel , Maharjan Rajani , Falk-Delgado Alberto , Crona Joakim , Cupisti Kenko , Stålberg Peter , Hellman Per , Björklund Peyman
Published: March 2017

Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.
Erratum: Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation
Authors: Lin Jing , Lu Ming , Shao Wei-qing , Chen Zong-you , Zhu Wen-wei , Lu Lu , Jia Hu-liang , Cai Duan , Qin Lun-xiu , Chen Jin-hong
Published: March 2017

Scientific Reports 6: Article number: 30215; published online: 03 August 2016; updated: 22 March 2017. The original version of this Article contained an error in the order of author names, which were incorrectly given as ‘Jing Lin, Wei-qing Shao, Zong-you Chen, Wen-wei Zhu, Lu Lu, Duan Cai, Lun-xiu Qin, Hu-liang Jia, Ming Lu & Jin-hong Chen’.
Erratum: Antibodies from multiple sclerosis patients preferentially recognize hyperglucosylated adhesin of non-typeable Haemophilus influenzae
Authors: Walvoort Marthe T. C. , Testa Chiara , Eilam Raya , Aharoni Rina , Nuti Francesca , Rossi Giada , Real-Fernandez Feliciana , Lanzillo Roberta , Brescia Morra Vincenzo , Lolli Francesco , Rovero Paolo , Imperiali Barbara , Papini Anna Maria
Published: March 2017

Scientific Reports 6: Article number: 39430; published online: 23 December 2016; updated: 22 March 2017. The original version of this Article contained typographical errors in the Abstract. ‘In autoimmune diseases, there have been proposals that exogenous “molecular triggers”, i.e., specific this should be ‘non-self antigens’ accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies’.
Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons
Authors: Choi Won-Seok , Kim Hyung-Wook , Tronche François , Palmiter Richard D. , Storm Daniel R. , Xia Zhengui
Published: March 2017

Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of theNdufs4gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in whichNdufs4was selectively deleted in dopaminergic neurons (Ndufs4cKO). This conditional deletion ofNdufs4,which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However,Ndufs4cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected,Ndufs4cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss.
Estimated Daily Intake and Cumulative Risk Assessment of Phthalates in the General Taiwanese after the 2011 DEHP Food Scandal
Authors: Chang Jung-Wei , Lee Ching-Chang , Pan Wen-Harn , Chou Wei-Chun , Huang Han-Bin , Chiang Hung-Che , Huang Po-Chin
Published: March 2017

A food scandal occurred in Taiwan in 2011 because the DEHP (di-2-ethylhexyl phthalate) had been intentionally used in food products. We assessed the daily intakes (DIs) and cumulative risk of phthalates in Taiwan’s general population after the scandal. The DIs of 6 phthalates, including di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), and DEHP, were evaluated using urinary phthalate metabolites. Hazard quotients of phthalates classified as affecting the reproductive (HQrep) and hepatic (HQhep) systems were assessed using cumulative approach. The creatinine-based model showed that the highest DI values in children 7-to 12- years-old were for DEHP (males: median: 4.79 μg/kg bw/d; females: median: 2.62 μg/kg bw/d). The 95th percentile (P95) of HQrep values were all >1 in the 7- to 12-year-old and 18- to 40-year-old male groups. The P95 of HQhep values were all >1 in the 7- to 18- year-old male groups. Most of the HQrep was attributable to the HQs of DnBP and DiBP (53.9–84.7%), and DEHP contributed most to HQhep (83.1–98.6%), which reveals that DnBP, DiBP and DEHP were the main risk of phthalate exposure for Taiwanese. Taiwan’s general population is widely exposed to DnBP, DiBP and DEHP, especially for young children.
Scleraxis is required for maturation of tissue domains for proper integration of the musculoskeletal system
Authors: Yoshimoto Yuki , Takimoto Aki , Watanabe Hitomi , Hiraki Yuji , Kondoh Gen , Shukunami Chisa
Published: March 2017

Scleraxis (Scx) is a basic helix-loop-helix transcription factor that is expressed persistently in tendons/ligaments, but transiently in entheseal cartilage. In this study, we generated a novel ScxCre knock-in (KI) allele, by in-frame replacement of most of Scx exon 1 with Cre recombinase (Cre), to drive Cre expression using Scx promoter and to inactivate the endogenous Scx. Reflecting the intensity and duration of endogenous expression, Cre-mediated excision occurs in tendinous and ligamentous tissues persistently expressing Scx. Expression of tenomodulin, a marker of mature tenocytes and ligamentocytes, was almost absent in tendons and ligaments of ScxCre/Cre KI mice lacking Scx to indicate defective maturation. In homozygotes, the transiently Scx-expressing entheseal regions such as the rib cage, patella cartilage, and calcaneus were small and defective and cartilaginous tuberosity was missing. Decreased Sox9 expression and phosphorylation of Smad1/5 and Smad3 were also observed in the developing entheseal cartilage, patella, and deltoid tuberosity of ScxCre/Cre KI mice. These results highlighted the functional importance of both transient and persistent expression domains of Scx for proper integration of the musculoskeletal components.
Dynasore impairs VEGFR2 signalling in an endocytosis-independent manner
Authors: Basagiannis Dimitris , Zografou Sofia , Galanopoulou Katerina , Christoforidis Savvas
Published: March 2017

VEGFR2 is a critical angiogenic receptor playing a key role in vascular homeostasis. Upon activation by VEGF, VEGFR2 becomes endocytosed. Internalisation of VEGFR2 is facilitated, in part, through clathrin mediated endocytosis (CME), the role of which in VEGFR2 function is debated. Here, we confirm the contribution of CME in VEGFR2 uptake. However, curiously, we find that different approaches of inhibition of CME exert contradictory effects on VEGF signalling; knockdown of clathrin, or of dynamin, or overexpression of dynamin K44A, do not affect VEGF-induced phosphorylation of ERK1/2, while dynasore causes strong inhibition. We resolve this discrepancy by showing that although dynasore inhibits CME of VEGFR2, its inhibitory action in ERK1/2 phosphorylation is not related to attenuation of VEGFR2 endocytosis; it is rather due to an off-target effect of the drug. Dynasore inhibits VEGF-induced calcium release, a signalling event that lies upstream of ERK1/2, which implies that this effect could be responsible, at least in part, for the inhibitory action of the drug on VEGF-to-ERK1/2 signalling. These results raise caution that although dynasore is specific in inhibiting clathrin- and dynamin-mediated endocytosis, it may also exert off-target effects on signalling molecules, hence influencing the interpretation of the role of endocytosis in signalling.
Tandem UIMs confer Lys48 ubiquitin chain substrate preference to deubiquitinase USP25
Authors: Kawaguchi Kohei , Uo Kazune , Tanaka Toshiaki , Komada Masayuki
Published: March 2017

Ubiquitin-specific protease (USP) 25, belonging to the USP family of deubiquitinases, harbors two tandem ubiquitin-interacting motifs (UIMs), a ~20-amino-acid α-helical stretch that binds to ubiquitin. However, the role of the UIMs in USP25 remains unclear. Here we show that the tandem UIM region binds to Lys48-, but not Lys63-, linked ubiquitin chains, where the two UIMs played a critical and cooperative role. Purified USP25 exhibited higher ubiquitin isopeptidase activity to Lys48-, than to Lys63-, linked ubiquitin chains. Mutations that disrupted the ubiquitin-binding ability of the tandem UIMs resulted in a reduced ubiquitin isopeptidase activity of USP25, suggesting a role for the UIMs in exerting the full catalytic activity of USP25. Moreover, when mutations that convert the binding preference from Lys48- to Lys63-linked ubiquitin chains were introduced into the tandem UIM region, the USP25 mutants acquired elevated and reduced isopeptidase activity toward Lys63- and Lys48-linked ubiquitin chains, respectively. These results suggested that the binding preference of the tandem UIMs toward Lys48-linked ubiquitin chains contributes not only to the full catalytic activity but also to the ubiquitin chain substrate preference of USP25, possibly by selectively holding the Lys48-linked ubiquitin chain substrates in the proximity of the catalytic core.
Anisotropy of hydrogen diffusion in nickel single crystals: the effects of self-stress and hydrogen concentration on diffusion
Authors: Li J. , Oudriss A. , Metsue A. , Bouhattate J. , Feaugas X.
Published: March 2017

Hydrogen diffusion has an important role in solute-dependent hydrogen embrittlement in metals and metallic alloys. In spite of extensive studies, the complexity of hydrogen diffusion in solids remains a phenomenon that needs to be clarified. In this paper, we investigate the anisotropy of hydrogen diffusion in pure nickel single crystals using both an experimental approach and a thermodynamic development. As a first approximation, experimental data from electrochemical permeation and thermal desorption spectroscopy are described using the classical Fick’s laws and an apparent diffusion tensor. Within a thermodynamic framework, the diffusion equation can be derived from Fick’s laws with an apparent diffusion coefficient which contains an added solute content dependent term β. This term is due to the elastic strain field associated with the insertion of solute atoms. For nickel crystals, the dependence of β on the crystallographic orientation arises from the elastic anisotropy. Additionally, our results elucidate the discrepancies between the thermodynamic model and experimental observations of the effect of the solute concentration on the diffusion process. Moreover, this highlights the importance of the impact of hydrogen on vacancy formation and the subsequent consequences on the anisotropy of the apparent diffusion coefficient.
Correlation between Ultrasound Elastography and Histologic Characteristics of Papillary Thyroid Carcinoma
Authors: Yi Li , Qiong Wu , Yan Wang , Youben Fan , Bing Hu
Published: March 2017

The aim of this study was to investigate the correlation between elastography and histologic characteristics including fibrosis and calcification. We also wanted to investigate whether other clinicopathologic indexes influence the strain ratio (SR) of papillary thyroid carcinomas (PTCs). We retrospectively reviewed 126 papillary thyroid carcinomas (PTCs) from 103 patients who underwent ultrasonography and elastography before surgery. The histologic characteristics and clinicopathologic indexes were compared with the SR of ultrasound elastography (UE). The results showed that there was a significantly positive correlation between fibrosis degree and SR measurements (r = 0.754, p = 0.000); the SR was significantly different between the groups with and without calcification (11.34 ± 10.08 vs. 6.81 ± 7.33, p = 0.000). The standard coefficients of collagen and stromal calcification were 0.684 and 0.194, respectively. There was no significant correlation between SR and indices such as size, position, co-existence with Hashimoto’s thyroiditis (HT), multifocality or cervical lymph node (CLN) metastasis. In conclusion, we found that the SR of UE is positively correlated with the fibrosis of PTC. Stromal calcification will elevate the SR dramatically, but psammoma bodies will not when they exist in the absence of stromal calcification.
Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin
Authors: Li Teng-Fei , Wu Hai-Yun , Wang Yi-Rui , Li Xin-Yan , Wang Yong-Xiang
Published: March 2017

Bulleyaconitine (BAA) has been shown to possess antinociceptive activities by stimulation of dynorphin A release from spinal microglia. This study investigated its underlying signal transduction mechanisms. The data showed that (1) BAA treatment induced phosphorylation of CREB (rather than NF-κB) and prodynorphin expression in cultured primary microglia, and antiallodynia in neuropathy, which were totally inhibited by the CREB inhibitor KG-501; (2) BAA upregulated phosphorylation of p38 (but not ERK or JNK), and the p38 inhibitor SB203580 (but not ERK or JNK inhibitor) and p38β gene silencer siRNA/p38β (but not siRNA/p38α) completely blocked BAA-induced p38 phosphorylation and/or prodynorphin expression, and antiallodynia; (3) BAA stimulated cAMP production and PKA phosphorylation, and the adenylate cyclase inhibitor DDA and PKA inhibitor H-89 entirely antagonized BAA-induced prodynorphin expression and antiallodynia; (4) The Gs-protein inhibitor NF449 completely inhibited BAA-increased cAMP level, prodynorphin expression and antiallodynia, whereas the antagonists of noradrenergic, corticotrophin-releasing factor, A1 adenosine, formyl peptide, D1/D2 dopamine, and glucagon like-peptide-1 receptors failed to block BAA-induced antiallodynia. The data indicate that BAA-induced microglial expression of prodynorphin is mediated by activation of the cAMP-PKA-p38β-CREB signaling pathway, suggesting that its possible target is a Gs-protein-coupled receptor – “aconitine receptor”, although the chemical identity is not illustrated.
Significant Role of Collagen XVII And Integrin β4 in Migration and Invasion of The Less Aggressive Squamous Cell Carcinoma Cells
Authors: Moilanen Jyri M. , Löffek Stefanie , Kokkonen Nina , Salo Sirpa , Väyrynen Juha P. , Hurskainen Tiina , Manninen Aki , Riihilä Pilvi , Heljasvaara Ritva , Franzke Claus-Werner , Kähäri Veli-Matti , Salo Tuula , Mäkinen Markus J. , Tasanen Kaisa
Published: March 2017

Collagen XVII and integrin α6β4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin α6β4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin γ2, collagen XVII and integrin β4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen’s disease. The expression of laminin γ2 was highest in SCC samples, whereas the expression of collagen XVII and integrin β4 varied greatly in SCC and its precursors. Collagen XVII and integrin β4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin β4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin β4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin β4 contribute to SCC tumorigenesis.
Transition of Temporal Scaling Behavior in Percolation Assisted Shear-branching Structure during Plastic Deformation
Authors: Ren Jingli , Chen Cun , Wang Gang , Liaw Peter K.
Published: March 2017

This paper explores the temporal scaling behavior induced shear-branching structure in response to variant temperatures and strain rates during plastic deformation of Zr-based bulk metallic glass (BMG). The data analysis based on the compression tests suggests that there are two states of shear-branching structures: the fractal structure with a long-range order at an intermediate temperature of 223 K and a larger strain rate of 2.5 × 10−2 s−1; the disordered structure dominated at other temperature and strain rate. It can be deduced from the percolation theory that the compressive ductility, ec, can reach the maximum value at the intermediate temperature. Furthermore, a dynamical model involving temperature is given for depicting the shear-sliding process, reflecting the plastic deformation has fractal structure at the temperature of 223 K and strain rate of 2.5 × 10−2 s−1.
Compatibility Study of Danggui Buxue Tang on Chemical Ingredients, Angiogenesis and Endothelial Function
Authors: Lin Ping-Lan , Li Zhi-Cheng , Xie Rui-Fang , Wang You-Hua , Zhou Xin
Published: March 2017

Danggui Buxue Tang (DBT) is a classic Chinese herbal formula which consists of Astragali mongholici Radix and Angelica sinensis Radix (ASR). For chemical ingredients, HPLC were performed. Results showed compared with single herbs, DBT decoction could promote the dissolution of ingredients such as ferulic acid and calycosin. Furthermore, when ratio of AMR to ASR was 5 to 1, synthetic score was the best. For angiogenesis, normal and injured zebrafish model were applied. Results showed DBT and its ingredients had angiogenesis effects on Sub Intestinal vessels (SIVs) of normal zebrafish. Meanwhile, DBT and its single herbs could also recover Inter-Segmental Vessels (ISVs) injured by VRI. Angiogenesis effects of DBT on ISVs were better than single herbs. AMR extract, Total Saponins of AMR, Polysaccharide of ASR, ferulic acid, calycosin and calycosin-7-glucoside could be effective ingredients for angiogenisis. For endothelium functions, Lysoph-Osphatidyl choline was used to damage rat endothelial function of thoracic aorta. The results showed DBT and its single herbs could improve endothelial dysfunctions in dose-dependence. Both ferulic acid and calycosin-7-glucoside could also improve endothelium dysfunction in dose dependence. Therefore, compatibility of DBT was reasonable. Compared with single herbs, DBT could promote dissolution of effective ingredients, enhance angiogenesis and relieve endothelial dysfunction.
Hybrid Core-Shell (HyCoS) Nanoparticles produced by Complex Coacervation for Multimodal Applications
Authors: Vecchione D. , Grimaldi A. M. , Forte E. , Bevilacqua Paolo , Netti P. A. , Torino E.
Published: March 2017

Multimodal imaging probes can provide diagnostic information combining different imaging modalities. Nanoparticles (NPs) can contain two or more imaging tracers that allow several diagnostic techniques to be used simultaneously. In this work, a complex coacervation process to produce core-shell completely biocompatible polymeric nanoparticles (HyCoS) for multimodal imaging applications is described. Innovations on the traditional coacervation process are found in the control of the reaction temperature, allowing a speeding up of the reaction itself, and the production of a double-crosslinked system to improve the stability of the nanostructures in the presence of a clinically relevant contrast agent for MRI (Gd-DTPA). Through the control of the crosslinking behavior, an increase up to 6 times of the relaxometric properties of the Gd-DTPA is achieved. Furthermore, HyCoS can be loaded with a high amount of dye such as ATTO 633 or conjugated with a model dye such as FITC for in vivo optical imaging. The results show stable core-shell polymeric nanoparticles that can be used both for MRI and for optical applications allowing detection free from harmful radiation. Additionally, preliminary results about the possibility to trigger the release of a drug through a pH effect are reported.
Characterisation of mental health conditions in social media using Informed Deep Learning
Authors: Gkotsis George , Oellrich Anika , Velupillai Sumithra , Liakata Maria , Hubbard Tim J. P. , Dobson Richard J. B. , Dutta Rina
Published: March 2017

The number of people affected by mental illness is on the increase and with it the burden on health and social care use, as well as the loss of both productivity and quality-adjusted life-years. Natural language processing of electronic health records is increasingly used to study mental health conditions and risk behaviours on a large scale. However, narrative notes written by clinicians do not capture first-hand the patients’ own experiences, and only record cross-sectional, professional impressions at the point of care. Social media platforms have become a source of ‘in the moment’ daily exchange, with topics including well-being and mental health. In this study, we analysed posts from the social media platform Reddit and developed classifiers to recognise and classify posts related to mental illness according to 11 disorder themes. Using a neural network and deep learning approach, we could automatically recognise mental illness-related posts in our balenced dataset with an accuracy of 91.08% and select the correct theme with a weighted average accuracy of 71.37%. We believe that these results are a first step in developing methods to characterise large amounts of user-generated content that could support content curation and targeted interventions.
Coupled gyration modes in one-dimensional skyrmion arrays in thin-film nanostrips as new type of information carrier
Authors: Kim Junhoe , Yang Jaehak , Cho Young-Jun , Kim Bosung , Kim Sang-Koog
Published: March 2017

We report on a micromagnetic numerical simulation study of dynamic coupling between neighboring skyrmions periodically arranged in narrow-width nanostrips. We explored the coupled gyration modes and their characteristic dispersions in terms of the interdistance between the neighboring skyrmions. The application of perpendicular magnetic fields allows for the control and modification of the dispersion of the coupled gyration modes. The coupled gyration modes of individual skyrmions might provide a new type of information carrier in narrow-width straight and curved nanostrips, as driven by magnetic interactions in such continuous thin films.
TOX and ADIPOQ Gene Polymorphisms Are Associated with Antipsychotic-Induced Weight Gain in Han Chinese
Authors: Li Shen , Xu Chengai , Tian Yuan , Wang Xueshi , Jiang Rui , Zhang Miaomiao , Wang Lili , Yang Guifu , Gao Ying , Song Chenyu , He Yukun , Zhang Ying , Li Jie , Li Wei-Dong
Published: March 2017

To find the genetic markers related to the antipsychotic-induced weight gain (AIWG), we analyzed associations among candidate gene single-nucleotide polymorphisms (SNPs) and quantitative traits of weight changes and lipid profiles in a Chinese Han population. A total of 339 schizophrenic patients, including 86 first-episode patients (FEPs), meeting the entry criteria were collected. All patients received atypical antipsychotic drug monotherapy and hospitalization and were followed for 12 weeks. Forty-three SNPs in 23 candidate genes were calculated for quantitative genetic association with AIWG, performed by PLINK. The TOX gene SNP rs11777927 (P = 0.009) and the ADIPOQ gene SNP rs182052 (P = 0.019) were associated with AIWG (in body mass index, BMI). In addition, the BDNF SNP rs6265 (P = 0.002), BDAF SNP rs11030104 SNP (P = 0.001), and ADIPOQ SNPs rs822396 (P = 0.003) were significantly associated with the change of waist-to-hip ratio (WHR) induced by atypical antipsychotics. These results were still significant after age and gender adjustments. These findings provide preliminary evidence supporting the role of TOX, ADIPOQ and BDNF in weight and WHR gain induced by atypical antipsychotics.