bluuebunny/crossref_metadata_2025_split huggingface dataset:
A medial prefrontal cortex-nucleus acumens corticotropin-releasing factor circuitry for neuropathic pain-increased susceptibility to opioid reward
Authors: Kai Yuanzhong , Li Yanhua , Sun Tingting , Yin Weiwei , Mao Yu , Li Jie , Xie Wen , Chen Shi , Wang Likui , Li Juan , Zhang Zhi , Tao Wenjuan 
Published: May 2018

AbstractRecent studies have shown that persistent pain facilitates the response to morphine reward. However, the circuit mechanism underlying this process remains ambiguous. In this study, using chronic constriction injury (CCI) of the sciatic nerve in mice, we found that persistent neuropathic pain reduced the minimum number of morphine conditioning sessions required to induce conditioned place preference (CPP) behavior. This dose of morphine had no effect on the pain threshold. In the medial prefrontal cortex (mPFC), which is involved in both pain and emotion processing, corticotropin-releasing factor (CRF) expressing neuronal activity was increased in CCI mice. Chemogenetic inhibition of mPFC CRF neurons reversed CCI-induced morphine CPP facilitation. Furthermore, the nucleus acumens (NAc) received mPFC CRF functional projections that exerted excitatory effects on NAc neurons. Optogenetic inhibition of mPCF neuronal terminals or local infusion of the CRF receptor 1 (CRFR1) antagonist in the NAc restored the effects of neuropathic pain on morphine-induced CPP behavior, but not in normal mice. On a molecular level, in CCI mice, CRFR1 protein expression was increased in the NAc by a histone dimethyltransferase G9a-mediated epigenetic mechanism. Local G9a knockdown increased the expression of CRFR1 and mimicked CCI-induced hypersensitivity to acquiring morphine CPP. Taken together, these findings demonstrate a previously unknown and specific mPFC CRF engagement of NAc neuronal circuits, the sensitization of which facilitates behavioral responses to morphine reward in neuropathic pain states via CRFR1s.
Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia
Authors: Lehmann-Che Jacqueline , Bally Cécile , Letouzé Eric , Berthier Caroline , Yuan Hao , Jollivet Florence , Ades Lionel , Cassinat Bruno , Hirsch Pierre , Pigneux Arnaud , Mozziconacci Marie-Joelle , Kogan Scott , Fenaux Pierre , de Thé Hugues 
Published: May 2018

AbstractRetinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.
Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain
Authors: Scheib Ulrike , Broser Matthias , Constantin Oana M. , Yang Shang , Gao Shiqiang , Mukherjee Shatanik , Stehfest Katja , Nagel Georg , Gee Christine E. , Hegemann Peter 
Published: May 2018

AbstractThe cyclic nucleotides cAMP and cGMP are important second messengers that orchestrate fundamental cellular responses. Here, we present the characterization of the rhodopsin-guanylyl cyclase from Catenaria anguillulae (CaRhGC), which produces cGMP in response to green light with a light to dark activity ratio >1000. After light excitation the putative signaling state forms with τ = 31 ms and decays with τ = 570 ms. Mutations (up to 6) within the nucleotide binding site generate rhodopsin-adenylyl cyclases (CaRhACs) of which the double mutated YFP-CaRhAC (E497K/C566D) is the most suitable for rapid cAMP production in neurons. Furthermore, the crystal structure of the ligand-bound AC domain (2.25 Å) reveals detailed information about the nucleotide binding mode within this recently discovered class of enzyme rhodopsin. Both YFP-CaRhGC and YFP-CaRhAC are favorable optogenetic tools for non-invasive, cell-selective, and spatio-temporally precise modulation of cAMP/cGMP with light.
Assisted reverse electrodialysis—principles, mechanisms, and potential
Authors: Vanoppen Marjolein , Criel Ella , Walpot Griet , Vermaas David A. , Verliefde Arne 
Published: May 2018

AbstractAlthough seawater reverse osmosis (RO) is nearing its thermodynamic minimum energy limit, it is still an energy-intensive process, requiring 2–3 kWh/m³ at a recovery of 50%. Pre-desalination of the seawater by reverse electrodialysis (RED), using an impaired water source, can further decrease this energy demand by producing energy and reducing the seawater concentration. However, RED is hampered by the initial high resistance of the fresh water source, resulting in a high required membrane area (i.e., high investment costs). In this paper, a new process is presented that can overcome this initial resistance and decrease the RED investment cost without the need for additional infrastructure: assisted RED (ARED). In ARED, a small potential difference is applied in the direction of the natural salinity gradient, increasing the ionic transport rate and rapidly decreasing the initial diluate resistance. This decreasing resistance is shown to outweigh any negative effects caused by, for example, concentration polarization, resulting in a process that is more efficient than theoretically expected. As this effect is mainly important at low diluate concentrations (up to 0.1 M), ARED is proposed as a first step in an economic and energy efficient (A)RED-RO hybrid process.
A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease
Authors: Martin D. D. O. , Kay C. , Collins J. A. , Nguyen Y. T. , Slama R. A. , Hayden M. R. 
Published: May 2018

AbstractPost-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.
Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain
Authors: Boeckel Jes-Niels , Palapies Lars , Klotsche Jens , Zeller Tanja , von Jeinsen Beatrice , Perret Maya F. , Kleinhaus Soeren L. , Pieper Lars , Tzikas Stergios , Leistner David , Bickel Christoph , Stalla Günter K. , Lehnert Hendrik , Lindahl Bertil , Wittchen Hans-Ulrich , Silber Sigmund , Baldus Stephan , Maerz Winfried , Dimmeler Stefanie , Blankenberg Stefan , Münzel Thomas , Zeiher Andreas M. , Keller Till 
Published: May 2018

AbstractThe use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Extended-conjugation π-electron systems in carbon nanotubes
Authors: Miyaura Kenshi , Miyata Yasumitsu , Thendie Boanerges , Yanagi Kazuhiro , Kitaura Ryo , Yamamoto Yuta , Arai Shigeo , Kataura Hiromichi , Shinohara Hisanori 
Published: May 2018

AbstractExtending π-electron systems are among the most important topics in physics, chemistry and materials science because they can result in functional materials with applications in electronics and optics. Conventional processes for π-electron extension, however, can generate products exhibiting chemical instability, poor solubility or disordered structures. Herein, we report a novel strategy for the synthesis of π-conjugated polymers within the interiors of carbon nanotubes (CNTs). In this process, thiophene-based oligomers are encapsulated within CNTs as precursors and are subsequently polymerized by thermal annealing. This polymerization increases the effective conjugation length of the thiophenes, as confirmed by transmission electron microscopy and absorption peak red shifts. This work also demonstrates that these polythiophenes can serve as effective markers for individual CNTs during Raman imaging with single-wavelength laser excitation due to their strong absorbance. In addition, stable carrier injection into the encapsulated polythiophenes is found to be possible via electrochemical doping. Such doping has the potential to produce π-electron-based one-dimensional conductive wires and highly stable electrochromic devices.
Socioeconomic, environmental and lifestyle factors associated with gestational diabetes mellitus: A matched case-control study in Beijing, China
Authors: Carroll Xianming , Liang Xianhong , Zhang Wenyan , Zhang Wenjing , Liu Gaifen , Turner Nannette , Leeper-Woodford Sandra 
Published: May 2018

AbstractGestational diabetes mellitus (GDM) is a common health problem during pregnancy and its prevalence is increasing globally, especially in China. The aim of this study was to investigate socioeconomic, environmental and lifestyle factors associated with GDM in Chinese women. A matched pair case-control study was conducted with 276 GDM women and 276 non-GDM women in two hospitals in Beijing, China. Matched factors include age and pre-pregnancy body mass index (BMI). GDM subjects were defined based on the International Association of Diabetes Study Group criteria for GDM. A conditional logistic regression model with backward stepwise selection was performed to predict the odds ratio (OR) for associated factors of GDM. The analyses of data show that passive smoking at home (OR = 1.52, p = 0.027), passive smoking in the workplace (OR = 1.71, p = 0.01), and family history of diabetes in first degree relatives (OR = 3.07, p = 0.004), were significant factors associated with GDM in Chinese women. These findings may be utilized as suggestions to decrease the incidence of GDM in Chinese women by improving the national tobacco control policy and introducing public health interventions to focus on the social environment of pregnant women in China.
A novel SNP in the 5’ regulatory region of organic anion transporter 1 is associated with chronic kidney disease
Authors: Sun Chiao-Yin , Wu Mai-Szu , Lee Chin-Chan , Chen Shu-Hong , Lo Kang-Chieh , Chen Yau-Hung 
Published: May 2018

AbstractWe aimed to analyze the associations of single nucleotide polymorphisms (SNP) in the 5′ regulatory region of the human organic anion transporter 1 (OAT1) gene with chronic kidney disease (CKD). A case-control study including age- and sex-matched groups of normal subjects and patients with CKD (n = 162 each) was designed. Direct sequencing of the 5′ regulatory region (+88 to −1196 region) showed that patients with CKD had a higher frequency of the −475 SNP (T > T/G) than normal subjects (14/162vs. 2/162). The luciferase activity assay results indicated that the −475G SNP had a higher promoter efficiency than the −475T SNP. Chromatin immunoprecipitation (ChIP) and LC/MS/MS analyses showed that the −475G SNP up-regulated 26 proteins and down-regulated 74 proteins. The Southwestern blot assay results revealed that the −475G SNP decreased the binding of Hepatoma-derived growth factor (HDGF), a transcription repressor, compared to the −475T SNP. Overexpression of HDGF significantly down-regulated OAT1 in renal tubular cells. Moreover, a zebrafish animal model showed that HDGF-knockdown zebrafish embryos had higher rates of kidney malformation than wild-type controls [18/78 (23.1%) vs. 1/30 (3.3%)]. In conclusion, our results suggest that an OAT1 SNP might be clinically associated with CKD. Renal tubular cells with the −475 SNP had increased OAT1 expression, which resulted in increased transportation of organic anion toxins into cells. Cellular accumulation of organic anion toxins caused cytotoxicity and resulted in CKD.
Maternal predator odour exposure programs metabolic responses in adult offspring
Authors: St-Cyr Sophie , Abuaish Sameera , Welch Kenneth C. , McGowan Patrick O. 
Published: May 2018

AbstractA cardinal feature of the reaction to stress is the promotion of energy mobilization, enabling appropriate behavioural responses. Predator odours are naturalistic and ecologically relevant stressors present over evolutionary timescales. In this study, we asked whether maternal predator odour exposure could program long-term energy mobilization in C57BL/6 mice offspring. To test this hypothesis, we measured rates of oxygen consumption in prenatally predator odour exposed mice in adulthood while controlling for levels of locomotor activity at baseline and under stress. Circulating thyroid hormone levels and the transcript abundance of key regulators of the hypothalamic-pituitary-thyroid axis within the periventricular nucleus (PVN) of the hypothalamus and in the liver, including carriers and receptors and thyrotropin-releasing hormone, were measured as endocrine mediators facilitating energy availability. Prenatally predator odour exposed mice of both sexes mobilized more energy during lower energy demand periods of the day and under stressful conditions. Further, prenatally predator odour exposed mice displayed modifications of their hypothalamic-pituitary-thyroid axis through increased circulating thyroxine and thyroid hormone receptor α within the PVN and decreased transthyretin in the liver. Overall, these results suggest that maternal exposure to predator odour is sufficient to increase long-term energy mobilization in adult offspring.
Mutations in BRCA1, BRCA2, and PALB2, and a panel of 50 cancer-associated genes in pancreatic ductal adenocarcinoma
Authors: Takeuchi Shoko , Doi Manami , Ikari Naoki , Yamamoto Masakazu , Furukawa Toru 
Published: May 2018

AbstractMutations in genes of the breast cancer susceptibility gene (BRCA) pathway, namely, BRCA1, BRCA2, and PALB2, can provide useful information for the efficacy of platinum-based or poly ADP-ribose polymerase inhibitors chemotherapeutic regimens. Pancreatic ductal adenocarcinoma (PDAC) is an important target for such precision chemotherapies because of its dismal prognosis. We analyzed mutations in the entire coding regions of the BRCA pathway genes, expression of breast cancer 2 (BRCA2), and mutations in hotspots of 50 cancer-associated genes in 42 surgically resected PDACs, and evaluated their associations with clinicopathological features. We identified 13 rare germline mutations in the BRCA pathway genes; 68 somatic mutations in KRAS, TP53, SMAD4, CDKN2A, GNAS, SMARCB1, and RB1; and 2 germline variations in MLH1. Among them, BRCA2S2148fs was known to be pathogenic. BRCA2R18H and BRCA2G2044V were enriched in tumor tissues. BRCA2K799R and BRCA2R2964T were novel germline variations. Patients harboring potentially deleterious mutations in the BRCA pathway genes showed significantly better prognosis than those with benign mutations or no mutation. These results indicate that rare germline variations in BRCA pathway genes could be found more frequently than previously anticipated and, more importantly, potentially deleterious mutations of them could be a favorable prognostic factor in patients with resectable PDACs.
Salvianolic acids from antithrombotic Traditional Chinese Medicine Danshen are antagonists of human P2Y1 and P2Y12 receptors
Authors: Liu Xuyang , Gao Zhan-Guo , Wu Yiran , Stevens Raymond C. , Jacobson Kenneth A. , Zhao Suwen 
Published: May 2018

AbstractMany hemorheologic Traditional Chinese Medicines (TCMs) that are widely-used clinically lack molecular mechanisms of action. We hypothesized that some of the active components of hemorheologic TCMs may function through targeting prothrombotic P2Y1 and/or P2Y12 receptors. The interactions between 253 antithrombotic compounds from TCM and these two G protein-coupled P2Y receptors were evaluated using virtual screening. Eleven highly ranked hits were further tested in radioligand binding and functional assays. Among these compounds, salvianolic acid A and C antagonized the activity of both P2Y1 and P2Y12 receptors in the low µM range, while salvianolic acid B antagonized the P2Y12 receptor. These three salvianolic acids are the major active components of the broadly-used hemorheologic TCM Danshen (Salvia militorrhiza), the antithrombotic molecular mechanisms of which were largely unknown. Thus, the combination of virtual screening and experimental validation identified potential mechanisms of action of multicomponent drugs that are already employed clinically.
A practical approach to scale-adaptive deep convection in a GCM by controlling the cumulus base mass flux
Authors: Ahn Min-Seop , Kang In-Sik 
Published: May 2018

AbstractAs the horizontal resolution of general circulation model (GCM) is increased, the sub-grid scale vertical transport has to be decreased appropriately. In the present study, a resolution-dependent (so-called scale-adaptive or scale-aware) deep convection was formulated by controlling the cumulus base mass flux. Using a three-dimensional cloud resolving model simulation, we estimated the appropriate ratios of the sub-grid scale vertical transport to the total vertical transport of moist static energy for different horizontal resolutions, whose values are about 0.8 for 100 km resolution and about 0.6 for 50 km resolution. Those values were used as a guideline to decrease to the ratio of convective precipitation to the total precipitation in a high-resolution GCM. The cumulus base mass flux is reduced by multiplying a reduction coefficient, which is 0.2 for the 100 km resolution and 0.09 for the 50 km resolution in the present GCM. The GCM with the scale-adaptive deep convection produces the climatological mean precipitation similar to that of the original GCM, whereas it simulates the heavy precipitation frequency and the Madden and Julian Oscillation much better than those of the original GCM.
Role of xenobiotics in the induction and progression of fatty liver disease
Authors: Klaunig James E. , Li Xilin , Wang Zemin 
Published: May 2018

Abstract
Non-alcoholic fatty liver disease is a major cause of chronic liver pathology in humans. Fatty liver disease involves the accumulation of hepatocellular fat in hepatocytes that can progress to hepatitis. Steatohepatitis is categorized into alcoholic (ASH) or non-alcoholic (NASH) steatohepatitis based on the etiology of the insult. Both pathologies involve an initial steatosis followed by a progressive inflammation of the liver and eventual hepatic fibrosis (steatohepatitis) and cirrhosis. The involvement of pharmaceuticals and other chemicals in the initiation and progression of fatty liver disease has received increased study. This review will examine not only how xenobiotics initiate hepatic steatosis and steatohepatitis but also how the presence of fatty liver may modify the metabolism and pathologic effects of xenobiotics. The feeding of a high fat diet results in changes in the expression of nuclear receptors that are involved in adaptive and adverse liver effects following xenobiotic exposure. High fat diets also modulate cellular and molecular pathways involved in inflammation, metabolism, oxidative phosphorylation and cell growth. Understanding the role of hepatic steatosis and steatohepatitis on the sequelae of toxic and pathologic changes seen following xenobiotic exposure has importance in defining proper and meaningful human risk characterization of the drugs and other chemical agents.
The role of molecular gas in the nuclear regions of IRAS 00183-7111
Authors: Ruffa I. , Vignali C. , Mignano A. , Paladino R. , Iwasawa K. 
Published: May 2018

Aims. We present a multi-frequency study of the ultraluminous infrared galaxy (ULIRG) IRAS 00183-7111 (z = 0.327), selected from the Spoon diagnostic diagram as a highly obscured active galactic nucleus (AGN) candidate. ALMA millimetre and X-ray observations are used; the main aim is to verify at what level the molecular gas, traced by the CO, may be responsible for the obscuration observed at X-ray energies. Theory and observations both suggest that galaxy-scale absorption may play a role in the AGN obscuration at intermediate (i.e. Compton-thin) column densities.
Methods. We calibrated and analysed ALMA archival Cycle 0 data in two bands (Bands 3 and 6). The X-ray properties of IRAS 00183-7111 were studied by reducing and analysing separately archival Chandra and XMM-Newton data; recently acquired NuSTAR spectra were first examined individually and then added to the Chandra and XMM spectra for the broad-band (0.5 − 24 keV, observed frame) analysis.
Results. We derived a molecular gas column density of (8.0 ± 0.9) × 1021 cm−2 from the ALMA CO(1−0) detection, while the best-fit column density of cold gas obtained from X-ray spectral fitting is 6.8−1.5+2.1×1022 cm−. The two quantities suggest that the molecular gas may contribute only a fraction of the AGN obscuration; however, the link between them is not straightforward. The nuclear regions of IRAS 00183-7111 are likely stratified into different layers of matter: one inner and highly ionized by the strong radiation field of the AGN (as inferred from the high-ionization iron line found in the X-ray spectra), and one outer and colder, extending more than 5 kpc from the nucleus (as traced by the molecular gas observed with ALMA). The molecular gas regions also give rise to a vigorous starburst with SFR ~260 ± 28 M⊙ yr−1. The complexity of this nuclear environment makes it difficult to identify the origin of the AGN obscuration given the quality of the data currently available. Higher resolution observations in the millimetre regime are needed to deeply investigate this issue.