bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Dual‐Administration Microtracer Technique to Characterize the Absorption, Distribution, Metabolism, and Excretion of [14C]Seletalisib (UCB5857) in Healthy Subjects
Authors: Helmer Eric , Nicolas Jean‐Marie , Long Jeff , Roffel Ad F. , Jones Emma , Chanteux Hugues , Diaz Nieves , Garratt Holly , Bosje Tjerk 
Published: June 2017

AbstractPhosphoinositide 3 kinases are targets for development of small‐molecule inhibitors to disrupt progression of immune‐inflammatory diseases. This phase 1 open‐label study (Eudract 2014‐005353‐39) evaluated the safety and relative bioavailability of 2 new seletalisib (UCB5857) formulations (A and B) compared with a reference formulation. Absolute bioavailability (period 1a, n = 6) and disposition and metabolism (period 1b, n = 6) of the reference formulation were evaluated: healthy subjects received 30 mg orally plus ∼20 μg of a 14C‐labeled microtracer (intravenously in 1a, orally in 1b). New formulations were evaluated: subjects from periods 1a and 1b were pooled and randomly distributed to receive a single oral dose (30 mg) of formulation A (n = 6) or B (n = 6) in periods 2 and 3, using a crossover design. Absolute oral bioavailability of seletalisib was 97% (90% confidence interval 87, 107). Unchanged [14C]seletalisib was the predominant radioactive component in plasma (94.8%). After oral dosing, the radioactive dose was primarily recovered in feces (74.6%, geometric coefficient of variation [GeoCV] 18.1%), mostly as metabolites. Seletalisib demonstrated a 24‐hour terminal half‐life, volume of distribution of 60.9 L (GeoCV 23.8%), and a total plasma clearance of 1.7 L/h (GeoCV 35.4%). Formulations A and B displayed similar or even higher exposure compared with reference seletalisib (areas under the concentration‐time curves 19 337 [GeoCV 30.8%], 20 380 [GeoCV 37.7%], and 15 932 [GeoCV 36.4%] h·ng/mL, respectively). New formulations A and B were bioequivalent with each other, and all 3 formulations showed acceptable safety profiles. This radiolabeled microtracer approach successfully informed on the absorption, distribution, metabolism, and excretion of seletalisib and further guided the mechanistic pharmacokinetic modeling.
Impact of Time Since Last Childbirth on Survival of Women with Premenopausal and Postmenopausal Breast Cancers
Authors: Balakrishnan Nanthini , Teo Soo‐Hwang , Sinnadurai Siamala , Bhoo Pathy Nanthini Thevi , See Mee‐Hoong , Taib Nur Aishah , Yip Cheng‐Har , Bhoo Pathy Nirmala 
Published: June 2017

AbstractBackgroundReproductive factors are associated with risk of breast cancer, but the association with breast cancer survival is less well known. Previous studies have reported conflicting results on the association between time since last childbirth and breast cancer survival. We determined the association between time since last childbirth (LCB) and survival of women with premenopausal and postmenopausal breast cancers in Malaysia.MethodA historical cohort of 986 premenopausal, and 1123 postmenopausal, parous breast cancer patients diagnosed from 2001 to 2012 in University Malaya Medical Centre were included in the analyses. Time since LCB was categorized into quintiles. Multivariable Cox regression was used to determine whether time since LCB was associated with survival following breast cancer, adjusting for demographic, tumor, and treatment characteristics.ResultsPremenopausal breast cancer patients with the most recent childbirth (LCB quintile 1) were younger, more likely to present with unfavorable prognostic profiles and had the lowest 5‐year overall survival (OS) (66.9; 95% CI 60.2–73.6%), compared to women with longer duration since LCB (quintile 2 thru 5). In univariable analysis, time since LCB was inversely associated with risk of mortality and the hazard ratio for LCB quintile 2, 3, 4, and 5 versus quintile 1 were 0.53 (95% CI 0.36–0.77), 0.49 (95% CI 0.33–0.75), 0.61 (95% CI 0.43–0.85), and 0.64 (95% CI 0.44–0.93), respectively; Ptrend = 0.016. However, this association was attenuated substantially following adjustment for age at diagnosis and other prognostic factors. Similarly, postmenopausal breast cancer patients with the most recent childbirth were also more likely to present with unfavorable disease profiles. Compared to postmenopausal breast cancer patients in LCB quintile 1, patients in quintile 5 had a higher risk of mortality. This association was not significant following multivariable adjustment.ConclusionTime since LCB is not independently associated with survival in premenopausal or postmenopausal breast cancers. The apparent increase in risks of mortality in premenopausal breast cancer patients with a recent childbirth, and postmenopausal patients with longer duration since LCB, appear to be largely explained by their age at diagnosis.
Ultra-large-scale phase-field simulation study of ideal grain growth
Authors: Miyoshi Eisuke , Takaki Tomohiro , Ohno Munekazu , Shibuta Yasushi , Sakane Shinji , Shimokawabe Takashi , Aoki Takayuki 
Published: June 2017

AbstractGrain growth, a competitive growth of crystal grains accompanied by curvature-driven boundary migration, is one of the most fundamental phenomena in the context of metallurgy and other scientific disciplines. However, the true picture of grain growth is still controversial, even for the simplest (or ‘ideal’) case. This problem can be addressed only by large-scale numerical simulation. Here, we analyze ideal grain growth via ultra-large-scale phase-field simulations on a supercomputer for elucidating the corresponding authentic statistical behaviors. The performed simulations are more than ten times larger in time and space than the ones previously considered as the largest; this computational scale gives a strong indication of the achievement of true steady-state growth with statistically sufficient number of grains. Moreover, we provide a comprehensive theoretical description of ideal grain growth behaviors correctly quantified by the present simulations. Our findings provide conclusive knowledge on ideal grain growth, establishing a platform for studying more realistic growth processes.
Integrative analysis of pathway deregulation in obesity
Authors: Font-Clos Francesc , Zapperi Stefano , La Porta Caterina A.M. 
Published: June 2017

AbstractObesity is a pandemic disease, linked to the onset of type 2 diabetes and cancer. Transcriptomic data provides a picture of the alterations in regulatory and metabolic activities associated with obesity, but its interpretation is typically blurred by noise. Here, we solve this problem by collecting publicly available transcriptomic data from adipocytes and removing batch effects using singular value decomposition. In this way we obtain a gene expression signature of 38 genes associated to obesity and identify the main pathways involved. We then show that similar deregulation patterns can be detected in peripheral markers, in type 2 diabetes and in breast cancer. The integration of different data sets combined with the study of pathway deregulation allows us to obtain a more complete picture of gene-expression patterns associated with obesity, breast cancer, and diabetes.
Post-secretional activation of Protease IV by quorum sensing in Pseudomonas aeruginosa
Authors: Oh Jungmin , Li Xi-Hui , Kim Soo-Kyong , Lee Joon-Hee 
Published: June 2017

AbstractProtease IV (PIV), a key virulence factor of Pseudomonas aeruginosa is a secreted lysyl-endopeptidase whose expression is induced by quorum sensing (QS). We found that PIV expressed in QS mutant has severe reduction of activity in culture supernatant (CS), even though it is overexpressed to high level. PIV purified from the QS mutant (M-PIV) had much lower activity than the PIV purified from wild type (P-PIV). We found that the propeptide cleaved from prepro-PIV was co-purified with M-PIV, but never with P-PIV. Since the activity of M-PIV was restored by adding the CS of QS-positive and PIV-deficient strain, we hypothesized that the propeptide binds to and inhibits PIV, and is degraded to activate PIV by a QS-dependent factor. In fact, the CS of the QS-positive and PIV-deficient strain was able to degrade the propeptide. Since the responsible factor should be a QS-dependently expressed extracellular protease, we tested QS-dependent proteases of P. aeruginosa and found that LasB (elastase) can degrade the propeptide and activate M-PIV. We purified the propeptide of PIV and confirmed that the propeptide can bind to and inhibit PIV. We suggest that PIV is post-secretionally activated through the extracellular degradation of the propeptide by LasB, a QS-dependent protease.
Crystal structure of Pelagibacterium halotolerans PE8: New insight into its substrate-binding pattern
Authors: Huo Ying-Yi , Li Suhua , Huang Jing , Rong Zhen , Wang Zhao , Li Zhengyang , Ji Rui , Kuang Siyun , Cui Heng-Lin , Li Jixi , Xu Xue-Wei 
Published: June 2017

AbstractLysophospholipase_carboxylesterase (LPCE) has highly conserved homologs in many diverse species ranging from bacteria to humans, as well as substantial biological significance and potential therapeutic implications. However, its biological function and catalytic mechanism remain minimally investigated because of the lack of structural information. Here, we report the crystal structure of a bacterial esterase PE8 belonging to the LPCE family. The crystal structure of PE8 was solved with a high resolution of 1.66 Å. Compared with other homologs in the family, significant differences were observed in the amino acid sequence, three-dimensional structure, and substrate-binding pattern. Residue Arg79 undergoes configuration switching when binding to the substrate and forms a unique wall, leading to a relatively closed cavity in the substrate-binding pocket compared with the relatively more open and longer clefts in other homologs. Moreover, the mutant Met122Ala showed much stronger substrate affinity and higher catalytic efficiency because less steric repulsion acted on the substrates. Taken together, these results showed that, in PE8, Arg79 and Met122 play important roles in substrate binding and the binding pocket shaping, respectively. Our study provides new insight into the catalytic mechanism of LPCE, which may facilitate the development of structure-based therapeutics and other biocatalytic applications.
Quantity of alcohol drinking positively correlates with serum levels of endotoxin and markers of monocyte activation
Authors: Liangpunsakul Suthat , Toh Evelyn , Ross Ruth A. , Heathers Laura E. , Chandler Kristina , Oshodi AdePeju , McGee Breann , Modlik Elizabeth , Linton Tobyn , Mangiacarne Darrin , Jimenez Claudie , Dong X. Charlie , Wang Li , Tu Wanzhu , Nelson David E. 
Published: June 2017

AbstractIt is unknown if LPS (lipopolysaccharides) and markers of immune activation, soluble CD14 (sCD14) and CD163 (sCD163) are associated with the quantity of alcohol consumption. 148 subjects were enrolled (97 excessive drinkers (ED) and 51 controls). Time Line Follow-Back questionnaire was used to quantify the amount of alcohol consumed. Serum LPS, sCD14, and sCD163 were measured. Peripheral blood mononuclear cells (PBMCs) were also isolated. Compared to controls, ED had higher total drinks in the past 30 days, higher levels of LPS, sCD14 and sCD163. The levels of serum LPS, sCD14, and sCD163 were higher among ED with recent alcohol consumption (last drink <10 days before enrollment) compared to those without recent drinking. Similar bacterial genome copy numbers were detected in control and ED groups. We found that ethanol primed PBMCs for LPS-induced inflammatory responses. A positive correlation between serum LPS, sCD14, sCD163 and the quantity of alcohol drinking was observed after adjusting for covariates and that abstinence was associated with decline in the levels of LPS, sCD14 and sCd163. We found an increase in the levels of LPS and markers of monocyte activations in ED. Further studies are needed to determine whether these can be used as the biomarkers for excessive alcohol use.
Maintaining ecosystem resilience: functional responses of tree cavity nesters to logging in temperate forests of the Americas
Authors: Ibarra José Tomás , Martin Michaela , Cockle Kristina L. , Martin Kathy 
Published: June 2017

AbstractLogging often reduces taxonomic diversity in forest communities, but little is known about how this biodiversity loss affects the resilience of ecosystem functions. We examined how partial logging and clearcutting of temperate forests influenced functional diversity of birds that nest in tree cavities. We used point-counts in a before-after-control-impact design to examine the effects of logging on the value, range, and density of functional traits in bird communities in Canada (21 species) and Chile (16 species). Clearcutting, but not partial logging, reduced diversity in both systems. The effect was much more pronounced in Chile, where logging operations removed critical nesting resources (large decaying trees), than in Canada, where decaying aspenPopulus tremuloideswere retained on site. In Chile, logging was accompanied by declines in species richness, functional richness (amount of functional niche occupied by species), community-weighted body mass (average mass, weighted by species densities), and functional divergence (degree of maximization of divergence in occupied functional niche). In Canada, clearcutting did not affect species richness but nevertheless reduced functional richness and community-weighted body mass. Although some cavity-nesting birds can persist under intensive logging operations, their ecosystem functions may be severely compromised unless future nest trees can be retained on logged sites.
E2F1-regulated long non-coding RNA RAD51-AS1 promotes cell cycle progression, inhibits apoptosis and predicts poor prognosis in epithelial ovarian cancer
Authors: Zhang Xiaodan , Liu Guoping , Qiu Junjun , Zhang Ning , Ding Jingxin , Hua Keqin 
Published: June 2017

AbstractLong non-coding RNA RAD51 antisense RNA 1 (RAD51-AS1, also known as TODRA) has been shown to be down-regulated by E2F1, a key cell cycle and apoptosis regulator, in breast cancer. Little is known regarding the role of RAD51-AS1 in disease. Here, we investigate the role of RAD51-AS1 in epithelial ovarian cancer (EOC). Using luciferase reporter and chromatin immunoprecipitation experiments, we verified RAD51-AS1 as a target of E2F1 under negative regulation in EOC. We then examined RAD51-AS1 expression in EOC samples using in situ hybridization (ISH). RAD51-AS1 was localized to the nucleus and found to be a critical marker for clinical features that significantly correlated with poor survival in EOC patients. RAD51-AS1 was also an independent prognostic factor for EOC. Overexpression of RAD51-AS1 promoted EOC cell proliferation, while silencing of RAD51-AS1 inhibited EOC cell proliferation, delayed cell cycle progression and promoted apoptosis in vitro and in vivo. RAD51-AS1 may participate in carcinogenesis via regulation of p53 and p53-related genes. Our study highlights the role of RAD51-AS1 as a prognostic marker of EOC. Based on its regulation of the tumor suppressor p53, RAD51-AS1-based therapy may represent a viable therapeutic option for EOC in the near future.
Contrasting dynamics of leaf potential and gas exchange during progressive drought cycles and recovery in Amorpha fruticosa and Robinia pseudoacacia
Authors: Yan Weiming , Zheng Shuxia , Zhong Yangquanwei , Shangguan Zhouping 
Published: June 2017

AbstractLeaf gas exchange is closely associated with water relations; however, less attention has been given to this relationship over successive drought events. Dynamic changes in gas exchange and water potential in the seedlings of two woody species, Amorpha fruticosa and Robinia pseudoacacia, were monitored during recurrent drought. The pre-dawn leaf water potential declined in parallel with gas exchange in both species, and sharp declines in gas exchange occurred with decreasing water potential. A significant correlation between pre-dawn water potential and gas exchange was observed in both species and showed a right shift in R. pseudoacacia in the second drought. The results suggested that stomatal closure in early drought was mediated mainly by elevated foliar abscisic acid (ABA) in R. pseudoacacia, while a shift from ABA-regulated to leaf-water-potential-driven stomatal closure was observed in A. fruticosa. After re-watering, the pre-dawn water potential recovered quickly, whereas stomatal conductance did not fully recover from drought in R. pseudoacacia, which affected the ability to tightly control transpiration post-drought. The dynamics of recovery from drought suggest that stomatal behavior post-drought may be restricted mainly by hydraulic factors, but non-hydraulic factors may also be involved in R. pseudoacacia.
Differential Membrane Dipolar Orientation Induced by Acute and Chronic Cholesterol Depletion
Authors: Sarkar Parijat , Chakraborty Hirak , Chattopadhyay Amitabha 
Published: June 2017

AbstractCholesterol plays a crucial role in cell membrane organization, dynamics and function. Depletion of cholesterol represents a popular approach to explore cholesterol-sensitivity of membrane proteins. An emerging body of literature shows that the consequence of membrane cholesterol depletion often depends on the actual process (acute or chronic), although the molecular mechanism underlying the difference is not clear. Acute depletion, using cyclodextrin-type carriers, is faster relative to chronic depletion, in which inhibitors of cholesterol biosynthesis are used. With the overall goal of addressing molecular differences underlying these processes, we monitored membrane dipole potential under conditions of acute and chronic cholesterol depletion in CHO-K1 cells, using a voltage-sensitive fluorescent dye in dual wavelength ratiometric mode. Our results show that the observed membrane dipole potential exhibits difference under acute and chronic cholesterol depletion conditions, even when cholesterol content was identical. To the best of our knowledge, these results provide, for the first time, molecular insight highlighting differences in dipolar reorganization in these processes. A comprehensive understanding of processes in which membrane cholesterol gets modulated would provide novel insight in its interaction with membrane proteins and receptors, thereby allowing us to understand the role of cholesterol in cellular physiology associated with health and disease.
Tuberculosis infection in rural labor migrants in Shenzhen, China: Emerging challenge to tuberculosis control during urbanization
Authors: Li Xiangwei , Yang Qianting , Feng Boxuan , Xin Henan , Zhang MingXia , Deng Qunyi , Deng Guofang , Shan Wanshui , Yue Jianrong , Zhang Haoran , Li Mufei , Li Hengjing , Jin Qi , Chen Xinchun , Gao Lei 
Published: June 2017

AbstractDuring China’s urbanization process, rural labor migrants have been suggested to be one important bridge population to change urban-rural distribution on tuberculosis (TB) burden. Aiming to estimate the prevalence of TB infection and to track the active disease development in rural labor migrants, a prospective study was conducted in Shenzhen city, southern China. TB infection was detected using interferon-γ release assay (IGRA). Here we mainly report the characteristics of TB infection in the study population based on the baseline survey. A total of 4,422 eligible participants completed baseline survey in July 2013. QuantiFERON (QFT) positivity rates 17.87% (790/4,422) and was found to be consistent with the local TB epidemic of the areas where the participants immigrated from. Age, smoking, residence registered place, and present of BCG scars were found to be independently associated with QFT positivity. Additionally, evidence for interaction between smoking and age was observed (p for likelihood ratio test < 0.001). Our results suggested that the development of TB control strategy including latent TB infection management should pay more attention to the rural flowing population due to their high mobility and higher prevalence of TB infection.
Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells
Authors: Metts Jonathan , Bradley Heath L. , Wang Zhengqi , Shah Neil P. , Kapur Reuben , Arbiser Jack L. , Bunting Kevin D. 
Published: June 2017

AbstractAberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200–300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75–150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML.
Hidden defensive morphology in rotifers: benefits, costs, and fitness consequences
Authors: Yin Xuwang , Jin Wen , Zhou Yanchun , Wang Peipei , Zhao Wen 
Published: June 2017

AbstractTo cope with predation, many prey species have developed inducible defenses in terms of morphology, behavior, and life history. Rotifers were the first model organisms used to evaluate the ecology and evolution of inducible defenses in aquatic ecosystems. Since the middle of last century, only visible morphological defenses, such as spine development, have been found and only in a few rotifer species. Given the development of ultrastructural defenses is taxonomically widespread in aquatic ecosystems, we hypothesize that rotifer prey, particularly small-sized species, can develop such inducible defenses. We evaluated morphological response of two common Brachionus herbivores (B. calyciflorus and B. angularis) to predatory rotifer Asplanchna brightwellii. Results confirmed existence of predator-induced ultrastructural defenses, which are expressed as increased lorica thickness and enhanced lorica hardness. Such inducible defenses are more evident and effective in the smaller sized B. angularis, leading to higher fitness of B. angularis in predator-prey interactions. As anticipated, development of defenses has inevitable fitness costs manifested as decreased reproduction or reduced sex investment. Our results not only extend understanding of inducible ultrastructural defense to other planktonic taxa that were previously observed only in cladocerans, but also verify effective mechanical protection of such hidden defensive morphology.