bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of pyrrolopyrimidine derivative PP-13 as a novel microtubule-destabilizing agent with promising anticancer properties
Authors: Gilson Pauline , Josa-Prado Fernando , Beauvineau Claire , Naud-Martin Delphine , Vanwonterghem Laetitia , Mahuteau-Betzer Florence , Moreno Alexis , Falson Pierre , Lafanechère Laurence , Frachet Véronique , Coll Jean-Luc , Fernando Díaz Jose , Hurbin Amandine , Busser Benoit
Published: August 2017

Despite the emergence of targeted therapies and immunotherapy, chemotherapy remains the gold-standard for the treatment of most patients with solid malignancies. Spindle poisons that interfere with microtubule dynamics are commonly used in chemotherapy drug combinations. However, their troublesome side effects and the emergence of chemoresistance highlight the need for identifying alternative agents. We performed a high throughput cell-based screening and selected a pyrrolopyrimidine molecule (named PP-13). In the present study, we evaluated its anticancer properties in vitro and in vivo. We showed that PP-13 exerted cytotoxic effects on various cancer cells, including those resistant to current targeted therapies and chemotherapies. PP-13 induced a transient mitotic blockade by interfering with both mitotic spindle organization and microtubule dynamics and finally led to mitotic slippage, aneuploidy and direct apoptotic death. PP-13 was identified as a microtubule-targeting agent that binds directly to the colchicine site in β-tubulin. Interestingly, PP-13 overcame the multidrug-resistant cancer cell phenotype and significantly reduced tumour growth and metastatic invasiveness without any noticeable toxicity for the chicken embryo in vivo. Overall, PP-13 appears to be a novel synthetic microtubule inhibitor with interesting anticancer properties and could be further investigated as a potent alternative for the management of malignancies including chemoresistant ones.
Prerequisites for the acquisition of mammalian pathogenicity by influenza A virus with a prototypic avian PB2 gene
Authors: Lee Chung-Young , An Se-Hee , Kim Ilhwan , Go Du-Min , Kim Dae-Yong , Choi Jun-Gu , Lee Youn-Jeong , Kim Jae-Hong , Kwon Hyuk-Joon
Published: August 2017

The polymerase of avian influenza A virus (AIV) is a heterotrimer composed of PB2, PB1, and PA. PB2 plays a role in overcoming the host barrier; however, the genetic prerequisites for avian PB2 to acquire mammalian pathogenic mutations have not been well elucidated. Previously, we identified a prototypic avian PB2 that conferred non-replicative and non-pathogenic traits to a PR8-derived recombinant virus when it was used to infect mice. Here, we demonstrated that key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) of this prototypic avian PB2 increase the replication efficiency of recombinant PR8 virus carrying the mutated PB2 in both avian and mammalian hosts. The MVV mutations caused no weight loss in mice, but they did allow replication in infected lungs, and the viruses acquired fatal mammalian pathogenic mutations such as Q591R/K, E627K, or D701N in the infected lungs. The MVV mutations are located at the interfaces of the trimer and are predicted to increase the strength of this structure. Thus, gaining MVV mutations might be the first step for AIV to acquire mammalian pathogenicity. These results provide new insights into the evolution of AIV in birds and mammals.
Type 3 inositol 1,4,5-trisphosphate receptor is dispensable for sensory activation of the mammalian vomeronasal organ
Authors: Chamero Pablo , Weiss Jan , Alonso María Teresa , Rodríguez-Prados Macarena , Hisatsune Chihiro , Mikoshiba Katsuhiko , Leinders-Zufall Trese , Zufall Frank
Published: August 2017

Signal transduction in sensory neurons of the mammalian vomeronasal organ (VNO) involves the opening of the canonical transient receptor potential channel Trpc2, a Ca2+-permeable cation channel that is activated by diacylglycerol and inhibited by Ca2+-calmodulin. There has been a long-standing debate about the extent to which the second messenger inositol 1,4,5-trisphosphate (InsP3) and type 3 InsP3 receptor (InsP3R3) are involved in the opening of Trpc2 channels and in sensory activation of the VNO. To address this question, we investigated VNO function of mice carrying a knockout mutation in the Itpr3 locus causing a loss of InsP3R3. We established a new method to monitor Ca2+ in the endoplasmic reticulum of vomeronasal sensory neurons (VSNs) by employing the GFP-aequorin protein sensor erGAP2. We also performed simultaneous InsP3 photorelease and Ca2+ monitoring experiments, and analysed Ca2+ dynamics, sensory currents, and action potential or field potential responses in InsP3R3-deficient VSNs. Disruption of Itpr3 abolished or minimized the Ca2+ transients evoked by photoactivated InsP3, but there was virtually no effect on sensory activation of VSNs. Therefore, InsP3R3 is dispensable for primary chemoelectrical transduction in mouse VNO. We conclude that InsP3R3 is not required for gating of Trpc2 in VSNs.
MAPK1 of Leishmania donovani interacts and phosphorylates HSP70 and HSP90 subunits of foldosome complex
Authors: Kaur Pavneet , Garg Mansi , Hombach-Barrigah Antje , Clos Joachim , Goyal Neena
Published: August 2017

MAP kinases (MAPK) are the most downstream kinases in signal transduction cascades and regulate critical cellular activities such as cell proliferation, differentiation, mortality, stress response, and apoptosis. The Leishmania donovani MAPK1 (LdMAPK1) is involved in parasite viability and drug resistance, but its substrates have not been identified yet. Aiming to identify the possible targets(s) of LdMAPK1, we sought to isolate interacting partners by co-immunoprecipitation, gel electrophoresis and mass spectrometry. Out of fifteen analyzed protein bands, four were identified as subunits of the HSP90 foldosome complex, namely HSP 90, HSP70, STI and SGT. Western blot analysis not only confirmed that LdMAPK1 interacts with HSP70 and HSP90 but also demonstrated that MAPK1 abundance modulates their expression. The interaction is sensitive to treatment with AMTZD, a competitive ERK inhibitor. MAPK1 also displayed kinase activity with HSP90 or HSP70 as substrates. By phosphorylating HSPs in the foldosome complex, MAPK1 may regulate the stability and activity of the foldosome which in turn plays a pivotal role in the parasitic life cycle of L. donovani. Our study therefore implicates LdMAPK1 in the post-translational modification and possibly the regulation of heat shock proteins. Conversely, HSP90 and HSP70 are identified as the first substrates of LdMAPK1.
Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection
Authors: Di Paola Monica , Sani Cristina , Clemente Ann Maria , Iossa Anna , Perissi Eloisa , Castronovo Giuseppe , Tanturli Michele , Rivero Damariz , Cozzolino Federico , Cavalieri Duccio , Carozzi Francesca , De Filippo Carlotta , Torcia Maria Gabriella
Published: August 2017

Changes in cervico-vaginal microbiota with Lactobacillus depletion and increased microbial diversity facilitate human papillomavirus (HPV) infection and might be involved in viral persistence and cancer development. To define the microbial Community State Types (CSTs) associated with high-risk HPV−persistence, we analysed 55 cervico-vaginal samples from HPV positive (HPV+) women out of 1029 screened women and performed pyrosequencing of 16S rDNA. A total of 17 samples from age-matched HPV negative (HPV−) women were used as control. Clearance or Persistence groups were defined by recalling women after one year for HPV screening and genotyping. A CST IV subgroup, with bacterial genera such as Gardnerella, Prevotella, Megasphoera, Atopobium, frequently associated with anaerobic consortium in bacterial vaginosis (BV), was present at baseline sampling in 43% of women in Persistence group, and only in 7.4% of women in Clearance group. Atopobium genus was significantly enriched in Persistence group compared to the other groups. Sialidase-encoding gene from Gardnerella vaginalis, involved in biofilm formation, was significantly more represented in Persistence group compared to the other groups. Based on these data, we consider the CST IV-BV as a risk factor for HPV persistence and we propose Atopobium spp and sialidase gene from G. vaginalis as microbial markers of HPV−persistence.
Regulation of androgen receptor signaling by ubiquitination during folliculogenesis and its possible dysregulation in polycystic ovarian syndrome
Authors: Lim Jung Jin , Lima Patricia D. A. , Salehi Reza , Lee Dong Ryul , Tsang Benjamin K.
Published: August 2017

Although chronic hyperandrogenism suppresses antral follicular development, a phenomenon often observed in polycystic ovarian syndrome (PCOS), whether and how deregulation of androgen receptor (AR) signaling is involved, is not well understood. In the present study, we examined the role of ring finger protein 6 (RNF6) in AR ubiquitination and the possible dysregulation in the expression and actions of growth differentiation factor 9 (GDF9) and kit-ligand (Kitlg) in a chronic androgenized PCOS rat model. 5α-dihydrotestosterone (DHT) treatment in vivo inhibited antral follicle growth, a response mediated through increased RNF6 content, suppressed K63- but increased K48-linked AR ubiquitination as well as the mRNA expression and content of soluble KIT-L (sKitlg) and content of GDF9. These androgenic responses were attenuated by gonadotropin treatment in vivo. Growth of antral follicles from DHT-treated rats in vitro was significantly slower when compared to those of control but was significantly enhanced by exogenous GDF9, suggesting the DHT-induced antral follicular growth arrest is in part the results of GDF9 suppression. Our findings indicate how hyperandrogenism modulates RNF6 content and subsequently AR ubiquitination, resulting in antral follicle growth arrest in a chronically androgenized PCOS rat model.
Proteome-wide acetylation dynamics in human cells
Authors: Kori Yekaterina , Sidoli Simone , Yuan Zuo-Fei , Lund Peder J. , Zhao Xiaolu , Garcia Benjamin A.
Published: August 2017

Protein acetylation plays a critical role in biological processes by regulating the functions and properties of proteins. Thus, the study of protein acetylation dynamics is critical for understanding of how this modification influences protein stability, localization, and function. Here we performed a comprehensive characterization of protein acetylation dynamics using mass spectrometry (MS) based proteomics through utilization of 13C-glucose or D3-acetate, which are metabolized into acetyl-coA, labeling acetyl groups through subsequent incorporation into proteins. Samples were collected at eight time points to monitor rates and trends of heavy acetyl incorporation. Through this platform, we characterized around 1,000 sites with significantly increasing acetylation trends, which we clustered based on their rates of acetylation. Faster rates were enriched on proteins associated with chromatin and RNA metabolism, while slower rates were more typical on proteins involved with lipid metabolism. Among others, we identified sites catalyzed at faster rates with potential critical roles in protein activation, including the histone acetyltransferase p300 acetylated in its activation loop, which could explain self-acetylation as an important feedback mechanism to regulate acetyltransferases. Overall, our studies highlight the dynamic nature of protein acetylation, and how metabolism plays a central role in this regulation.
The EAL-domain protein FcsR regulates flagella, chemotaxis and type III secretion system in Pseudomonas aeruginosa by a phosphodiesterase independent mechanism
Authors: Rossello Jessica , Lima Analía , Gil Magdalena , Rodríguez Duarte Jorge , Correa Agustín , Carvalho Paulo C. , Kierbel Arlinet , Durán Rosario
Published: August 2017

The second messenger c-di-GMP regulates the switch between motile and sessile bacterial lifestyles. A general feature of c-di-GMP metabolism is the presence of a surprisingly large number of genes coding for diguanylate cyclases and phosphodiesterases, the enzymes responsible for its synthesis and degradation respectively. However, the physiological relevance of this apparent redundancy is not clear, emphasizing the need for investigating the functions of each of these enzymes. Here we focused on the phosphodiesterase PA2133 from Pseudomonas aeruginosa, an important opportunistic pathogen. We phenotypically characterized P. aeruginosa strain K overexpressing PA2133 or its inactive mutant. We showed that biofilm formation and motility are severely impaired by overexpression of PA2133. Our quantitative proteomic approach applied to the membrane and exoprotein fractions revealed that proteins involved in three processes were mostly affected: flagellar motility, type III secretion system and chemotaxis. While inhibition of biofilm formation can be ascribed to the phosphodiesterase activity of PA2133, down-regulation of flagellar, chemotaxis, and type III secretion system proteins is independent of this enzymatic activity. Based on these unexpected effects of PA2133, we propose to rename this gene product FcsR, for Flagellar, chemotaxis and type III secretion system Regulator.
Vacancies, disorder-induced smearing of the electronic structure, and its implications for the superconductivity of anti-perovskite MgC0.93Ni2.85
Authors: Ernsting David , Billington David , Millichamp Thomas E. , Edwards Rebecca A. , Sparkes Hazel A. , Zhigadlo Nikolai D. , Giblin Sean R. , Taylor Jonathan W. , Duffy Jonathan A. , Dugdale Stephen B.
Published: August 2017

The anti-perovskite superconductor MgC0.93Ni2.85 was studied using high-resolution x-ray Compton scattering combined with electronic structure calculations. Compton scattering measurements were used to determine experimentally a Fermi surface that showed good agreement with that of our supercell calculations, establishing the presence of the predicted hole and electron Fermi surface sheets. Our calculations indicate that the Fermi surface is smeared by the disorder due to the presence of vacancies on the C and Ni sites, but does not drastically change shape. The 20% reduction in the Fermi level density-of-states would lead to a significant (~70%) suppression of the superconducting T
c
for pair-forming electron-phonon coupling. However, we ascribe the observed much smaller T
c
reduction at our composition (compared to the stoichiometric compound) to the suppression of pair-breaking spin fluctuations.
Deficiency of TLR4 homologue RP105 aggravates outward remodeling in a murine model of arteriovenous fistula failure
Authors: Bezhaeva Taisiya , Wong ChunYu , de Vries Margreet R. , van der Veer Eric P. , van Alem Carla M. A. , Que Ivo , Lalai Reshma A. , van Zonneveld Anton-Jan , Rotmans Joris I. , Quax Paul H. A.
Published: August 2017

Arteriovenous access dysfunction is a major cause of morbidity for hemodialysis patients. The pathophysiology of arteriovenous fistula (AVF) maturation failure is associated with inflammation, impaired outward remodeling (OR) and intimal hyperplasia. RP105 is a critical physiologic regulator of TLR4 signaling in numerous cell types. In the present study, we investigated the impact of RP105 on AVF maturation, and defined cell-specific effects of RP105 on macrophages and vascular smooth muscle cells (VSMCs). Overall, RP105−/− mice displayed a 26% decrease in venous OR. The inflammatory response in RP105−/− mice was characterized by accumulation of anti-inflammatory macrophages, a 76% decrease in pro- inflammatory macrophages, a 70% reduction in T-cells and a 50% decrease in MMP-activity. In vitro, anti-inflammatory macrophages from RP105−/− mice displayed increased IL10 production, while MCP1 and IL6 levels secreted by pro-inflammatory macrophages were elevated. VSMC content in RP105−/− AVFs was markedly decreased. In vitro, RP105−/− venous VSMCs proliferation was 50% lower, whereas arterial VSMCs displayed a 50% decrease in migration, relative to WT. In conclusion, the impaired venous OR in RP105−/− mice could result from of a shift in both macrophages and VSMCs towards a regenerative phenotype, identifying a novel relationship between inflammation and VSMC function in AVF maturation.
Trichel pulse in various gases and the key factor for its formation
Authors: Zhang Yu , Xia Qing , Jiang Zhaorui , Ouyang Jiting
Published: August 2017

We confirm in this paper that Trichel pulse of negative corona is a common phenomenon that can occur in various gases rather than only in electronegative gases as considered in the last 70 years since G W Trichel firstly reported. Trichel pulse is exactly a mode transition between low-current Townsend and high-current normal glow regime, two pulseless stages of negative corona with different operating conditions and ion flux threshold. The rising of the pulse corresponds to the breakdown and formation of temporal glow discharge, the decay corresponds to the destroy of temporal sheath, and the interval (or repetition frequency of pulses) is determined by the re-building of the positive ion cloud to enhance significantly the local electric field for glow discharge to form again. The positive ions play a predominant role for the pulse formation and the mode transition, while the negative ions in electronegative gas are not necessary even if they affect greatly the pulsing process.
Damaged fiber tracts of the nucleus basalis of Meynert in Parkinson’s disease patients with visual hallucinations
Authors: Hepp Dagmar H. , Foncke Elisabeth M. J. , Berendse Henk W. , Wassenaar Thomas M. , Olde Dubbelink Kim T. E. , Groenewegen Henk J. , D.J. van de Berg Wilma , Schoonheim Menno M.
Published: August 2017

Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson’s disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD − VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD − VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients.
Development of gold nanoparticle-aptamer-based LSPR sensing chips for the rapid detection of Salmonella typhimurium in pork meat
Authors: Oh Seo Yeong , Heo Nam Su , Shukla Shruti , Cho Hye-Jin , Vilian A. T. Ezhil , Kim Jinwoon , Lee Sang Yup , Han Young-Kyu , Yoo Seung Min , Huh Yun Suk
Published: August 2017

A non-labeled, portable plasmonic biosensor-based device was developed to enable the ultra-sensitive and selective detection of Salmonella typhimurium in pork meat samples. Specifically, a plasmonic sensor, using the self-assembly of gold nanoparticles (AuNPs) to achieve a regulated diameter of 20 nm for the AuNP monolayers, was used to conduct high-density deposition on a transparent substrate, which produced longitudinal wavelength extinction shifts via a localized surface plasmon resonance (LSPR) signal. The developed aptamers conjugated to the LSPR sensing chips revealed an ultra-sensitive upper limit of detection (LOD) of approximately 104 cfu/mL for S. typhimurium in pure culture under the optimal assay conditions, with a total analysis time of 30–35 min. When the LSPR sensing chips were applied on artificially contaminated pork meat samples, S. typhimurium in the spiked pork meat samples was also detected at an LOD of 1.0 × 104 cfu/mL. The developed method could detect S. typhimurium in spiked pork meat samples without a pre-enrichment step. Additionally, the LSPR sensing chips developed against S. typhimurium were not susceptible to any effect of the food matrix or background contaminant microflora. These findings confirmed that the developed gold nanoparticle-aptamer-based LSPR sensing chips could facilitate sensitive detection of S. typhimurium in food samples.
Characterization of a core region in the A2UCOE that confers effective anti-silencing activity
Authors: Zhang Fang , Santilli Giorgia , Thrasher Adrian J.
Published: August 2017

We have previously shown that reliability of the A2UCOE in driving transgene expression can be attributed to its resistance to DNA methylation, and its ability to confer this property to linked regulatory sequences. In order to gain a better understanding of how resistance to DNA methylation from the A2UCOE is conferred, and whether the anti-silencing effect from the A2UCOE is confined within a core region, we evaluated the anti-silencing effect of different sub-domains. We found that maximal epigenetic regulatory activity was contained within a 455 bp element derived from the CBX3 region when tested in the context of a lentiviral vector in murine embryonic stem (ES) cells and human inducible pluripotent stem (iPS) cells. This region possessed an active chromatin signature, and operated effectively in cis to protect linked heterologous regulatory elements from methylation, thereby conferring stable transgene expression. Defined UCOE elements may be particularly useful for use in vectors where gene expression is desired in methylation-prone chromatin environments such as those encountered in pluripotent stem cells.
Surface frontogenesis by surface heat fluxes in the upstream Kuroshio Extension region
Authors: Tozuka Tomoki , Cronin Meghan F. , Tomita Hiroyuki
Published: August 2017

Western boundary currents bring warm tropical water poleward and eastward and are characterized by a sharp sea surface temperature (SST) front on the poleward edge of the current as it extends into the interior basin. One of the most prominent such front is associated with the Kuroshio Extension (KE) as it extends east of Japan (“upstream KE”). Large latent and sensible heat fluxes that warm the atmosphere and cool the ocean project this front into the atmosphere, thereby affecting weather and climate both locally and remotely. While one might assume that these larger surface heat fluxes on the equatorward side would tend to damp the SST front, here we present observational evidence that the surface heat loss actually strengthens the front during October-April in monthly climatology and about 87% of months from October to January during the 2004/05–2014/15 period, although the percentage lowers to about 38% for February-April of the same period, suggesting some temporal/data dependency in the analysis. The key to understanding this counterintuitive result for frontogenesis is that the effective heat capacity of the surface water depends on mixed layer thickness. SSTs are more (less) sensitive to surface heat fluxes in regions with shallow (deep) mixed layer.
An Investigation on Attributes of Ambient Temperature and Diurnal Temperature Range on Mortality in Five East-Asian Countries
Authors: Lee Whan-Hee , Lim Youn-Hee , Dang Tran Ngoc , Seposo Xerxes , Honda Yasushi , Guo Yue-Liang Leon , Jang Hye-Min , Kim Ho
Published: August 2017

Interest in the health effects of extremely low/high ambient temperature and the diurnal temperature range (DTR) on mortality as representative indices of temperature variability is growing. Although numerous studies have reported on these indices independently, few studies have provided the attributes of ambient temperature and DTR related to mortality, concurrently. In this study, we aimed to investigate and compare the mortality risk attributable to ambient temperature and DTR. The study included data of 63 cities in five East-Asian countries/regions during various periods between 1972 and 2013. The attributable risk of non-accidental death to ambient temperature was 9.36% (95% confidence interval [CI]: 8.98–9.69%) and to DTR was 0.59% (95% CI: 0.53–0.65%). The attributable cardiovascular mortality risks to ambient temperature (15.63%) and DTR (0.75%) are higher than the risks to non-accidental/respiratory-related mortality. We verified that ambient temperature plays a larger role in temperature-associated mortality, and cardiovascular mortality is susceptible to ambient temperature and DTR.
Pathogenic lineage of Perkinsea associated with mass mortality of frogs across the United States
Authors: Isidoro-Ayza Marcos , Lorch Jeffrey M. , Grear Daniel A. , Winzeler Megan , Calhoun Daniel L. , Barichivich William J.
Published: August 2017

Emerging infectious diseases such as chytridiomycosis and ranavirus infections are important contributors to the worldwide decline of amphibian populations. We reviewed data on 247 anuran mortality events in 43 States of the United States from 1999–2015. Our findings suggest that a severe infectious disease of tadpoles caused by a protist belonging to the phylum Perkinsea might represent the third most common infectious disease of anurans after ranavirus infections and chytridiomycosis. Severe Perkinsea infections (SPI) were systemic and led to multiorganic failure and death. The SPI mortality events affected numerous anuran species and occurred over a broad geographic area, from boreal to subtropical habitats. Livers from all PCR-tested SPI-tadpoles (n = 19) were positive for the Novel Alveolate Group 01 (NAG01) of Perkinsea, while only 2.5% histologically normal tadpole livers tested positive (2/81), suggesting that subclinical infections are uncommon. Phylogenetic analysis demonstrated that SPI is associated with a phylogenetically distinct clade of NAG01 Perkinsea. These data suggest that this virulent Perkinsea clade is an important pathogen of frogs in the United States. Given its association with mortality events and tendency to be overlooked, the potential role of this emerging pathogen in amphibian declines on a broad geographic scale warrants further investigation.
A promising azeotrope-like mosquito repellent blend
Authors: Izadi Homa , Focke Walter W , Asaadi Erfan , Maharaj Rajendra , Pretorius Jannie , Loots Mattheüs Theodor
Published: August 2017

Topical repellents play a key role in reducing the outdoor transmission of mosquito-borne diseases by reducing human-vector contact. Excellent repellents are available, but there is always room for improvement. This article reports on a particularly effective binary repellent blend of ethyl butylacetylaminopropionate and nonanoic acid. A composition containing 25 mol% of the acid exhibits negative pseudo-azeotrope behaviour at 50 °C, meaning that the liquid vapour pressure is lower than that of the parent compounds and evaporation occurs without a change in the liquid composition. In tests performed using the South African Medical Research Council’s cup-on-arm procedure, this mixture provided better protection for a longer time than the “gold standard of mosquito repellents”, namely N,N-diethyl-m-toluamide, commonly known as DEET.
Development and validation of a multivariate predictive model for rheumatoid arthritis mortality using a machine learning approach
Authors: Lezcano-Valverde José M. , Salazar Fernando , León Leticia , Toledano Esther , Jover Juan A. , Fernandez-Gutierrez Benjamín , Soudah Eduardo , González-Álvaro Isidoro , Abasolo Lydia , Rodriguez-Rodriguez Luis
Published: August 2017

We developed and independently validated a rheumatoid arthritis (RA) mortality prediction model using the machine learning method Random Survival Forests (RSF). Two independent cohorts from Madrid (Spain) were used: the Hospital Clínico San Carlos RA Cohort (HCSC-RAC; training; 1,461 patients), and the Hospital Universitario de La Princesa Early Arthritis Register Longitudinal study (PEARL; validation; 280 patients). Demographic and clinical-related variables collected during the first two years after disease diagnosis were used. 148 and 21 patients from HCSC-RAC and PEARL died during a median follow-up time of 4.3 and 5.0 years, respectively. Age at diagnosis, median erythrocyte sedimentation rate, and number of hospital admissions showed the higher predictive capacity. Prediction errors in the training and validation cohorts were 0.187 and 0.233, respectively. A survival tree identified five mortality risk groups using the predicted ensemble mortality. After 1 and 7 years of follow-up, time-dependent specificity and sensitivity in the validation cohort were 0.79–0.80 and 0.43–0.48, respectively, using the cut-off value dividing the two lower risk categories. Calibration curves showed overestimation of the mortality risk in the validation cohort. In conclusion, we were able to develop a clinical prediction model for RA mortality using RSF, providing evidence for further work on external validation.
Telemonitoring in fasting individuals with Type 2 Diabetes Mellitus during Ramadan: A prospective, randomised controlled study
Authors: Lee Jun Yang , Wong Chee Piau , Tan Christina San San , Nasir Nazrila Hairizan , Lee Shaun Wen Huey
Published: August 2017

We determined the impact of a remote blood glucose telemonitoring program with feedback in type 2 diabetes mellitus patients fasting during Ramadan compared to conventional self-monitoring method. A twelve-week cluster randomised study, with 85 participants who wish to fast for at least 15 days during Ramadan was conducted. Self-measurement and transmission of blood glucose results were performed six times daily during Ramadan. Results were transmitted to a secure website for review with feedback from case manager if necessary. The control group received usual care. The main outcome was the number of participants experiencing hypoglycaemia during Ramadan and at the end of the study. During Ramadan, the number of participants reporting hypoglycaemia was significantly lower in the telemonitoring group [Odds ratio (OR): 0.186, 95% confidence interval: 0.04–0.936; p = 0.04]. Similarly, the proportion of participants reporting symptomatic hypoglycaemia at the end of the study was significantly lower in the telemonitoring group (OR: 0.257, 95% CI: 0.07–0.89; p = 0.03). A reduction of 1.07% in glycated haemoglobin levels was observed in the telemonitoring group compared to 0.24% in the control group (p < 0.01). Overall, telemonitoring was a useful adjunct to reduce the risk of hypoglycaemia during Ramadan with no deterioration in glycaemic control
Free-Space Nonlinear Beam Combining for High Intensity Projection
Authors: Rostami Fairchild Shermineh , Walasik Wiktor , Kepler Daniel , Baudelet Matthieu , Litchinitser Natalia M. , Richardson Martin
Published: August 2017

The controlled interaction of two high intensity beams opens new degrees of freedom for manipulating electromagnetic waves in air. The growing number of applications for laser filaments requires fine control of their formation and propagation. We demonstrate, experimentally and theoretically, that the attraction and fusion of two parallel ultrashort beams with initial powers below the critical value (70% Pcritical), in the regime where the non-linear optical characteristics of the medium become dominant, enable the eventual formation of a filament downstream. Filament formation is delayed to a predetermined distance in space, defined by the initial separation between the centroids, while still enabling filaments with controllable properties as if formed from a single above-critical power beam. This is confirmed by experimental and theoretical evidence of filament formation such as the individual beam profiles and the supercontinuum emission spectra associated with this interaction.
Activation of the peripheral immune system regulates neuronal aromatase in the adult zebra finch brain
Authors: Pedersen Alyssa L. , Gould Cassie J. , Saldanha Colin J.
Published: August 2017

Estradiol provision via neural aromatization decreases neuro-inflammation and –degeneration, but almost nothing is known about the interactions between the peripheral immune system and brain aromatase. Given the vulnerability of the CNS we reasoned that brain aromatization may protect circuits from the threats of peripheral infection; perhaps shielding cells that are less resilient from the degeneration associated with peripheral infection or trauma. Lipopolysaccharide (LPS) or vehicle was administered peripherally to adult zebra finches and sickness behavior was recorded 2 or 24 hours later. The central transcription of cytokines and aromatase was measured, as were telencephalic aromatase activity and immunoreactive aromatase (24 hour time point only). Two hours post LPS, sickness-like behaviors increased, the transcription of IL-1β was higher in both sexes, and TNFα was elevated in females. 24 hours post-LPS, the behavior of LPS birds was similar to controls, and cytokines had returned to baseline, but aromatase mRNA and activity were elevated in both sexes. Immunocytochemistry revealed greater numbers of aromatase-expressing neurons in LPS birds. These data suggest that the activation of the immune system via peripheral endotoxin increases neuronal aromatase; a mechanism that may rapidly generate a potent anti-neuroinflammatory steroid in response to peripheral activation of the immune system.
Condensation Mechanism of Hydrocarbon Field Formation
Authors: Batalin Oleg , Vafina Nailya
Published: August 2017

Petroleum geology explains how hydrocarbon fluids are generated, but there is a lack of understanding regarding how oil is expelled from source rocks and migrates to a reservoir. To clarify the process, the multi-layer Urengoy field in Western Siberia was investigated. Based on this example, we have identified an alternative mechanism of hydrocarbon field formation, in which oil and gas accumulations result from the phase separation of an upward hydrocarbon flow. There is evidence that the flow is generated by the gases released by secondary kerogen destruction. This study demonstrates that oil components are carried by the gas flow and that when the flow reaches a low-pressure zone, it condenses into a liquid with real oil properties. The transportation of oil components in the gas flow provides a natural explanation for the unresolved issues of petroleum geology concerning the migration process. The condensation mechanism can be considered as the main process of oil field formation.
SIRT1 rs10823108 and FOXO1 rs17446614 responsible for genetic susceptibility to diabetic nephropathy
Authors: Zhao Yanyan , Wei Junfang , Hou Xuefeng , Liu Huimiao , Guo Feng , Zhou Yingni , Zhang Yuanyuan , Qu Yunhui , Gu Junfei , Zhou Yuanli , Jia Xiaobin , Qin Guijun , Feng Liang
Published: August 2017

SIRT1 and FOXO1 play an important role in the pathogenesis of diabetic nephropathy (DN). However, the association between genetic polymorphisms and susceptibility to type 2 DN (T2DN) has not been explored. In this study, a total of 1066 patients with type 2 diabetes mellitus (T2DM) (413 without and 653 with DN) were enrolled. The genotypes of three htSNPs (rs3818292, rs4746720, rs10823108) within SIRT1 and two htSNPs (rs2721068, rs17446614) in FOXO1 were determined by PCR-RFLP. HbA1C, LDL, HDL, TC, and TG levels were also examined. SIRT1 rs10823108 AA genotype was significantly associated with a decreased risk of DN (OR = 0.60, 95%CI: 0.38–0.97), while GA genotype (OR = 1.77, 95%CI: 1.33–2.35) and AA genotype (OR = 2.32, 95%CI: 1.25–4.34) of FOXO1 rs17446614 was associated with an increased T2DN risk. The interactions among rs1744 6614, BMI and duration of diabetes (OR: 2.63, 95%CI: 1.23–4.31) were also observed. Subsequent haplotype analysis revealed that two haplotype defined by AC (OR: 1.50, 95%CI: 1.15–1.94) and AT (OR: 1.79, 95%CI: 1.06–2.80) within FOXO1 gene may increase the risk of T2DN. In conclusion, genetic variant rs10823108 in SIRT1 and variant rs17446614 in FoxO1 may contribute to the risk of DN in T2DM patients.
Indirect immobilized Jagged1 suppresses cell cycle progression and induces odonto/osteogenic differentiation in human dental pulp cells
Authors: Manokawinchoke Jeeranan , Nattasit Praphawi , Thongngam Tanutchaporn , Pavasant Prasit , Tompkins Kevin A. , Egusa Hiroshi , Osathanon Thanaphum
Published: August 2017

Notch signaling regulates diverse biological processes in dental pulp tissue. The present study investigated the response of human dental pulp cells (hDPs) to the indirect immobilized Notch ligand Jagged1 in vitro. The indirect immobilized Jagged1 effectively activated Notch signaling in hDPs as confirmed by the upregulation of HES1 and HEY1 expression. Differential gene expression profiling using an RNA sequencing technique revealed that the indirect immobilized Jagged1 upregulated genes were mainly involved in extracellular matrix organization, disease, and signal transduction. Downregulated genes predominantly participated in the cell cycle, DNA replication, and DNA repair. Indirect immobilized Jagged1 significantly reduced cell proliferation, colony forming unit ability, and the number of cells in S phase. Jagged1 treated hDPs exhibited significantly higher ALP enzymatic activity, osteogenic marker gene expression, and mineralization compared with control. Pretreatment with a γ-secretase inhibitor attenuated the Jagged1-induced ALP activity and mineral deposition. NOTCH2 shRNA reduced the Jagged1-induced osteogenic marker gene expression, ALP enzymatic activity, and mineral deposition. In conclusion, indirect immobilized Jagged1 suppresses cell cycle progression and induces the odonto/osteogenic differentiation of hDPs via the canonical Notch signaling pathway.
A membrane-inserted structural model of the yeast mitofusin Fzo1
Authors: De Vecchis Dario , Cavellini Laetitia , Baaden Marc , Hénin Jérôme , Cohen Mickaël M. , Taly Antoine
Published: August 2017

Mitofusins are large transmembrane GTPases of the dynamin-related protein family, and are required for the tethering and fusion of mitochondrial outer membranes. Their full-length structures remain unknown, which is a limiting factor in the study of outer membrane fusion. We investigated the structure and dynamics of the yeast mitofusin Fzo1 through a hybrid computational and experimental approach, combining molecular modelling and all-atom molecular dynamics simulations in a lipid bilayer with site-directed mutagenesis and in vivo functional assays. The predicted architecture of Fzo1 improves upon the current domain annotation, with a precise description of the helical spans linked by flexible hinges, which are likely of functional significance. In vivo site-directed mutagenesis validates salient aspects of this model, notably, the long-distance contacts and residues participating in hinges. GDP is predicted to interact with Fzo1 through the G1 and G4 motifs of the GTPase domain. The model reveals structural determinants critical for protein function, including regions that may be involved in GTPase domain-dependent rearrangements.
Age-related processing delay reveals cause of apparent sensory excitability following auditory stimulation
Authors: Volosin Márta , Gaál Zsófia Anna , Horváth János
Published: August 2017

When background auditory events lead to enhanced auditory event-related potentials (ERPs) for closely following sounds, this is generally interpreted as a transient increase in the responsiveness of the auditory system. We measured ERPs elicited by irrelevant probes (gaps in a continuous tone) at several time-points following rare auditory events (pitch glides) in younger and older adults, who watched movies during stimulation. Fitting previous results, in younger adults, gaps elicited increasing N1 auditory ERPs with decreasing glide-gap separation. N1 increase was paralleled by an ERP decrease in the P2 interval. In older adults, only a glide-gap separation dependent P2 decrease, but no N1-effect was observable. This ERP pattern was likely caused by a fronto-central negative waveform, which was delayed in the older adult group, thus overlapping N1 and P2 in the younger, but overlapping only P2 in the older adult group. Because the waveform exhibited a polarity reversal at the mastoids, it was identified as a mismatch negativity (MMN). This interpretation also fits previous studies showing that gap-related MMN is delayed in older adults, reflecting an age-related deterioration of fine temporal auditory resolution. These results provide a plausible alternative explanation for the ERP enhancement for sounds following background auditory events.
Understanding stability diagram of perpendicular magnetic tunnel junctions
Authors: Skowroński Witold , Czapkiewicz Maciej , Ziętek Sławomir , Chęciński Jakub , Frankowski Marek , Rzeszut Piotr , Wrona Jerzy
Published: August 2017

Perpendicular magnetic tunnel junctions (MTJ) with a bottom pinned reference layer and a composite free layer (FL) are investigated. Different thicknesses of the FL were tested to obtain an optimal balance between tunneling magnetoresistance (TMR) ratio and perpendicular magnetic anisotropy. After annealing at 400 °C, the TMR ratio for 1.5 nm thick CoFeB sublayer reached 180% at room temperature and 280% at 20 K with an MgO tunnel barrier thickness corresponding to the resistance area product RA = 10 Ohmμm2. The voltage vs. magnetic field stability diagrams measured in pillar-shaped MTJs with 130 nm diameter indicate the competition between spin transfer torque (STT), voltage controlled magnetic anisotropy (VCMA) and temperature effects in the switching process. An extended stability phase diagram model that takes into account all three effects and the effective damping measured independently using broadband ferromagnetic resonance technique enabled the determination of both STT and VCMA coefficients that are responsible for the FL magnetization switching.
Insect-bacteria parallel evolution in multiple-co-obligate-aphid association: a case in Lachninae (Hemiptera: Aphididae)
Authors: Chen Rui , Wang Zhe , Chen Jing , Jiang Li-Yun , Qiao Ge-Xia
Published: August 2017

Parallel phylogenies between aphid and its obligate symbiontBuchneraare hot topics which always focused on aphid lower taxonomic levels. Symbionts in the subfamily Lachninae are special.Buchnerain many lachnine species has undergone functional and genome size reduction that was replaced by other co-obligate symbionts. In this study, we constructed the phylogenetic relationships of Lachninae with a combined dataset of five genes sequenced fromBuchnerato estimate the effects of a dual symbiotic system in the aphid-Buchneracospeciation association. The phylogeny ofBuchnerain Lachninae was well-resolved in the combined dataset. Each of the genera formed strongly supported monophyletic groups, with the exception of the genusCinara. The phylogeny based on sequences fromBuchnerawas divided into five tribes according to the clades of the Lachninae hosts tree, with the phylogenies ofBuchneraand Lachninae being generally congruent. These results first provided evidence of parallel evolution at the aphid subfamily level comprehensively and supported the view that topological congruence between the phylogenies ofBuchneraand Lachninae would not be interfered with the other co-obligate symbionts, such asSarretia, in aphid-entosymbiont association. These results also provided new insight in understanding host-plant coevolution in lachnine lineages.
Stress buildup and drop in inland shallow crust caused by the 2011 Tohoku-oki earthquake events
Authors: Sakaguchi Kiyotoshi , Yokoyama Tatsuya , Lin Weiren , Watanabe Noriaki
Published: August 2017

To examine the change in stress between before and after the Tohoku-oki Mw9.0 earthquake, we performed stress measurements after the earthquake in the Kamaishi mine in Iwate prefecture in northern Japan, located near the northern termination of the mainshock rupture, following previous measurements before the earthquake in the same mine. The results showed that the magnitudes of the three-dimensional principal stresses and the vertical stress drastically increased after the mainshock and, at 1 year after the earthquake, were more than double those before the earthquake. The principal stress magnitudes then decreased with time and returned to almost pre-earthquake levels at about 3 years after the earthquake. These changes can be interpreted in terms of coseismic rupture of the mainshock and the occurrence of aftershocks in the Sanriku-oki low-seismicity region (SLSR), where the Kamaishi mine is located. The drastic increase in stress suggests that the SLSR may act as a barrier to further rupture propagation.
Long intergenic non-coding RNA GALMD3 in chicken Marek’s disease
Authors: Han Bo , He Yanghua , Zhang Li , Ding Yi , Lian Ling , Zhao Chunfang , Song Jiuzhou , Yang Ning
Published: August 2017

Long intergenic non-coding RNAs (lincRNAs) are transcribed from non-coding DNA sequences. Studies have revealed that aberrant expressions of lincRNAs are associated with various types of cancers and neurological disorders. Marek’s disease (MD) is a highly contagious T-cell lymphoid neoplasia of chicken induced by Marek’s disease virus (MDV). In this study, we first identified and validated linc-GALMD3 highly expressed in MDV-infected CD4+ T cells by RNA-Seq and qRT-PCR. By RNA-Seq analysis in MDCC-MSB1 cells after loss of function of linc-GALMD3 by shRNA, we found that linc-GALMD3 could positively cis-regulate its downstream gga-miR-223 gene expression. In contrast, it could trans-regulate the 748 differentially expressed genes (FDR < 0.01) that were mainly enriched into mitochondrial structure and cell cycle processes using GO analysis. Of these, the most significantly expressed gene EPYC might cause iris lesion in MD. The other eight genes, NDUFA4, NDUFB6, NDUFV1, NDUFS8, SDHB, UQCRC1, UQCRC2, and COX7A2, actively participated in oxidative phosphorylation in mitochondrial dysfunction and cell death. Most importantly, we found that the MDV replication was repressed when linc-GALMD3 was knocked down in CEF cells. Our results suggested that linc-GALMD3 might be a critical regulator in chicken MD and could be used as a candidate-promising mark for MD prevention, diagnosis, and treatment.
1α,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis
Authors: Lin Zongtao , Chen Hao , Belorusova Anna Y. , Bollinger John C. , Tang Edith K. Y. , Janjetovic Zorica , Kim Tae-Kang , Wu Zhongzhi , Miller Duane D. , Slominski Andrzej T. , Postlethwaite Arnold E. , Tuckey Robert C. , Rochel Natacha , Li Wei
Published: August 2017

1α,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents.