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- ArticleDu Z, Zhang W, Zhang D, Yu S, Hao Y.Sci Rep. 2016 11 16;6:36351.We explored the threshold effects of meteorological factors on hand, foot and mouth disease (HFMD) in mainland China to improve the prevention and early warning. Using HFMD surveillance and meteorological data in 2011, we identified the threshold effects of predictors on the monthly incidence of HFMD and predicted the high risk months, with classification and regression tree models (CART). The results of the classification tree showed that there was an 82.35% chance for a high risk of HFMD when the temperature was greater than 24.03 °C and the relative humidity was less than 60.9% during non-autumn seasons. According to the heatmap of high risk prediction, the HFMD incidence in most provinces was beyond the normal level during May to August. The results of regression tree showed that when the temperature was greater than 24.85 °C and the relative humidity was between 80.59% and 82.55%, the relative risk (RR) of HFMD was 3.49 relative to monthly average incidence. This study provided quantitative evidence for the threshold effects of meteorological factors on HFMD in China. The conditions of a temperature greater than 24.85 °C and a relative humidity between 80.59% and 82.55% would lead to a higher risk of HFMD.
- ArticleIQGAP1 protein regulates nuclear localization of β-catenin via importin-β5 protein in Wnt signaling.Goto T, Sato A, Adachi S, Iemura S, Natsume T, Shibuya H.J Biol Chem. 2013 Dec 20;288(51):36351-60.In the canonical Wnt signaling pathway, the translocation of β-catenin is important for the activation of target genes in the nucleus. However, the molecular mechanisms underlying its nuclear localization remain unclear. In the present study, we found IQGAP1 to be a regulator of β-catenin function via importin-β5. In Xenopus embryos, depletion of IQGAP1 reduced Wnt-induced nuclear accumulation of β-catenin and expression of Wnt target genes during early embryogenesis. Depletion of endogenous importin-β5 associated with IQGAP1 also reduced expression of Wnt target genes and the nuclear localization of IQGAP1 and β-catenin. Moreover, a small GTPase, Ran1, contributes to the nuclear translocation of β-catenin and the activation of Wnt target genes. These results suggest that IQGAP1 functions as a regulator of translocation of β-catenin in the canonical Wnt signaling pathway.
- ArticleBaysan M, Arbous MS, Mik EG, Juffermans NP, van der Bom JG.BMJ Open. 2020 05 17;10(5):e036351.INTRODUCTION: The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO2) in vivo at the bedside. MitoPO2might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study.
METHODS AND ANALYSIS: We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO2, which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods.
ETHICS AND DISSEMINATION: The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peer-reviewed journals and presented at scientific conferences.
TRIAL REGISTRATION NUMBER: NCT03092297. - ArticleTinoco LW, Da Silva A, Leite A, Valente AP, Almeida FC.J Biol Chem. 2002 Sep 27;277(39):36351-6.PW2 (HPLKQYWWRPSI) was selected from phage display libraries through an alternative panning method using living sporozoites of Eimeria acervulina as target. Synthetic PW2 shows anticoccidial activity against E. acervulina and Eimeria tenella with very low hemolytic activity. It also displays antifungal activity but no activity against bacteria. We present the solution structure of the PW2 bound to SDS micelles. In the absence of an interface, PW2 is in random coil conformation. In micelles, structural calculation shows that Trp-7 forms the hydrophobic core that is important for the peptide folding. Lys-4, Tyr-6, Trp-8, and Arg-9 are in the same surface, possibly facing the micelle interface. This possibility was supported by the fact that chemical shift differences for these residues were more pronounced when compared with PW2 in water and in SDS. PW2 gains structure upon binding to SDS micelles. Lys-4, Tyr-6, Trp-8, and Arg-9 were found to bind to the micelle. Trp-7, Trp-8, and Arg-9 composed the WW+ consensus found in the sequence of the peptides selected with the phage display technique against E. acervulina sporozoites. This suggested that Trp-7, Trp-8, and Arg-9 are probably key residues not only for the peptide interaction with SDS micelles but also for the interaction with E. acervulina sporozoites surface.
- ArticleWu JQ, Wang X, Beveridge NJ, Tooney PA, Scott RJ, Carr VJ, Cairns MJ.PLoS One. 2012;7(4):e36351.BACKGROUND: While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.
METHODOLOGY/PRINCIPAL FINDINGS: The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.
CONCLUSIONS: This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia. - ArticleBellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE, Lanzer M.J Biol Chem. 2014 Dec 26;289(52):36336-51.Mutations in the "chloroquine resistance transporter" (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest that PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT, which could be exploited to design potent inhibitors of this key mediator of drug resistance.
- ArticleOhashi K, Fujiwara S, Watanabe T, Kondo H, Kiuchi T, Sato M, Mizuno K.J Biol Chem. 2011 Oct 21;286(42):36340-51.Lamellipodium extension is crucial for cell migration and spreading. The rate of lamellipodium extension is determined by the balance between the rate of actin polymerization and the rate of actin retrograde flow. LIM kinase 1 (LIMK1) regulates actin dynamics by phosphorylating and inactivating cofilin, an actin-depolymerizing protein. We examined the role of LIMK1 in lamellipodium extension by measuring the rates of actin polymerization, actin retrograde flow, and lamellipodium extension using time-lapse imaging of fluorescence recovery after photobleaching. In the non-extending lamellipodia of active Rac-expressing N1E-115 cells, LIMK1 expression decelerated and LIMK1 knockdown accelerated actin retrograde flow. In the extending lamellipodia of neuregulin-stimulated MCF-7 cells, LIMK1 knockdown accelerated both the rate of actin polymerization and the rate of actin retrograde flow, but the accelerating effect on retrograde flow was greater than the effect on polymerization, thus resulting in a decreased rate of lamellipodium extension. These results indicate that LIMK1 has a dual role in regulating lamellipodium extension by decelerating actin retrograde flow and polymerization, and in MCF-7 cells endogenous LIMK1 contributes to lamellipodium extension by decelerating actin retrograde flow more effectively than decelerating actin polymerization.