The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder

In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844), Goldbeter and Koshland mathematically analyzed a reversible covalent modification system which is highly sensitive to the concentration of effectors. Its signal-response curve appears sigmoidal, constituting a biochemical switch. However, the switch behavior only emerges in the "zero-order region", i.e. when the signal molecule concentration is much lower than that of the substrate it modifies. In this work we showed that the switching behavior can also occur under comparable concentrations of signals and substrates, provided that the signal molecules catalyze the modification reaction in cooperation. We also studied the effect of dynamic disorders on the proposed biochemical switch, in which the enzymatic reaction rates, instead of constant, appear as stochastic functions of time. We showed that the system is robust to dynamic disorder at bulk concentration. But if the dynamic disorder is quasi-static, large fluctuations of the switch response behavior may be observed at low concentrations. Such fluctuation is relevant to many biological functions. It can be reduced by either increasing the conformation interconversion rate of the protein, or correlating the enzymatic reaction rates in the network.Comment: 23 pages, 4 figures, accepted by PLOS ON

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

Characteristics of transposable element exonization within human and mouse

Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs) revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.Comment: 11 pages, 4 figure

NR4A Gene Expression Is Dynamically Regulated in the Ventral Tegmental Area Dopamine Neurons and Is Related to Expression of Dopamine Neurotransmission Genes

The NR4A transcription factors NR4A1, NR4A2, and NR4A3 (also known as Nur77, Nurr1, and Nor1, respectively) share similar DNA-binding properties and have been implicated in regulation of dopamine neurotransmission genes. Our current hypothesis is that NR4A gene expression is regulated by dopamine neuron activity and that induction of NR4A genes will increase expression of dopamine neurotransmission genes. Eticlopride and γ-butyrolactone (GBL) were used in wild-type (+/+) and Nurr1-null heterozygous (+/−) mice to determine the mechanism(s) regulating Nur77 and Nurr1 expression. Laser capture microdissection and real-time PCR was used to measure Nurr1 and Nur77 mRNA levels in the ventral tegmental area (VTA). Nur77 expression was significantly elevated 1 h after both GBL (twofold) and eticlopride (fourfold). In contrast, GBL significantly decreased Nurr1 expression in both genotypes, while eticlopride significantly increased Nurr1 expression only in the +/+ mice. In a separate group of mice, haloperidol injection significantly elevated Nur77 and Nor1, but not Nurr1 mRNA in the VTA within 1 h and significantly increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression by 4 h. These data demonstrate that the NR4A genes are dynamically regulated in dopamine neurons with maintenance of Nurr1 expression requiring dopamine neuron activity while both attenuation of dopamine autoreceptors activation and dopamine neuronal activity combining to induce Nur77 expression. Additionally, these data suggest that induction of NR4A genes could regulate TH and DAT expression and ultimately regulate dopamine neurotransmission

Nicotine Dependence among Rural-Urban Migrants in China

<p>Abstract</p> <p>Background</p> <p>The complex mechanism of nicotine dependency makes it challenging to evaluate dependence or progress towards dependence. The aim of this study was to estimate nicotine dependence levels and identify determinants of dependence among Chinese rural-urban migrants.</p> <p>Methods</p> <p>Multi-stage systematic sampling was used to select 4,198 rural-urban migrants aged 18 years or older from three metropolises in China. A structured questionnaire was administered during face-to-face interviews. Nicotine dependence among participants was assessed by means of the six-item Mandarin Chinese Version of the Fagerström Test for Nicotine Dependence (CFTND). Determinants of dependence were analyzed using multivariate analysis of variance (MANOVA).</p> <p>Results</p> <p>Among 4,198 participants, estimated current, daily, and occasional smoking rates were 28.3%, 21.2%, and 7.1%, respectively. The CTFND score for the 894 daily smokers was 3.39(SD: 2.32). MANOVA showed that work type, age at first migration, length of migration, and number of cities ever lived were associated with nicotine dependence.</p> <p>Conclusion</p> <p>A migratory lifestyle is associated with nicotine dependence. Results could inform the design of tobacco control programs that target Chinese rural-urban migrant workers as a special at-risk population.</p

Study of B0(s)→K0Sh+h′− decays with first observation of B0s→K0SK±π∓ and B0s→K0Sπ+π−

A search for charmless three-body decays of B 0 and B0s mesons with a K0S meson in the final state is performed using the pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV recorded by the LHCb experiment. Branching fractions of the B0(s)→K0Sh+h′− decay modes (h (′) = π, K), relative to the well measured B0→K0Sπ+π− decay, are obtained. First observation of the decay modes B0s→K0SK±π∓ and B0s→K0Sπ+π− and confirmation of the decay B0→K0SK±π∓ are reported. The following relative branching fraction measurements or limits are obtained B(B0→K0SK±π∓)B(B0→K0Sπ+π−)=0.128±0.017(stat.)±0.009(syst.), B(B0→K0SK+K−)B(B0→K0Sπ+π−)=0.385±0.031(stat.)±0.023(syst.), B(B0s→K0Sπ+π−)B(B0→K0Sπ+π−)=0.29±0.06(stat.)±0.03(syst.)±0.02(fs/fd), B(B0s→K0SK±π∓)B(B0→K0Sπ+π−)=1.48±0.12(stat.)±0.08(syst.)±0.12(fs/fd)B(B0s→K0SK+K−)B(B0→K0Sπ+π−)∈[0.004;0.068]at90%CL

Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition

“The final publication is available at Springer via http://dx.doi.org/10.1007/s12678-013-0144-3”Composite materials made of porous SiO2 matrices filled with single-walled carbon nanotubes (SWCNTs) were deposited on electrodes by an electroassisted deposition method. The synthesized materials were characterized by several techniques, showing that porous silica prevents the aggregation of SWCNT on the electrodes, as could be observed by transmission electron microscopy and Raman spectroscopy. Different redox probes were employed to test their electrochemical sensing properties. The silica layer allows the permeation of the redox probes to the electrode surface and improves the electrochemical reversibility indicating an electrocatalytic effect by the incorporation of dispersed SWCNT into the silica films.This work was financed by the following research projects: MAT2010-15273 of the Spanish Ministerio de Economia y Competitividad and FEDER, PROMETEO/2013/038 of the GV, and CIVP16A1821 of the Fundacion Ramon Areces. Alonso Gamero-Quijano and David Salinas-Torres acknowledge Generalitat Valenciana (Santiago Grisolia Program) and Ministerio de Economia y Competitividad, respectively, for the funding of their research fellowships.Gamero-Quijano, A.; Huerta, F.; Salinas-Torres, D.; Morallón, E.; Montilla, F. (2013). Electrocatalytic performance of SiO2-SWCNT nanocomposites prepared by electroassisted deposition. Electrocatalysis. 4(4):259-266. https://doi.org/10.1007/s12678-013-0144-3S25926644P. Alivisatos, Nat. Biotechnol. 22, 47 (2004)S. Stankovich, D.A. Dikin, G.H. Dommett, K.M. Kohlhaas, E.J. Zimney, E.A. Stach, R.D. Piner, S.T. Nguyen, R.S. Ruoff, Nature 442, 282 (2006)D.W. Schaefer, R.S. Justice, Macromolecules 40, 8501 (2007)M. Endo, M.S. Strano, P.M. Ajayan, Carbon Nanotubes 111, 13 (2008)C.E. Banks, R.G. Compton, Analyst 131, 15 (2006)R.H. Baughman, A.A. Zakhidov, W.A. de Heer, Science 297, 787 (2002)Y.H. Lin, F. Lu, Y. Tu, Z.F. Ren, Nano Letters 4, 191 (2004)B.R. Azamian, J.J. Davis, K.S. Coleman, C.B. Bagshaw, M.L.H. Green, J. Am. Chem. Soc. 124, 12664 (2002)W. Yang, K. Ratinac, S. Ringer, P. Thordarson, J.G. Gooding, F. Braet, Angew. Chem. Int. Ed. 49, 2114 (2010)C.E. Banks, R.G. Compton, Analyst 130, 1232 (2005)L. Mazurenko, M. Etienne, O. Tananaiko, V. Zaitsev, A. Walcarius, Electrochim. Acta 83, 359 (2012)J.M.P. Paloma Yáñez-Sedeño, J. Riu, F.X. Rius, TrAC Trends in Analytical Chemistry 29, 939 (2010)Z.J. Wang, M. Etienne, S. Poller, W. Schuhmann, G.W. Kohring, V. Mamane, A. Walcarius, Electroanalysis 24, 376 (2012)R. Bandyopadhyaya, E. Nativ-Roth, O. Regev, R. Yerushalmi-Rozen, Nano Letters 2, 25 (2002)C. Park, Z. Ounaies, K.A. Watson, R.E. Crooks, J. Smith, S.E. Lowther, J.W. Connell, E.J. Siochi, J.S. Harrison, T.L.S. Clair, Chem. Phys. Lett. 364, 303 (2002)O. Matarredona, H. Rhoads, Z.R. Li, J.H. Harwell, L. Balzano, D.E. Resasco, Journal of Physical Chemistry B 107, 13357 (2003)L. Vaisman, H. Wagner, G. Marom, Advances in Colloid and Interface Science 128, 37 (2006)Y.C. Xing, Journal of Physical Chemistry B 108, 19255 (2004)J.J. Liang, Y. Huang, L. Zhang, Y. Wang, Y.F. Ma, T.Y. Guo, Y.S. Chen, Adv. Funct. Mater. 19, 2297 (2009)D. Salinas-Torres, F. Huerta, F. Montilla, E. Morallón, Electrochim. Acta 56, 2464 (2011)Z.F. Ren, Z.P. Huang, J.W. Xu, J.H. Wang, P. Bush, M.P. Siegal, P.N. Provencio, Science 282, 1105 (1998)W.Z. Li, S.S. Xie, L.X. Qian, B.H. Chang, B.S. Zou, W.Y. Zhou, R.A. Zhao, G. Wang, Science 274, 1701 (1996)M. Terrones, N. Grobert, J. Olivares, J.P. Zhang, H. Terrones, K. Kordatos, W.K. Hsu, J.P. Hare, P.D. Townsend, K. Prassides, A.K. Cheetham, H.W. Kroto, D.R.M. Walton, Nature 388, 52 (1997)R. Toledano, D. Mandler, Chem. Mater. 22, 3943 (2010)J.H. Rouse, Langmuir 21, 1055 (2005)X.B. Yan, B.K. Tay, Y. Yang, Journal of Physical Chemistry B 110, 25844 (2006)J. Lim, P. Malati, F. Bonet, B. Dunn, J. Electrochem. Soc. 154, A140 (2007)L.D. Zhu, C.Y. Tian, J.L. Zhai, R.L. Yang, Sensors and Actuators B-Chemical 125, 254 (2007)F. Montilla, M.A. Cotarelo, E. Morallón, J. Mater. Chem. 19, 305 (2009)D. Salinas-Torres, F. Montilla, F. Huerta, E. Morallón, Electrochim. Acta 56, 3620 (2011)T. Dobbins, R. Chevious, Y. Lvov, Polymers 3, 942 (2011)R. Esquembre, J.A. Poveda, C.R. Mateo, Journal of Physical Chemistry B 113, 7534 (2009)M.L. Ferrer, R. Esquembre, I. Ortega, C.R. Mateo, F. del Monte, Chem. Mater. 18, 554 (2006)M.J. O'Connell, S. Sivaram, S.K. Doorn, Physical Review B 69, 235415 (2004)C. Domingo, G. Santoro, Opt. Pura Apl 40, 175 (2007)M.S. Dresselhaus, G. Dresselhaus, R. Saito, A. Jorio, Physics Reports 409, 47 (2005)R.L. McCreery, Chem. Rev. 108, 2646 (2008)C.G. Zoski, in Handbook of Electrochemistry, 1st ed (Elsevier, Amsterdam, 2007

Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Barts and The London Trustees Studentship (SM), Marie Curie fellowships (MB, JD), Arthritis Research UK career development fellowship (JW), William Harvey Research Foundation grant (JW/RSS), Kidney Research UK fellowship (NSAP), Barts and The London Vacation Scholarship (ISN), Wellcome Trust senior fellowship (DWG), and a Wellcome Trust career development fellowship (RSS). This work forms part of the research themes contributing to the translational research portfolio of Barts and The London Cardiovascular Biomedical Research Unit, which is supported and funded by National Institute for Health Researc

FoxM1, a Forkhead Transcription Factor Is a Master Cell Cycle Regulator for Mouse Mature T Cells but Not Double Positive Thymocytes

FoxM1 is a forkhead box transcription factor and a known master regulator required for different phases of the cell cycle. In cell lines, FoxM1 deficient cells exhibit delayed S phase entry, aneuploidy, polyploidy and can't complete mitosis. In vivo, FoxM1 is expressed mostly in proliferating cells but is surprisingly also found in non-proliferating CD4+CD8+ double positive thymocytes. Here, we addressed the role of FoxM1 in T cell development by generating and analyzing two different lines of T-cell specific FoxM1 deficient mice. As expected, FoxM1 is required for proliferation of early thymocytes and activated mature T cells. Defective expression of many cell cycle proteins was detected, including cyclin A, cyclin B1, cdc2, cdk2, p27 and the Rb family members p107 and p130 but surprisingly not survivin. Unexpectedly, loss of FoxM1 only affects a few cell cycle proteins in CD4+CD8+ thymocytes and has little effect on their sensitivity to apoptosis and the subsequent steps of T cell differentiation. Thus, regulation of cell cycle genes by FoxM1 is stage- and context-dependent