Coupled Reversible and Irreversible Bistable Switches Underlying TGF-\beta-induced Epithelial to Mesenchymal Transition

Epithelial to mesenchymal transition (EMT) plays important roles in embryonic development, tissue regeneration and cancer metastasis. While several feedback loops have been shown to regulate EMT, it remains elusive how they coordinately modulate EMT response to TGF-\beta treatment. We construct a mathematical model for the core regulatory network controlling TGF-\beta-induced EMT. Through deterministic analyses and stochastic simulations, we show that EMT is a sequential two-step program that an epithelial cell first transits to partial EMT then to the mesenchymal state, depending on the strength and duration of TGF-\beta stimulation. Mechanistically the system is governed by coupled reversible and irreversible bistable switches. The SNAIL1/miR-34 double negative feedback loop is responsible for the reversible switch and regulates the initiation of EMT, while the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the establishment of the mesenchymal state. Furthermore, an autocrine TGF-\beta/miR-200 feedback loop makes the second switch irreversible, modulating the maintenance of EMT. Such coupled bistable switches are robust to parameter variation and molecular noise. We provide a mechanistic explanation on multiple experimental observations. The model makes several explicit predictions on hysteretic dynamic behaviors, system response to pulsed stimulation and various perturbations, which can be straightforwardly tested.Comment: 32 pages, 8 figures, accepted by Biophysical Journa

New pre-catalysts derived from calixarenes : synthesis, structural and polymerization studies

In this thesis, a series of V, Ti, Li and Pb compounds have been synthesized and fully characterized. The catalytic performance of these pre-catalysts towards different polymerization reactions, including ring opening polymerization (ROP) of cyclic esters, ethylene polymerization and co-polymerization of propylene oxide and CO2 are studied.Chapter 1 presents the history and research achievements of both calixarene and metallocalixarene compounds, with particular reference to polymerization reactions catalyzed by such coordination complexes, including ethylene polymerization, ring opening polymerization of cyclic esters and co-polymerization of propylene oxide and CO2.In Chapter 2, reactions of larger calix[n]arenes with vanadium precursors are studied. In particular, the reaction of Na[VO(tBuO)4] (generated in-situ from VOCl3 and NaOtBu) with p-tert-butyltetrahomodioxacalix[6]areneH6 (LO6H6) afforded, after work-up (in MeCN), the mixed-metal complex [(VO)2(μ-O)Na2(LO6)(MeCN)4]·5(MeCN) (1·5MeCN), whilst the oxo complex {[VO]4LO6} (2·6MeCN) was isolated via the use of [VO(OnPr)3]. Reaction of LO6H6 with [V(Np-CH3C6H4)(OtBu)3] afforded the complex {[V(Np-CH3C6H4)]2LO6} (3·7MeCN·0.5CH2Cl2). Use of similar methodology afforded the imido complexes {[V(Np-RC6H4)]2LO6} (R = OMe (4); CF3 (5); Cl (6); F (7)); on one occasion, reaction of [V(Np-CH3C6H4)(OEt)3] with LO6H6 afforded the product [VO(L6O’)]2·4MeCN (8·4MeCN) (L6O’ = 2-(p-CH3-C6H4NCH)-4-tBu-C6H2O-6-CH2)-4-tBuC6H2OH) in which LO6 has been cleaved. For comparative catalytic ring opening polymerization (ROP) studies, the known complexes [VOL3] (L3H3 = oxacalix[3]arene) (I), [V(Np-CH3-C6H4)L3]2 (II), [Li(MeCN)4][V2(O)2Li(MeCN)(L6H2)2] (L6H6 = p-tert-butylcalix[6]areneH6) (III) and [(VO)2L8H] (L8H8 = p-tert-butylcalix[8]areneH8) (IV) have also been prepared. ROP studies, with or with or without external alcohol present, indicated that complexes 1 to 8 exhibited moderate to good conversions for ε-Cl, δ-VL and the co-polymerization thereof. Within the imido series, a positive influence was observed when electron withdrawing substituents were present. These systems afforded relatively low molecular weight products and were also inactive toward the ROP of rac-lactide. In the case of ethylene polymerization, complexes 3, 5 and 7 exhibited highest activity when screened in the presence of dimethylaluminium chloride/ethyltrichloroacetate; the activity of 4 was much lower. The products were highly linear polyethylene with Mw in the range 74-120x103 Da.In Chapter 3, a number of metallocalix[n]arenes, where n = 4, 6, or 8, of titanium and vanadium have been screened for their ability to act as catalysts for the co-polymerization of propylene oxide and CO2 to form cyclic/polycarbonates. The vanadium-containing catalysts, namely [VO(L4Me)] (V), [(VO2)L8H6] (VI), [Na(NCMe)6]2[(Na(VO)4L8)(Na(NCMe))3]2 (VII), [VO(-OH)L4S/H2]2∙6CH2Cl2 (9/), [(VO)2(μ-O)Na2(LO6)(MeCN)4] (1), {[V(Np-CH3C6H4)]2LO6} (3) and [V(Np-RC6H4)Cl3] (R = Cl (VIII), OMe (IX), CF3 (X)), where L4H4 = p-tert-butylcalix[4]areneH4, L8H8 = p-tert-butylcalix[8]areneH8, L4SH4 = p-tert-butylthiacalix[4]areneH4, performed poorly, affording, in the majority of cases, TONs less than 1 at 90 oC over 6 h. In the case of the titanocalix[8]arenes, {(TiX)2[TiX(NCMe)]2(μ3-O)2(L8)} (X = Cl (10), Br (XI), I (XII)), which all adopt a similar ladder-type structure, the activity under the same conditions is somewhat higher (TONs > 6) and follows the trend Cl > Br > I; by comparison the non-calixarene species [TiCl4(THF)2] (XIII) was virtually inactive. The molecular structures of the complexes [HNEt3]2[VO(-O)L4SH2]2∙3CH2Cl2 (9∙3CH2Cl2), [VO(-OH)L4S/H2]2∙6CH2Cl2 (9/) (where L4S/H2 is a partially oxidized form of L4SH4) and {(TiCl)2[TiCl(NCMe)]2(μ3-O)2(L8)}·6.5MeCN (10·6.5MeCN) are reported.In Chapter 4, the coordination chemistry of azacalix[n]arenes is studied focusing on reactions with titanium precursors. Reaction of excess [Ti(OiPr)4] with L6OH6 afforded, after work-up (MeCN), the complex [Ti2(OiPr)2(MeCN)L6O]∙3.5MeCN (11∙3.5MeCN), whilst the oxo complex [Ti4O4(L6O)2]∙MeCN (12∙MeCN) was isolated via a fortuitous synthesis involving the use of two equivalents of [Ti(OiPr)4]. Reactions of p-methyl-dimethyldiazacalix[6]areneH6 (L6NH6) with [TiF4] (four equivalents), [TiCl4(THF)2] (two equivalents) or [TiBr4] (>four equivalents) resulted in the titanium-based azacalix[n]arene complexes [Ti4F14L6NH2(H)2]∙2.5MeCN (13∙2.5MeCN), [Ti2X4(H2O)2OL6NH2(H)2] (X = Cl (14∙5MeCN), Br (15∙4.5MeCN) and [Ti4Br12L6N(H)2(MeCN)6]∙7MeCN (16∙7MeCN), respectively. Reaction of four equivalents of [TiF4] with L3H4 (L4NH4 = p-methyl-dimethyldiazacalix[4]areneH4) afforded the product [Ti2F2(μ-F)3L4N(H)2(SiF5)]∙2MeCN (17∙2MeCN). These complexes have been screened for their potential to act as pre-catalysts in the ring opening polymerization (ROP) of ε-caprolactone (ε-CL), δ-valerolactone (δ-VL) and rac-lactide (r-LA). Generally, the titanium complexes bearing oxacalixarene exhibited better activities than the azacalixarene-based pre-catalysts. For ε-CL, δ-VL and r-LA, moderate activity at 130 °C over 24 h was observed for 11-16. In the case of the co-polymerization of ε-CL with r-LA, 11-16 afforded reasonable conversions and high molecular weight polymers; 17 exhibited lower catalytic performance due to low solubility. None of the complexes proved to be active in the polymerization of ω-pentadecalactone (ω-PDL) under the conditions employed herein.In Chapter 5, a variety of lithiated calix[n]arenes, where n = 6 or 8, have been isolated, structurally characterized and screened for their ability to act as catalysts for the ring opening polymerization (ROP) of the cyclic esters ε-caprolactone (ε-CL), δ-valerolactone (δ-VL) and r-lactide (r-LA). In particular, interaction of L6H6 with LiOtBu in THF afforded [Li14(L6H)2(CO3)2(THF)6(OH2)6]·14THF (18·14THF), whilst L8H8 afforded [Li10(L8)(OH)2(THF)8]·7THF (19·7THF). Similar use of de-butylated calix[8]areneH8 (deBuL8H8) led to an elongated dimer [Li18(deBuL8)2(OtBu)2(THF)14]·4THF (20·4THF). Interaction of L8H8 with LiOH·H2O afforded [Li4(L8H4)(OH2)4(THF)6]·5.5THF (21·5.5THF), whilst addition of Me3Al to the solution generated from L8H8 and LiOtBu led to the isolation of [(AlMe2)2Li20(L8H2)2(OH2)4(O2–)4(OH)2(NCMe)12]·10MeCN (22·10MeCN). These complexes have been screened for their potential to act as pre-catalysts in the ring opening polymerization (ROP) of ε-CL, δ-VL and r-LA. For ε-CL, δ-VL and r-LA, moderate activity for ROP at 130 °C over 8 h was observed for 18-21. In the case of ROP using the mixed-metal (Li/Al) system 22, better conversions and high molecular weight polymers were achieved. None of the complexes proved to be active in the ROP of ω-pentadecalactone (ω-PDL) under the conditions employed herein.In Chapter 6, the lead coordination chemistry of large calix[n]arenes is studied. Reaction of [LiPb(OiPr)3]2 (generated in-situ from Pb(OiPr)2 and LiOiPr) with either L4H4 or L6H6 resulted in the heterometallic lithium/lead complexes [Pb4Li2(L4)4H6(MeCN)3]∙4.5MeCN (23∙4.5MeCN) and [Pb8Li10Cl2(L6)4(H)8(O)4(H2O)2(MeCN)4]∙14MeCN (24∙14MeCN), respectively. Reaction of five equivalents of [Pb(OiPr)2] with L6OH6 afforded [Pb13(L6O)3O4(iPrOH)]∙11MeCN (25∙11MeCN). Reaction of L8H8 with [Pb(OtBu)2] or {Pb[N(TMS)2]} (TMS = SiMe3) afforded the products [Pb12(L8)2O4]∙8.7C7H8 (26∙8.7C7H8) or [Pb6(SiMe3)2(L8)O2Cl2] (27), respectively. Reaction of {Pb[N(TMS)2]} (generated in-situ from (Me3Si)2NH, nBuLi and PbCl2) with L6H6 afforded, after work-up (MeCN), the mixed-metal complex [Pb5Li(L6)O2.5Cl0.5]∙4.75MeCN (28·4.75MeCN). Complexes 23-27 have been screened for their potential to act as pre-catalysts in the ring opening polymerization (ROP) of ε-caprolactone (ε-CL) and δ-valerolactone (δ-VL) and the copolymerization thereof. Generally, the lithiated complexes 23 and 24 exhibited better activities than the other pre-catalysts screened herein. For ε-CL and δ-VL, moderate activity at 130 °C over 24 h was observed for 23-27. In the case of the co-polymerization of ε-CL with δ-VL, 23-27 afforded reasonable conversions and high molecular weight polymers. The catalysts 23-27 also be proved to be active in the ROP of the rac-lactide (r-LA), the activity trend was found to be 24 >23 >25 >26 ≈ 27.Chapter 7 presents the experimental section.Chapter 8 Appendix

Zener Tunneling in Semiconducting Nanotube and Graphene Nanoribbon p-n Junctions

A theory is developed for interband tunneling in semiconducting carbon nanotube and graphene nanoribbon p-n junction diodes. Characteristic length and energy scales that dictate the tunneling probabilities and currents are evaluated. By comparing the Zener tunneling processes in these structures to traditional group IV and III-V semiconductors, it is proved that for identical bandgaps, carbon based 1D structures have higher tunneling probabilities. The high tunneling current magnitudes for 1D carbon structures suggest the distinct feasibility of high-performance tunneling-based field-effect transistors.Comment: 4 Pages, 2 Figure

Horndeski Gravity and the Violation of Reverse Isoperimetric Inequality

We consider Einstein-Horndeski-Maxwell gravity, together with a cosmological constant and multiple Horndeski axions. We construct charged AdS planar black holes in general dimensions where the Horndeski anxions span over the planar directions. We analyse the thermodynamics and obtain the black hole volumes. We show that the reverse isoperimetric inequality can be violated, implying that these black holes can store information more efficiently than the Schwarzschild black hole.Comment: Latex, 25 pages, 1 figure, references adde

Mental Imagery of Speech and Movement Implicates the Dynamics of Internal Forward Models

The classical concept of efference copies in the context of internal forward models has stimulated productive research in cognitive science and neuroscience. There are compelling reasons to argue for such a mechanism, but finding direct evidence in the human brain remains difficult. Here we investigate the dynamics of internal forward models from an unconventional angle: mental imagery, assessed while recording high temporal resolution neuronal activity using magnetoencephalography. We compare two overt and covert tasks; our covert, mental imagery tasks are unconfounded by overt input/output demands – but in turn necessitate the development of appropriate multi-dimensional topographic analyses. Finger tapping (studies 1 and 2) and speech experiments (studies 3–5) provide temporally constrained results that implicate the estimation of an efference copy. We suggest that one internal forward model over parietal cortex subserves the kinesthetic feeling in motor imagery. Secondly, observed auditory neural activity ~170 ms after motor estimation in speech experiments (studies 3–5) demonstrates the anticipated auditory consequences of planned motor commands in a second internal forward model in imagery of speech production. Our results provide neurophysiological evidence from the human brain in favor of internal forward models deploying efference copies in somatosensory and auditory cortex, in finger tapping and speech production tasks, respectively, and also suggest the dynamics and sequential updating structure of internal forward models

A New Cost-Profit Model for Measuring the Optimal Scale of China’s Foreign Exchange Reserve

The fast increase of foreign exchange reserve in developing countries has raised a number of important financial questions in recent years. The analysis of the optimal scale of the foreign exchange reserve can provide important indicator to measure the strength and stability of country’s financial standing. In this work we propose a cost-profit model and use the financial data during 2000 to 2008 to analyze the optimal scale of China’s foreign exchange reserve. We identify a number of financial factors to measure the cost and profit of holding the reserves. Our prediction suggested that China’s foreign exchange reserves were still within the moderate range in 1999–2001. However, during 2002–2008 the foreign exchange reserve began to exceed the appropriate scale, and this upward trend was accelerated each year