Synthesis of chrysosplenol B, chrysosplenol D, and their analogs and synthesis of 3-(carboxymethylthio)-picolinic acid and its analog

Synthesis of natural products or their analogs is interesting and challenging work. During the course of the investigation, chemists can not only prepare various kinds of bioactive compounds, but also discover new synthetic methodologies. The first chapter of this thesis deals with the development of modified methods to synthesize chrysosplenol B, chrysosplenol D, and their analogs. Both chrysosplenol B and chrysosplenol D have the flavone skeleton with 3-methoxyl and 5-hydroxyl groups. They have ability to potentiate the potent anti-malarial activity of artemisinin and have ability to potentiate the activity of norfloxacin. The second chapter deals with the synthetic effort towards 3-(carboxymethylthio)-picolinic acid and a functionalized analog. They were synthesized in order to determine the minimum structural requirements for activity. This may enable researchers to study the mechanisms of molecular recognition of phosphoenolpyruvate (PEP) and oxaloacetate (OAA) by cytosolic phosphoenolpyruvate carboxykinase (cPEPCK)

Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein

The XPA (Xeroderma pigmentosum A) protein is one of the six core factors of the human nucleotide excision repair system. In this study we show that XPA is a rate-limiting factor in all human cell lines tested, including a normal human fibroblast cell line. The level of XPA is controlled at the transcriptional level by the molecular circadian clock and at the post-translational level by a HECT domain family E3 ubiquitin ligase called HERC2. Stabilization of XPA by downregulation of HERC2 moderately enhances excision repair activity. Conversely, downregulation of XPA by siRNA reduces excision repair activity in proportion to the level of XPA. Ubiquitination and proteolysis of XPA are inhibited by DNA damage that promotes tight association of the protein with chromatin and its dissociation from the HERC2 E3 ligase. Finally, in agreement with a recent report, we find that XPA is post-translationally modified by acetylation. However, contrary to the previous claim, we find that in mouse liver only a small fraction of XPA is acetylated and that downregulation of SIRT1 deacetylase in two human cell lines does not affect the overall repair rate. Collectively, the data reveal that XPA is a limiting factor in excision repair and that its level is coordinately regulated by the circadian clock, the ubiquitin–proteasome system and DNA damage

Electroweak Phase Transition and Baryogenesis in the nMSSM

We analyze the nMSSM with CP violation in the singlet sector. We study the static and dynamical properties of the electroweak phase transition. We conclude that electroweak baryogenesis in this model is generic in the sense that if the present limits on the mass spectrum are applied, no severe additional tuning is required to obtain a strong first-order phase transition and to generate a sufficient baryon asymmetry. For this we determine the shape of the nucleating bubbles, including the profiles of CP-violating phases. The baryon asymmetry is calculated using the advanced transport theory to first and second order in gradient expansion presented recently. Still, first and second generation sfermions must be heavy to avoid large electric dipole moments.Comment: 36 pages, 10 figures; minor changes, published versio

MSSM Electroweak Baryogenesis and Flavour Mixing in Transport Equations

We make use of the formalism developed in Ref. [1], and calculate the chargino mediated baryogenesis in the Minimal Supersymmetric Standard Model. The formalism makes use of a gradient expansion of the Kadanoff-Baym equations for mixing fermions. For illustrative purposes, we first discuss the semiclassical transport equations for mixing bosons in a space-time dependent Higgs background. To calculate the baryon asymmetry, we solve a standard set of diffusion equations, according to which the chargino asymmetry is transported to the top sector, where it biases sphaleron transitions. At the end we make a qualitative and quantitative comparison of our results with the existing work. We find that the production of the baryon asymmetry of the Universe by CP-violating currents in the chargino sector is strongly constrained by measurements of electric dipole moments.Comment: 30 pages, 6 figures; minor changes, published versio

Electroweak Baryogenesis and New TeV Fermions

New fermions, strongly coupled to the Standard Model Higgs boson provide a well motivated extension of the Standard Model (SM). In this work we show that, once new physics at heavier scales is added to stabilize the Higgs potential, such an extension of the SM can strengthen the first order electroweak phase transition and make the electroweak baryogenesis mechanism feasible. We propose a SM extension with TeV Higgsinos, Winos and Binos that satisfy the following properties: a) The electroweak phase transition is strong enough to avoid sphaleron erasure in the broken phase for values of the Higgs mass mH < 300 GeV; b) It provides large CP-violating currents that lead to the observed baryon asymmetry of the Universe for natural values of the CP-violating phase; c) It also provides a natural Dark Matter candidate that can reproduce the observed dark matter density; d) It is consistent with electroweak precision measurements; e) It may arise from a softly broken supersymmetric theory with an extra (asymptotically free) gauge sector; e) It may be tested by electron electric dipole moment experiments in the near future.Comment: LateX, 40 pages, 12 embedded postscript figures. A discussion of the stability of the Higgs potential and its connection to a possible ultraviolet completion of the model has been adde

Singlino-driven Electroweak Baryogenesis in the Next-to-MSSM

We explore a new possibility of electroweak baryogenesis in the next-to-minimal supersymmetric standard model. In this model, a strong first-order electroweak phase transition can be achieved due to the additional singlet Higgs field. The new impact of its superpartner (singlino) on the baryon asymmetry is investigated by employing the closed-time-path formalism. We find that the CP violating source term fueled by the singlino could be large enough to generate the observed baryon asymmetry of the Universe without any conflicts with the current constraints from the non-observation of the Thallium, neutron and Mercury electric dipole moments.Comment: 11 pages, 2 figures. To appear in PL

Identification of a functionally essential amino acid for Arabidopsis cyclic nucleotide gated ion channels using the chimeric AtCNGC11/12 gene

We used the chimeric Arabidopsis cyclic nucleotide-gated ion channel AtCNGC11/12 to conduct a structure-function study of plant cyclic nucleotide-gated ion channels (CNGCs). AtCNGC11/12 induces multiple pathogen resistance responses in the Arabidopsis mutant constitutive expresser of PR genes 22 (cpr22). A genetic screen for mutants that suppress cpr22-conferred phenotypes identified an intragenic mutant, #73, which has a glutamate to lysine substitution (E519K) at the beginning of the eighth β-sheet of the cyclic nucleotide-binding domain in AtCNGC11/12. The #73 mutant is morphologically identical to wild-type plants and has lost cpr22-related phenotypes including spontaneous cell death and enhanced pathogen resistance. Heterologous expression analysis using a K+-uptake-deficient yeast mutant revealed that this Glu519 is important for AtCNGC11/12 channel function, proving that the occurrence of cpr22 phenotypes requires active channel function of AtCNGC11/12. Additionally, Glu519 was also found to be important for the function of the wild-type channel AtCNGC12. Computational structural modeling and in vitro cAMP-binding assays suggest that Glu519 is a key residue for the structural stability of AtCNGCs and contributes to the interaction of the cyclic nucleotide-binding domain and the C-linker domain, rather than the binding of cAMP. Furthermore, a mutation in the α-subunit of the human cone receptor CNGA3 that causes total color blindness aligned well to the position of Glu519 in AtCNGC11/12. This suggests that AtCNGC11/12 suppressors could be a useful tool for discovering important residues not only for plant CNGCs but also for CNGCs in general. © 2008 The Authors

Neuropilin-1 functions as a VEGFR2 co-receptor to guide developmental angiogenesis independent of ligand binding

During development, tissue repair, and tumor growth, most blood vessel networks are generated through angiogenesis. Vascular endothelial growth factor (VEGF) is a key regulator of this process and currently both VEGF and its receptors, VEGFR1, VEGFR2, and Neuropilin1 (NRP1), are targeted in therapeutic strategies for vascular disease and cancer. NRP1 is essential for vascular morphogenesis, but how NRP1 functions to guide vascular development has not been completely elucidated. In this study, we generated a mouse line harboring a point mutation in the endogenous Nrp1 locus that selectively abolishes VEGF-NRP1 binding (Nrp1VEGF−). Nrp1VEGF− mutants survive to adulthood with normal vasculature revealing that NRP1 functions independent of VEGF-NRP1 binding during developmental angiogenesis. Moreover, we found that Nrp1-deficient vessels have reduced VEGFR2 surface expression in vivo demonstrating that NRP1 regulates its co-receptor, VEGFR2. Given the resources invested in NRP1-targeted anti-angiogenesis therapies, our results will be integral for developing strategies to re-build vasculature in disease. DOI: http://dx.doi.org/10.7554/eLife.03720.00