Metastability of native proteins and the phenomenon of amyloid formation

An experimental determination of the thermodynamic stabilities of a series of amyloid fibrils reveals that this structural form is likely to be the most stable one that protein molecules can adopt even under physiological conditions. This result challenges the conventional assumption that functional forms of proteins correspond to the global minima in their free energy surfaces and suggests that living systems are conformationally as well as chemically metastable.     

Figure-of-eight Shaped Metal-free Amide-containing Schiff-base Macrocycles and Two Dicobalt(III) Amide Complexes

Abstract

Two 36-membered (2+2) Schiff-base macrocycles have been prepared and characterised without the use of template ions or high dilution techniques. Rather, intramolecular hydrogen-bonding and π-π interactions promote the isolation of these “figure-of-eight” products in good yields. Two cobalt(III) complexes of the 18-membered (1+1) Schiff-base macrocycles are formed when cobalt(II) is used as a template. The structures of one “figure-of-eight' metal-free (2+2) macrocycle and of one dicobalt(III) complex of a (1+1) macrocycle, in which the cobalt centres are octahedral, are presented. [H₄L1tBu]₂: C₇₀H₇₀N₈O₉, space group P-1, a=7.747(1), b=17.106(3), c=23.662(4) å, α=104.83(3), β=95.86(3), γ=97.80(3)°, U=2972.4(8) å³, Z=2, D_c=1.30 g cm^?3, T=100K, 554 parameters, R1=0.072 [for 4137 reflections having F>4[(F)], wR₂=0.191 and goodness of fit 0.97 (for all 8343 independent F² data). [Co₂(L1tBu)(OAc)₂(pyridine)] 1.5DMF 0.5MeCN, C_47.5H₄₉N₇O9.5Co₂, space group P2(1)/n, a=13.067(2), b=26.071(4), c=14.023(3) å, β=93.02(1)°, U=4770.6(15) å³, Z=4, D_c=1.38 g cm^?3, T=168 K, 622 parameters, R1=0.075 [for 5233 reflections having F > 4[?F?], wR2=0.133 and good ness of fit 1.08 (for all 8512 independent F² data).     

Inhibiting the NLRP3 Inflammasome

Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches.     

The effective W approximation

We generalize the effective photon approximation to include the massive W^± and Z gauge bosons of the Weinberg-Salam model. The W^± and Z bosons are treated as partons in the proton and we present predictions for the structure functions of both transversely and longitudinally polarized W's and Z's. Our results are valid only at high energies, (√s ? 20 TeV), and greatly simplify calculations involving vector bosons in the intermediate state of a scattering process. As examples, we use our treatment of the W and Z as partons to calculate hadronic production of heavy Higgs bosons from WW scattering and also to compute the associated production of a heavy charge $\text{2}\text{3}$ and charge $\text{?}\text{1}\text{3}$ quark from W-gluon scattering.     

ALPHA-TERTHIENYL, A NON-PHOTODYNAMIC PHOTOTOXIC COMPOUND

Abstract— Alpha-terthienyl (αT), a natural product first isolated in the plant Tagetes erecta (family Compositae), is the first member of a new class of phototoxic compounds, whose activity is not based on the generation of singlet oxygen. Its maximum activity against Candida utilis was at 370 nm, and was not affected by the presence of sodium azide. Furthermore, its phototoxicity against E. coli B cells was expressed under nitrogen, but not under oxygen. In the presence of UVA, radioactive αT formed covalent bonds with calf thymus DNA, and was also incorporated into the DNA of C. utilis. Two different methods proved that the photochemical interaction of αT and DNA did not involve cross linking of double strands.