Hsp90 inhibitors disrupt mitochondrial homeostasis in cancer cells

Hsp90 is a cytosolic molecular chaperone whose paralog in mitochondria, TRAP1, protects cells from oxidative stress. The recent study in Cell by Kang et al. now identifies the molecular components of the proapoptotic network regulated by TRAP1, that includes Hsp90. Targeting Hsp90/TRAP1 inhibitors to mitochondria induces rapid tumor cell-specific apoptosis.     

Investigating direct current potentials that affect native protein conformation during trapped ion mobility spectrometry–mass spectrometry

Trapped ion mobility spectrometry–time-of-flight mass spectrometry (TIMS-TOFMS) has emerged as a tool to study protein conformational states. In TIMS, gas-phase ions are guided across the IM stages by applying direct current (DC) potentials (D1–6), which, however, might induce changes in protein structures through collisional activation. To define conditions for native protein analysis, we evaluated the influence of these DC potentials using the metalloenzyme bovine carbonic anhydrase (BCA) as primary test compound. The variation of DC potentials did not change BCA-ion charge and heme content but affected (relative) charge-state intensities and adduct retention. Constructed extracted-ion mobilograms and corresponding collisional cross-section (CCS) profiles gave useful insights in (alterations of) protein conformational state. For BCA, the D3 and D6 potential (which are applied between the deflection transfer and funnel 1 [F1] and the accumulation exit and the start of the ramp, respectively) had most profound effects, showing multimodal CCS distributions at higher potentials indicating gradual unfolding. The other DC potentials only marginally altered the CCS profiles of BCA. To allow for more general conclusions, five additional proteins of diverse molecular weight and conformational stability were analyzed, and for the main protein charge states, CCS profiles were constructed. Principal component analysis (PCA) of the obtained data showed that D1 and D3 exhibit the highest degree of correlation with the ratio of folded and unfolded protein (F/U) as extracted from the mobilograms obtained per set D potential. The correlation of D6 with F/U and protein charge were similar, and D2, D4, and D5 showed an inverse correlation with F/U but were correlated with protein charge. Although DC boundary values for induced conformational changes appeared protein dependent, a set of DC values could be determined, which assured native analysis of most proteins.     

Statistical and Numerical Considerations of Backus-Average Product Approximation

In this paper, we examine the applicability of the approximation, \(\overline{f g}\approx \overline{f}\,\overline{g}\), within Backus (J. Geophys. Res. 67(11):4427–4440, 1962) averaging. This approximation is a crucial step in the method proposed by Backus (J. Geophys. Res. 67(11):4427–4440, 1962), which is widely used in studying wave propagation in layered Hookean solids. According to this approximation, the average of the product of a rapidly varying function and a slowly varying function is approximately equal to the product of the averages of those two functions.Considering that the rapidly varying function represents the mechanical properties of layers, we express it as a step function. The slowly varying function is continuous, since it represents the components of the stress or strain tensors. In this paper, beyond the upper bound of the error for that approximation, which is formulated by Bos et al. (J. Elast. 127:179–196, 2017), we provide a statistical analysis of the approximation by allowing the function values to be sampled from general distributions.Even though, according to the upper bound, Backus (J. Geophys. Res. 67(11):4427–4440, 1962) averaging might not appear as a viable approach, we show that—for cases representative of physical scenarios modelled by such an averaging—the approximation is typically quite good. We identify the cases for which there can be a deterioration in its efficacy.In particular, we examine a special case for which the approximation results in spurious values. However, such a case—though physically realizable—is not likely to appear in seismology, where Backus (J. Geophys. Res. 67(11):4427–4440, 1962) averaging is commonly used. Yet, such values might occur in material sciences, in general, for which Backus (J. Geophys. Res. 67(11):4427–4440, 1962) averaging is also considered.     

Coordination chemistry of 5,6,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine with first-row transition-metal salts: Synthesis, spectroscopy and single-crystal structures, with counter-anion dependence of the structures

A variety of new coordination compounds with transition-metal salts and the ligand trimethyl[1,2,4]triazolo[1,5-a]pyrimidine (abbreviated as tmtp) is described, together with several of their 3D crystal structures and spectroscopic and magnetic properties. The compounds were selected based on the coordination ability of the counterion, halide, nitrate, sulfate, thiocyanate and perchlorate. The formed coordination compounds and their coordination numbers were found to be strongly dependent on both the cation and the used counter-anion. The several compounds studied have the following structural formulae: [CuCl₂(tmtp)₂], [CuBr₂(tmtp)₂], [ZnBr₂(tmtp)₂], [Cu(NO₃)₂(tmtp)₂], [CuSO₄(tmtp)₂]₂(H₂O)(MeOH), [Cu(H₂O)(NCS)₂(tmtp)₂], [Zn(NCS)₂(tmtp)₂], [Cd(NCS)₂(tmtp)₂] and [M(H₂O)₂(tmtp)₄](BF₄)₂, in which M = Co, Ni, Zn.The new coordination compounds have been further characterized by NMR, (far-)IR and LF spectra, as well as by C, H, N element analyses, and EPR spectra for the Cu(II) compounds. The coordination around the metal varies from 4 (Zn, Cu), via 5 (Cu) to 6 (for Co, Cu and Cd). The anions usually complete the coordination sphere; only the Co and Zn compounds with the tetrafluoridoborate anions have no coordinated anions, but water ligands complete the octahedral coordination sphere. In the 5-coordinated [Cu(H₂O)(NCS)₂(tmtp)₂] water completes the square pyramid geometry.     

Enantioselective Artificial Metalloenzymes Based on a Bovine Pancreatic Polypeptide Scaffold

Site creation : Enantioselective artificial metalloenzymes have been created by grafting a new active site onto bovine pancreatic polypeptide through the introduction of an amino acid capable of coordinating a copper(II) ion. This hybrid catalyst gave good enantioselectivities in the Diels–Alder and Michael addition reactions in water (see scheme) and displayed a very high substrate selectivity.

     

Essential Spectral Inclusions for Operators on Banach Spaces

This paper centers on local spectral conditions that are both necessary and sufficient for the equality of the essential spectra of two bounded linear operators on complex Banach spaces that are intertwined by a pair of bounded linear mappings. In particular, if the operators T and S are intertwined by a pair of injective operators, then S is Fredholm provided that T is Fredholm and S has property (δ) in a neighborhood of 0. In this case, ind(T) ≤ ind(S), and equality holds precisely when the eigenvalues of the adjoint T* do not cluster at 0. By duality, we obtain refinements of results due to Putinar, Takahashi, and Yang concerning operators with Bishop’s property (β) intertwined by pairs of operators with dense range. Moreover, we establish an extension of a result due to Eschmeier that, under appropriate assumptions regarding the single-valued extension property, leads to necessary and sufficient conditions for quasi-similar operators to have equal essential spectra. In particular it turns out that the single-valued extension property plays an essential role in the preservation of the index in this context.      

Solid phase microextraction and gas chromatography with ion trap detector (GC-ITD) analysis of amitraz residues in beeswax after hydrolysis to 2,4-dimethylaniline

An analytical method for the determination of amitraz residues in beeswax after hydrolysis to 2,4-dimethylaniline is reported. It consists of wax extraction with an acid buffer solution, head space solid phase microextraction and GC-ITD analysis. The limit of determination is 1 ng g⁻¹. Wax samples from beekepers and commercial foundations were analysed, content of residues varied from <1 to 20.5 ng g⁻¹.     

Weakly Admissible Meshes and Discrete Extremal Sets

We present a brief survey on (Weakly) Admissible Meshes and corresponding Discrete Extremal Sets, namely Approximate Fekete Points and Discrete Leja Points. These provide new computational tools for polynomial least squares and interpolation on multidimensional compact sets, with different applications such as numerical cubature, digital filtering, spectral and high-order methods for PDEs.     

Electrostatic interactions in the adhesion of an ion-penetrable and ion-impenetrable bacterial strain to glass

Deposition to glass of Streptococcus salivarius HB-C12 and Staphylococcus epidermidis 3399 in a parallel plate flow chamber has been studied as a function of ionic strength. Electrophoretic mobility measurements revealed that S. epidermidis 3399 possesses a thick ion-penetrable layer, probably associated with its encapsulation, while S. salivarius HB-C12 has an ion-impenetrable surface. Streaming potential measurements indicated that also the glass surface was covered with a relatively thin, ion-penetrable layer. Theoretical initial deposition rates of both strains to glass were obtained by numerically solving the convective-diffusion equation, while accounting for the ion-penetrability of the interacting surfaces. Experimentally, the initial deposition rate of the ion-penetrable strain S. epidermidis 3399 was found to be higher and less dependent on ionic strength than of the ion-impenetrable S. salivarius HB-C12, in accordance with theoretical expectations. Agreement between theoretical and experimental deposition rates could be obtained when glass was considered ion-penetrable when interacting with the ion-penetrable organism S. epidermidis 3399, while glass behaved as an ion-impenetrable surface when interacting with the ion-impenetrable S. salivarius HB-C12. Probably, interaction with an ion-impenetrable strain drives the diffuse double layer charges into the limited volume of the thin ion-penetrable layer on the glass, readily filling it up and making it appear ion-impenetrable. During interaction of glass with another ion-penetrable surface, as of S. epidermidis 3399, diffuse double layer charges move into both ion-penetrable surfaces, resulting in a much lower mobile charge density in the ion-penetrable layer on the glass which consequently continues to behave as ion-penetrable.     

Asymmetric allylic alkylation of acyclic allylic ethers with organolithium reagents

A highly efficient, regio- and enantioselective Cu(I) /phosphoramidite-catalyzed asymmetric allylic alkylation of allyl ethers with organolithium reagents is reported. The use of organolithium reagents is essential for this catalytic C?C bond formation due to their compatibility with different Lewis acids. The versatility of allylic ethers under the copper-catalyzed reaction conditions with organolithium reagents is demonstrated in the shortest synthesis of (S)-Arundic acid.