Directed evolution of cyclic peptides for inhibition of autophagy

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Unfortunately, chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of the autophagosome maturation machinery—with mid-nanomolar affinities and disrupted protein–protein interactions (PPIs) between LC3 and its binding partners in vitro. The most promising LC3-binding SUPR peptide accessed the cytosol at low micromolar concentrations as measured by chloroalkane penetration assay (CAPA) and inhibited starvation-mediated GFP-LC3 puncta formation in a concentration-dependent manner. LC3-binding SUPR peptides re-sensitized platinum-resistant ovarian cancer cells to cisplatin treatment and triggered accumulation of the adapter protein p62 suggesting decreased autophagic flux through successful disruption of LC3 PPIs in cell culture. In mouse models of metastatic ovarian cancer, treatment with LC3-binding SUPR peptides and carboplatin resulted in almost complete inhibition of tumor growth after four weeks of treatment. These results indicate that SUPR peptide mRNA display can be used to develop cell-penetrating macrocyclic peptides that target and disrupt the autophagic machinery in vitro and in vivo.

SUPR peptide mRNA display was used to evolve a cell-permeable, macrocyclic peptide for autophagy inhibition.     

Positivity and Stability for One-Sided Coupled Operator Matrices

Many evolutionary systems can be described by an abstract Cauchy problem governed by an operator matrix. Assuming this problem to be one-sided coupled and well-posed we study in this paper the positivity and the stability of the associated matrix semigroup. The abstract results are illustrated by several examples.     

A noncontextualist account of contextualist linguistic data

The paper takes as its starting point the observation that people can be led to retract knowledge claims when presented with previously ignored error possibilities, but offers a noncontextualist explanation of the data. Fallibilist epistemologies are committed to the existence of two kinds of Kp-falsifying contingencies: (i) Non-Ignorable contingencies [NI-contingencies] and (ii) Properly-Ignorable contingencies [PI-contingencies]. For S to know that p, S must be in an epistemic position to rule out all NI-contingencies, but she need not be able to rule out the PI-contingencies. What is required vis-à-vis PI-contingencies is that they all be false. In mentioning PI-contingencies, an interlocutor can lead S mistakenly to think that these contingencies are NI-contingencies, when in fact they are not. Since S cannot rule out these newly mentioned contingencies and since she mistakenly takes them to be NI-contingencies, it is quite natural that she retract her earlier knowledge claim. In short, mentioning NI-contingencies creates a distortion effect. It makes S think that the standards for knowledge are higher than they actually are, which in turn explains why she mistakenly thinks she lacks knowledge. Conclusion: The primary linguistic data offered in support of contextualism can be explained without resorting to contextualism.     

On perturbations of linear m-accretive operators on reflexive Banach spaces

In this note we prove some results on the m-accretivity of sums and products of linear operators. In particular we obtain the following theorem: LetA, B be two m-accretive operators on a reflexive Banach space. IfA is invertible and (A)^–1 B is accretive thenBA ^–1 andA+B are m-accretive.     

Diffractive meson production from virtual photons with odd charge-parity exchange

We calculate the cross section of diffractive charge-parity neutral meson production in virtual photon proton collision at high energies. Due to the opposite -parities of photon and meson () this process probes the -channel odderon exchange which is described here as noninteracting three–gluon exchange. Estimates for the cross section of inelastic diffractive process are presented. The total cross section of diffractive meson photoproduction is found to be 47 pb. The cross sections for the diffractive production of light mesons () in collisions are of the same order if the photon virtuality is . Received: 30 July 1997     

Relativistic density functional calculations for Pt2

First full-relativistic density functional calculations with the extension of the spin-polarization functional for the relativistic density functional theory in their collinear and noncollinear form are presented here for the molecular system Pt2. The agreement with experiment is very good.