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.     

A proof of the Faber-Krahn inequality for the first eigenvalue of thep-Laplacian

Summary In this work we present an elementary proof of the Faber-Krahn inequality for the first eigenvalue of the p-Laplacian on bounded domains in ℝⁿ. Let λ₁ be the first eigenvalue and λ ₁ ^* be the first eigenvalue for the ball of the same volume. Then we show that λ₁=λ ₁ ^* iff the domain is a ball. Our proof makes considerable use of the corresponding Talenti's inequality and some well known properties of the first eigenfunction. Entrata in Redazione il 20 aprile 1998.     

Study on the structure functions of electrons and the energy flow in the soft component of cosmic-ray extensive air showers

Summary Cosmic-ray air shower structure functions for the distance dependence of electron density in cosmic-ray air showers in the size range 10⁴⋎10⁸ have been computed for their intercomparison and comparison with Monte Carlo simulation results and measurements from recent experiments. The analysis has yielded the present status of theoretical structure functionsvis à vis experimental results and Monte Carlo simulation distributions. The effect of core location error on the lateral distribution of electrons is also discussed from the point of view of different theoretical and experimental results. The energy flow in the soft component of air showers of size ∼4·10⁵ has been evaluated within a ring of radius 10m about the axis of the showers.     

Anisotropy of the electron momentum distribution in Bi2Sr2CaCu2O8+δ superconductor studied by positron annihilation

The temperature dependent (30-300 K) Doppler broadening of the positron annihilated γ-radiation measurement has been investigated on single crystalline Bi₂Sr₂CaCu₂O_8+δ (Bi-2212) high T_c superconducting samples along two different crystallographic orientations. It has been observed that throughout the temperature range the electron momentum distribution has a larger value along the crystallographic c-axis than in the a-b plane. The temperature dependent Doppler broadened positron annihilation γ-radiation lineshape analysis shows a step like increase of S-parameter at the temperature region 92-116 K.     

Synthesis and characterization of L‐leucine containing chiral vinyl monomer and its polymer,poly(2‐(methacryloyloxyamino)‐4‐methyl pentanoic acid)

A chiral monomer containing L ‐leucine as a pendant group was synthesized from methacryloyl chloride and L ‐leucine in presence of sodium hydroxide at 4 °C. The monomer was polymerized by free radical polymerization in propan‐2‐ol at 60 °C using 2,2′‐azobis isobutyronitrile (AIBN) as an initiator under nitrogen atmosphere. The polymer, poly(2‐(Methacryloyloxyamino)‐4‐methyl pentanoic acid) is thus obtained. The molecular weight of the polymer was determined to be: M_w is 6.9 × 10³ and M_n is 5.6 × 10³. The optical rotation of both chiral monomer and its polymer varies with the solvent polarity. The amplification of optical rotation due to transformation of monomer to polymer is associated with the ordered conformation of chiral monomer unit in the polymeric chain due to some secondary interactions like H‐bonding. The synthesized monomer and polymer exhibit intense Cotton effect at 220 nm. The conformation of the chain segments is sensitive to external stimuli, particularly the pH of the medium. In alkaline medium, the ordered chain conformation is destroyed resulting disordered random coils. The ordered coiling conformation is more firmly present on addition of HCl. The polymer exhibits swelling‐deswelling characteristics with the change of pH of the medium, which is reversible. The Cotton effect decreases linearly with the increase of temperature which is reversible on cooling. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2228–2242, 2009     

A note on exponent of convergence of zeros of entire functions

If f(z) is an entire function with ρ ₁ > 0 as its exponent of convergence of zeros and if 0 ≤ α < ρ ₁, then we prove the existence of entire functions each having α as its exponent of convergence of zeros.      

Bethe ansatz for an open Heisenberg spin chain with impurity

We have set up the algebraic Bethe ansatz equation for an open Heisenberg spin chain having an impurity of a different type of spin. The chain is considered to be open and hence the QISM approach as modified by Sklyanin is used to set up the equations for the Bethe ansatz.     

On the study of ion-acoustic solitary waves and double-layers in a drift multicomponent plasma with electron-inertia

Using the pseudopotential method, theoretical investigation has been made on the firstorder Korteweg-deVries ion-acoustic solitons in a multicomponent plasma consisting of warm positive ions, negative ions and isothermal electrons. The effects of electron-inertia and drift motion of the ions on the amplitudes and widths of the solitons have been studied in a plasma having (H⁺, Cl⁻), (H⁺, O⁻), (He⁺, H⁻) and (He⁺, O⁻) ions. Ion-acoustic double-layers have also been investigated for such plasmas. It has been found that drift velocity and electron-inertia have significant contribution on the formation of double-layers in multicomponent plasma     

Proton and α sequential emission in the 16O + 58Ni deep inelastic reaction: A semi-classical approach

The 132 MeV ¹⁶O + ⁵⁸Ni reaction has been experimentally investigated by using coincident charged particle techniques. A closed-form theoretical approach, describing in a simple picture the non-equilibrium component and the evaporative one of the angular correlation between light particles and reaction residues emitted in a peripheral heavy-ion collision, is applied — in the hypotesis of a sequential process — to the (C,N,O)-α and (C,N,O)-p differential multiplicities for the ¹⁶O + ⁵⁸Ni at 8.25 MeV/A deep inelastic collision. From this analysis some reaction mechanism information is deduced.     

Electrical spin injection and threshold reduction in a semiconductor laser

A spin-polarized vertical-cavity surface-emitting laser is demonstrated with electrical spin injection from an Fe/Al0.1Ga0.9As Schottky tunnel barrier. Laser operation with a spin-polarized current results in a maximum threshold current reduction of 11% and degree of circular polarization of 23% at 50 K. A cavity spin polarization of 16.8% is estimated from spin-dependent rate equation analysis of the observed threshold reduction.