Directed Evolution of Macrocyclic 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. 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. 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 substantially reduced 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 intracellular PPIs that govern the autophagic machinery

The roles of resident, central and effector memory CD4 T cells in protective immunity following infection or vaccination

Immunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include HIV, tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T cells we need to understand how memory CD4 T cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T cells that are found in peripheral tissues (tissue resident memory T cells) and in the circulation (central and effector memory T cells). We discuss the generation of these cells and the evidence that demonstrates how they provide immune protection in animal and human challenge models

Forensically-Sound Analysis of Security Risks of using Local Password Managers

Password managers have been developed to address the human challenges associated with password security, i.e., to solve usability issues in a secure way. They offer, e.g., features to create strong passwords, to manage the increasing number of passwords a typical user has, and to auto-fill passwords, sparing users the hassle of not only remembering but also typing them. Previous studies have focused mainly on the security analysis of cloud-based and browser-based password managers; security of local password managers remains mostly under-explored. This paper takes a forensic approach and reports on a case study of three popular local password managers: KeePass (v2.28), Password Safe (v3.35.1) and RoboForm (v7.9.12). Results revealed that either the master password or the content of the password database could be found unencrypted in Temp folders, Page files or Recycle bin, even after the applications had been closed. Therefore, an attacker or malware with temporary access to the computer on which the password managers were running may be able to steal sensitive information, even though these password managers are meant to keep the databases encrypted and protected at all times

Innovativeness and Innovation: Implications for the Renewable Materials Supply Chain

innovativeness, innovation, supply chain management, triple bottom line, corporate social responsibility, Agribusiness, Agricultural Finance, Demand and Price Analysis, Financial Economics, Q10, Q27, Q42, Q47,

Valuing Limited Information in Decision Making Under Uncertainty

Fresh Juice Inc. (FJI) is in the process of determining whether they should launch a new fruit juice in a market that has been relatively stagnant for the last 15 years. Management of FJI is faced with uncertainty surrounding market share, market size, price, and competitor entry. In addition, FJI has the ability to chose between alternative production processes; this choice directly affects the likelihood the investment will return a positive Net Present Value. This case teaches students how to develop a stochastic simulation models given limited information to analyze risk investment decisions.: simulation, uncertainty, strategic management, flexibility, limited information, investment analysis