Immunotherapy with Native Molecule rather than Hypoallergenic Variant of Pru p 3, the Major Peach Allergen, Shows Beneficial Effects in Mice

Background. The use of hypoallergenic derivatives is considered beneficial to promote the safety and efficacy of allergen-specific immunotherapy. We aimed to assess the efficacy of reduced and alkylated (R/A) Pru p 3, a hypoallergenic folding variant of the major peach allergen, in subcutaneous immunotherapy (SCIT) using a murine model of peach allergy. Methods and Results. After sensitization with Pru p 3, BALB/c mice received SCIT with Pru p 3 or R/A Pru p 3 and were challenged with Pru p 3. SCIT with Pru p 3, but not with R/A Pru p 3, suppressed anaphylaxis upon the challenge significantly. SCIT with Pru p 3 did not suppress Pru p 3-specific IgE and IgG1 production, but enhanced IgG2a production. In contrast, SCIT with R/A Pru p 3 suppressed IgE and IgG1 production, but enhanced IgG2a production only moderately. The therapeutic efficacy of SCIT with Pru p 3 was associated with induction of IL-10 and IFN-γ. Conclusion. Hypoallergenic folding variant of Pru p 3 is not likely an efficacious therapeutic component in SCIT of peach allergy. The lower efficacy of R/A Pru p 3 might be attributed to poor antigenicity and/or weak stability due to its unfolded conformation.

Cooperative Non-bonded Forces Control Membrane Binding of the pH-Low Insertion Peptide pHLIP

ABSTRACTPeptides with the ability to bind and insert into the cell membrane have immense potential in biomedical applications. pH (Low) Insertion Peptide (pHLIP), a water-soluble polypeptide derived from helix C of bacteriorhodopsin, can insert into a membrane at acidic pH to form a stable transmembrane α-helix. The insertion process takes place in three stages: pHLIP is unstructured and soluble in water at neutral pH (state I), unstructured and bound to the surface of a membrane at neutral pH (state II), and inserted into the membrane as an α-helix at low pH (state III). Using molecular dynamics (MD) simulations, we have modeled state II of pHLIP and a fast-folding variant of pHLIP, in which each peptide is bound to a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer surface. Our results provide strong support for recently published spectroscopic studies, namely that pHLIP preferentially binds to the bilayer surface as a function of location of anionic amino acids and that backbone dehydration occurs upon binding. Unexpectedly, we also observed several instances of segments of pHLIP folding into a stable helical turn. Our results provide a molecular level of detail that is essential to providing new insights into pHLIP function and to facilitate design of variants with improved cell-penetrating capabilities.

Inspecting Maude variants withGLINTS

This paper introducesGLINTS, a graphical tool for exploring variant narrowing computations in Maude. The most recent version of Maude, version 2.7.1, provides quite sophisticated unification features, including order-sorted equational unification for convergent theories modulo axioms such as associativity, commutativity, and identity. This novel equational unification relies on built-in generation of the set ofvariantsof a termt, i.e., the canonical form oftσ for a computed substitution σ. Variant generation relies on a novel narrowing strategy calledfolding variant narrowingthat opens up new applications in formal reasoning, theorem proving, testing, protocol analysis, and model checking, especially when the theory satisfies thefinite variant property, i.e., there is a finite number of most general variants for every term in the theory. However, variant narrowing computations can be extremely involved and are simply presented in text format by Maude, often being too heavy to be debugged or even understood. TheGLINTSsystem provides support for (i) determining whether a given theory satisfies the finite variant property, (ii) thoroughly exploring variant narrowing computations, (iii) automatic checking of nodeembeddingandclosednessmodulo axioms, and (iv) querying and inspecting selected parts of the variant trees.