Size-fitting of Intravaginal Rings for Macaques and in vitro Release Kinetics of Zinc Finger Inhibitors

Background: Small molecule inhibitors of the zinc finger domain (ZFI) in the nucleocapsid protein (NCp7) of HIV-1 are potent inhibitors of HIV and SIV
replication and may have utility as topical products to prevent infection. Furthermore, intravaginal rings (IVRs) were developed as coitally-independent,
sustained release devices which could be used for administration of HIV microbicides. The aims of these studies were to demonstrate that IVRs sized for
macaques are practical and compatible with the current generation of thioester-based NCp7 inhibitors.

Methods: Non-medicated silicone elastomer vaginal rings of various sizes thought to be applicable for macaques were prepared and tested for vaginal fit in Pigtailed and Chinese Rhesus macaques. Macaques were monitored for 8 weeks for mucosal disruption by colposcopy and proinflammatory cytokine markers in cervical vaginal lavages (CVL) using Luminex bead-based technology. Three different ZFIs (compounds 52, 89 and 122, each derived from an N-substituted S-acyl-2-mercaptobenzamide thioester scaffold) were loaded at 50 mg into an optimal matrix-type ring design. In vitro continuous release studies were then conducted over 28 days and analyzed by HPLC. Rate of release was determined by linear regression analysis.

Results: Qualitative evaluation at the time of ring insertion suggested that the 25 mm ring provided optimal fit in both macaque species. All rings remained in
place during the study period (2 to 4 weeks), and the animals did not attempt to remove the rings. No tissue irritation was observed, and no signs of physical
discomfort were noted. Also, no significant induction of cervicovaginal proinflammatory markers was observed during the 8-week period during and following ring insertion. One Pigtailed macaque showed elevated IL-8 levels in the CVL during the period when the ring was in place; however, these levels were comparable to those observed in two control macaques. In vitro release of the ZFIs peaked at day 1 and then continually declined to near steady-state rates between 20-30 mcg/day. The percent release after 14 days was 2.9, 2.0 and 0.9 for ZFI 89, 52 and 122, respectively.

Conclusions: IVRs of 25mm diameter, determined to be the optimal size for macaques, were well tolerated and did not induce inflammation. Release of all ZFI compounds followed t 0.5 kinetics. These findings suggest that efficacy testing in primate models is warranted to fully evaluate the potential to prevent
transmission.

Semiring induced valuation algebras: Exact and approximate local computation algorithms

Local computation in join trees or acyclic hypertrees has been shown to be linked to a particular algebraic structure, called valuation algebra.There are many models of this algebraic structure ranging from probability theory to numerical analysis, relational databases and various classical and non-classical logics. It turns out that many interesting models of valuation algebras may be derived from semiring valued mappings. In this paper we study how valuation algebras are induced by semirings and how the structure of the valuation algebra is related to the algebraic structure of the semiring. In particular, c-semirings with idempotent multiplication induce idempotent valuation algebras and therefore permit particularly efficient architectures for local computation. Also important are semirings whose multiplicative semigroup is embedded in a union of groups. They induce valuation algebras with a partially defined division. For these valuation algebras, the well-known architectures for Bayesian networks apply. We also extend the general computational framework to allow derivation of bounds and approximations, for when exact computation is not feasible.

Minimal Hilbert series for quadratic algebras and the Anick conjecture

We study the question on whether the famous Golod–Shafarevich estimate, which gives a lower bound for the Hilbert series of a (noncommutative) algebra, is attained. This question was considered by Anick in his 1983 paper ‘Generic algebras and CW-complexes’, Princeton Univ. Press, where he proved that the estimate is attained for the number of quadratic relations $d\leq n^2/4$
and $d\geq n^2/2$, and conjectured that it is the case for any number of quadratic relations. The particular point where the number of relations is equal to $n(n-1)/2$ was addressed by Vershik. He conjectured that a generic algebra with this number of relations is finite dimensional. We announce here the result that over any infinite field, the Anick conjecture holds for $d \geq 4(n2+n)/9$ and an arbitrary number of generators. We also discuss the result that confirms the Vershik conjecture over any field of characteristic 0, and a series of related
asymptotic results.

Finite domination and Novikov rings: Laurent polynomial rings in two variables

Let C be a bounded cochain complex of finitely generatedfree modules over the Laurent polynomial ring L = R[x, x−1, y, y−1].The complex C is called R-finitely dominated if it is homotopy equivalentover R to a bounded complex of finitely generated projective Rmodules.Our main result characterises R-finitely dominated complexesin terms of Novikov cohomology: C is R-finitely dominated if andonly if eight complexes derived from C are acyclic; these complexes areC ⊗L R[[x, y]][(xy)−1] and C ⊗L R[x, x−1][[y]][y−1], and their variants obtainedby swapping x and y, and replacing either indeterminate by its inverse.

Sets of multiplicity and closable multipliers on group algebras

We undertake a detailed study of the sets of multiplicity in a second countable locally compact group G and their operator versions. We establish a symbolic calculus for normal completely bounded maps from the space B(L-2(G)) of bounded linear operators on L-2 (G) into the von Neumann algebra VN(G) of G and use it to show that a closed subset E subset of G is a set of multiplicity if and only if the set E* = {(s,t) is an element of G x G : ts(-1) is an element of E} is a set of operator multiplicity. Analogous results are established for M-1-sets and M-0-sets. We show that the property of being a set of multiplicity is preserved under various operations, including taking direct products, and establish an Inverse Image Theorem for such sets. We characterise the sets of finite width that are also sets of operator multiplicity, and show that every compact operator supported on a set of finite width can be approximated by sums of rank one operators supported on the same set. We show that, if G satisfies a mild approximation condition, pointwise multiplication by a given measurable function psi : G -> C defines a closable multiplier on the reduced C*-algebra G(r)*(G) of G if and only if Schur multiplication by the function N(psi): G x G -> C, given by N(psi)(s, t) = psi(ts(-1)), is a closable operator when viewed as a densely defined linear map on the space of compact operators on L-2(G). Similar results are obtained for multipliers on VN(C).

Ideals of A(G) and bimodules over maximal abelian selfadjoint algebras

This paper is concerned with weak⁎ closed masa-bimodules generated by A(G)-invariant subspaces of VN(G). An annihilator formula is established, which is used to characterise the weak⁎ closed subspaces of B(L2(G)) which are invariant under both Schur multipliers and a canonical action of M(G) on B(L2(G)) via completely bounded maps. We study the special cases of extremal ideals with a given null set and, for a large class of groups, we establish a link between relative spectral synthesis and relative operator synthesis.

Two dimensional unital Riesz algebras, their representations and norms

We describe all two dimensional unital Riesz algebras and study representations of them in Riesz algebras of regular operators. Although our results are not complete, we do demonstrate that very varied behaviour can occur even though all these algebras can be given a Banach lattice algebra norm.

Finite domination and Novikov rings. Laurent polynomial rings in several variables

We present a homological characterisation of those chain complexes of modules over a Laurent polynomial ring in several indeterminates which are finitely dominated over the ground ring (that is, are a retract up to homotopy of a bounded complex of finitely generated free modules). The main tools, which we develop in the paper, are a non-standard totalisation construction for multi-complexes based on truncated products, and a high-dimensional mapping torus construction employing a theory of cubical diagrams that commute up to specified coherent homotopies.

Microbicide Vaginal Rings: Technological Challenges and Clinical Development

Vaginal rings (VRs) are flexible, torus-shaped, polymeric devices designed to sustain delivery of pharmaceutical drugs to the vagina for clinical benefit. Following first report in a 1970 patent application, several steroid-releasing VR products have since been marketed for use in hormone replacement therapy and contraception. Since 2002, there has been growing interest in the use of VR technology for delivery of drugs that can reduce the risk of sexual acquisition of human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Although no vaginally-administered product has yet been approved for HIV reduction/prevention, extensive research efforts are continuing and a number of VR devices offering sustained release of so-called ‘HIV microbicide’ compounds are currently being evaluated in late-stage clinical studies. This review article provides an overview of the published scientific literature within this important field of research, focusing primarily on articles published within peer-reviewed journal publications. Many important aspects of microbicide-releasing VR technology are discussed, with a particular emphasis on the technological, manufacturing and clinical challenges that have emerged in recent years.