Translation of structure‐activity relationships from cyclic mixed efficacy opioid peptides to linear analogues

Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR‐related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr‐DThr‐Gly‐Phe‐Leu‐Ser‐NH 2 ( DTLES ), as a lead scaffold, we replaced Phe 4 with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C‐terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 107–114, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102641/1/bip22437.pd

Variation and genetic structure of Melipona quadrifasciata Lepeletier (Hymenoptera, Apidae) populations based on ISSR pattern

For a study of diversity and genetic structuring in Melipona quadrifasciata, 61 colonies were collected in eight locations in the state of Minas Gerais, Brazil. By means of PCR analysis, 119 ISSR bands were obtained, 80 (68%) being polymorphic. He and H B were 0.20 and 0.16, respectively. Two large groups were obtained by the UPGMA method, one formed by individuals from Januária, Urucuia, Rio Vermelho and Caeté and the other by individuals from São João Del Rei, Barbacena, Ressaquinha and Cristiano Otoni. The Φst and θB values were 0.65 and 0.58, respectively, thereby indicating high population structuring. UPGMA grouping did not reveal genetic structuring of M. quadrifasciata in function of the tergite stripe pattern. The significant correlation between dissimilarity values and geographic distances (r = 0.3998; p < 0.05) implies possible geographic isolation. The genetic differentiation in population grouping was probably the result of an interruption in gene flow, brought about by geographic barriers between mutually close geographical locations. Our results also demonstrate the potential of ISSR markers in the study of Melipona quadrifasciata population structuring, possibly applicable to the studies of other bee species

Variable CW RF power coupler for 345 MHz superconducting cavities

This paper reports the development of a CW variable coupler for 345 MHz spoke-loaded superconducting (SC) cavities. The coupler inserts an 80 K copper loop into a 5 cm (2 inch) interior diameter coupling port on several types of spoke-loaded cavity operating at 2 K or 4 K. The coupling loop can be moved during operation to vary the coupling over a range of 50 dB. The coupler is designed to facilitate high-pressure water rinsing and low-particulate clean assembly. Design details and operating characteristics are discussed

Multiple (inverse) binomial sums of arbitrary weight and depth and the all-order epsilon-expansion of generalized hypergeometric functions with one half-integer value of parameter

We continue the study of the construction of analytical coefficients of the epsilon-expansion of hypergeometric functions and their connection with Feynman diagrams. In this paper, we show the following results: Theorem A: The multiple (inverse) binomial sums of arbitrary weight and depth (see Eq. (1.1)) are expressible in terms of Remiddi-Vermaseren functions. Theorem B: The epsilon expansion of a hypergeometric function with one half-integer value of parameter (see Eq. (1.2)) is expressible in terms of the harmonic polylogarithms of Remiddi and Vermaseren with coefficients that are ratios of polynomials. Some extra materials are available via the www at this http://theor.jinr.ru/~kalmykov/hypergeom/hyper.htmlComment: 24 pages, latex with amsmath and JHEP3.cls; v2: some typos corrected and a few references added; v3: few references added

Holomorphic Quantization on the Torus and Finite Quantum Mechanics

We construct explicitly the quantization of classical linear maps of $SL(2, R)$ on toroidal phase space, of arbitrary modulus, using the holomorphic (chiral) version of the metaplectic representation. We show that Finite Quantum Mechanics (FQM) on tori of arbitrary integer discretization, is a consistent restriction of the holomorphic quantization of $SL(2, Z)$ to the subgroup $SL(2, Z)/\Gamma_l$, $\Gamma_l$ being the principal congruent subgroup mod l, on a finite dimensional Hilbert space. The generators of the ``rotation group'' mod l, $O_{l}(2)\subset SL(2,l)$, for arbitrary values of l are determined as well as their quantum mechanical eigenvalues and eigenstates.Comment: 12 pages LaTeX (needs amssymb.sty). Version as will appear in J. Phys.

H\"older-continuous rough paths by Fourier normal ordering

We construct in this article an explicit geometric rough path over arbitrary $d$-dimensional paths with finite $1/\alpha$-variation for any $\alpha\in(0,1)$. The method may be coined as 'Fourier normal ordering', since it consists in a regularization obtained after permuting the order of integration in iterated integrals so that innermost integrals have highest Fourier frequencies. In doing so, there appear non-trivial tree combinatorics, which are best understood by using the structure of the Hopf algebra of decorated rooted trees (in connection with the Chen or multiplicative property) and of the Hopf shuffle algebra (in connection with the shuffle or geometric property). H\"older continuity is proved by using Besov norms. The method is well-suited in particular in view of applications to probability theory (see the companion article \cite{Unt09} for the construction of a rough path over multidimensional fractional Brownian motion with Hurst index $\alpha<1/4$, or \cite{Unt09ter} for a short survey in that case).Comment: 50 pages, 6 figure

Linac Coherent Light Source Undulator RF BPM System

The Linac Coherent Light Source (LCLS) will be the world's first x-ray free-electron laser (FEL) when it becomes operational in 2009. The LCLS is currently in the construction phase. The beam position monitor (BPM) system planned for the LCLS undulator will incorporate a high-resolution X-band cavity BPM system described in this paper. The BPM system will provide high-resolution measurements of the electron beam trajectory on a pulse-to-pulse basis and over many shots. The X-band cavity BPM size, simple fabrication, and high resolution make it an ideal choice for LCLS beam position detection. We will discuss the system specifications, design, and prototype test results

Design and Performance of the LCLS Cavity BPM System

In this paper we present the design of the beam position monitor (BPM) system for the LCLS undulator, which features a high-resolution X-band cavity BPM. Each BPM has a TM{sub 010} monopole reference cavity and a TM{sub 110} dipole cavity designed to operate at a center frequency of 11.384 GHz. The signal processing electronics features a low noise single-stage three-channel heterodyne receiver that has selectable gain and a phase locking local oscillator. We will discuss the system specifications, design, and prototype test results

Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression

Background. End-stage renal disease (ESRD) results in increased susceptibility to infections, impaired response to vaccination and diffuse B-cell lymphopenia. However, the precise nature and mechanism of ESRD-induced B-cell lymphopenia remains unclear. Therefore, we studied the distribution of major B-cell subsets, B-cell growth, differentiation and survival factors, IL-7 and BAFF, and their receptors in 21 haemodialysis patients and 21 controls