The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4

The inflammatory toxicity of lipopolysaccharide (LPS), a component of bacterial cell walls, is driven by the adaptor proteins myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta (TRIF), which together mediate signaling by the endotoxin receptor Toll-like receptor 4 (TLR4). Monophosphoryl lipid A (MPLA) is a low-toxicity derivative of LPS with useful immunostimulatory properties, which is nearing regulatory approval for use as a human vaccine adjuvant. We report here that, in mice, the low toxicity of MPLA's adjuvant function is associated with a bias toward TRIF signaling, which we suggest is likely caused by the active suppression, rather than passive loss, of proinflammatory activity of this LPS derivative. This finding may have important implications for the development of future vaccine adjuvants.     

Interaction of calcitonin and calcitonin gene-related peptide at receptor sites in target tissues

Discrete receptor sites for calcitonin (CT) and calcitonin gene-related peptide (CGRP) were found in the nervous system and in peripheral tissues. Each peptide was capable of cross-reacting with the specific receptor of the other. In contrast to CT receptors, CGRP receptors were not linked to adenylate cyclase. However, CGRP could stimulate adenylate cyclase in CT target tissues apparently by interacting with CT receptors. The relative abilities of CGRP and mammalian CT to inhibit CT binding suggest that CGRP could serve as an endogenous ligand for CT receptors in the central nervous system.     

Sex pheromones and reproductive isolation of the lesser peachtree borer and the peachtree borer

(E,Z)-3,13-octadecadien-1-ol acetate, and (Z,Z)-3,13-octadecadien-1-ol acetate, isolated from the female lesser peachtree borer, Synanthedon pictipes (Grote and Robinson), and the female peachtree borer, Sanninoidea exitiosa (Say), respectively, strongly attract the respective males of these species in field bioassays. These compounds are the largest pheromones isolated thus far from a lepidopterous species. Sanninoidea exitiosa males did not respond to the synthesized (E,Z)-isomer, and low concentrations of it in the synthesized (Z,Z)-isomer did not interfere with their response to the (Z,Z)-isomer. In contrast, even very low concentrations of the (Z,Z)-isomer (1 percent) in the (E,Z)-isomer significantly inhibited the response of Synanthedon pictipes males.     

Self-trapping of dark incoherent light beams

"Dark beams" are nonuniform optical beams that contain either a one-dimensional (1D) dark stripe or a two-dimensional (2D) dark hole resulting from a phase singularity or an amplitude depression in their optical field. Thus far, self-trapped dark beams (dark solitons) have been observed using coherent light only. Here, self-trapped dark incoherent light beams (self-trapped dark incoherent wavepackets) were observed. Both dark stripes and dark holes nested in a broad partially spatially incoherent wavefront were self-trapped to form dark solitons in a host photorefractive medium. These self-trapped 1D and 2D dark beams induced refractive-index changes akin to planar and circular dielectric waveguides. The experiments introduce the possibility of controlling high-power coherent laser beams with low-power incoherent light sources such as light emitting diodes.     

Feline attractant, cis,trans-nepetalactone: metabolism in the domestic cat

cis,trans-Nepetalactone, the biologically active component of catnip, was force-fed to the domestic cat. When the (14)C-labeled compound was fed, 86 to 94 percent of the radioactivity was recovered in the urine, 1 to 2 percent was found in the feces, and 1 to 12 percent was collected as carbon dioxide. The major (50 to 75 percent) metabolite was alpha-nepetalinic acid, which was excreted in the urine together with small amounts of dihydronepetalactone, unchanged cis,-trans-nepetalactone, and several unidentified compounds. No marked physiological or histological eflects were observed when 20 to 80 milligrams of cis, trans-nepetalactone was administered orally. This is the first report on the metabolism of a mammalian attractant.     

Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice

DARPP-32, a dopamine- and adenosine 3',5'-monophosphate (cAMP)-regulated phosphoprotein (32 kilodaltons in size), is an obligate intermediate in progesterone (P)-facilitated sexual receptivity in female rats and mice. The facilitative effect of P on sexual receptivity in female rats was blocked by antisense oligonucleotides to DARPP-32. Homozygous mice carrying a null mutation for the DARPP-32 gene exhibited minimal levels of P-facilitated sexual receptivity when compared to their wild-type littermates. P significantly increased hypothalamic cAMP levels and cAMP-dependent protein kinase activity. These increases were not inhibited by a D1 subclass dopamine receptor antagonist. P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice. DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice.