The C9 methyl group of retinal interacts with glycine-121 in rhodopsin

The visual pigment rhodopsin is a prototypical G protein-coupled receptor. These receptors have seven transmembrane helices and are activated by specific receptor–ligand interactions. Rhodopsin is unusual in that its retinal prosthetic group serves as an antagonist in the dark in the 11-cis conformation but is rapidly converted to an agonist on photochemical cis to trans isomerization. Receptor–ligand interactions in rhodopsin were studied in the light and dark by regenerating site-directed opsin mutants with synthetic retinal analogues. A progressive decrease in light-dependent transducin activity was observed when a mutant opsin with a replacement of Gly121 was regenerated with 11-cis-retinal analogues bearing progressively larger R groups (methyl, ethyl, propyl) at the C9 position of the polyene chain. A progressive decrease in light activity was also observed as a function of increasing size of the residue at position 121 for both the 11-cis-9-ethyl- and the 11-cis-9-propylretinal pigments. In contrast, a striking increase of receptor activity in the dark—i.e., without chromophore isomerization—was observed when the molecular volume at either position 121 of opsin or C9 of retinal was increased. The ability of bulky replacements at either position to hinder ligand incorporation and to activate rhodopsin in the dark suggests a direct interaction between these two sites. A molecular model of the retinal-binding site of rhodopsin is proposed that illustrates the specific interaction between Gly121 and the C9 methyl group of 11-cis-retinal. Steric interactions in this region of rhodopsin are consistent with the proposal that movement of transmembrane helices 3 and 6 is concomitant with receptor activation.

Investigation by Parkinson’s Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson’s disease: further results of randomised trial and confidential inquiry

Objective: To determine whether the excess mortality observed in patients who received both levodopa and selegiline in a randomised trial could be explained by revised diagnosis of Parkinson’s disease, autonomic or cardiovascular effects, more rapid disease progression, or drug interactions.

Involvement of a cytosine side chain in proton transfer in the rate-determining step of ribozyme self-cleavage

Ribozymes of hepatitis delta virus have been proposed to use an active-site cytosine as an acid-base catalyst in the self-cleavage reaction. In this study, we have examined the role of cytosine in more detail with the antigenomic ribozyme. Evidence that proton transfer in the rate-determining step involved cytosine 76 (C76) was obtained from examining cleavage activity of the wild-type and imidazole buffer-rescued C76-deleted (C76Δ) ribozymes in D2O and H2O. In both reactions, a similar kinetic isotope effect and shift in the apparent pKa indicate that the buffer is functionally substituting for the side chain in proton transfer. Proton inventory of the wild-type reaction supported a mechanism of a single proton transfer at the transition state. This proton transfer step was further characterized by exogenous base rescue of a C76Δ mutant with cytosine and imidazole analogues. For the imidazole analogues that rescued activity, the apparent pKa of the rescue reaction, measured under kcat/KM conditions, correlated with the pKa of the base. From these data a Brønsted coefficient (β) of 0.51 was determined for the base-rescued reaction of C76Δ. This value is consistent with that expected for proton transfer in the transition state. Together, these data provide strong support for a mechanism where an RNA side chain participates directly in general acid or general base catalysis of the wild-type ribozyme to facilitate RNA cleavage.

Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells

Marrow stromal cells are adult stem cells from bone marrow that can differentiate into multiple nonhematopoietic cell lineages. Previous reports demonstrated that single-cell-derived colonies of marrow stromal cells contained two morphologically distinct cell types: spindle-shaped cells and large flat cells. Here we found that early colonies also contain a third kind of cell: very small round cells that rapidly self-renew. Samples enriched for the small cells had a greater potential for multipotential differentiation than samples enriched for the large cells. Also, the small cells expressed a series of surface epitopes and other proteins that potentially can be used to distinguish the small cells from the large cells. The results suggested it will be important to distinguish the major subpopulations of marrow stromal cells in defining their biology and their potential for cell and gene therapy.

Acridones: a chemically new group of protonophores.

Although the interaction of proton-conducting ionophores (protonophores) with photosynthetic electron transport has been extensively studied during the past decade, the mode of action of protonophores remained uncertain. For a better understanding of the molecular mechanism of the action of protonophores, the introduction of chemically new types of molecules will be required. In this work, we demonstrate that acridones (9-azaanthracene-10-ones) completely fulfill this requirement. At low concentrations of acridones, the thermoluminescence bands at +20 degrees C and +10 degrees C were strongly inhibited, while normal electron transport activity was retained. This indicates that the concentrations of S2 and S3 states involved in the generation of these bands are reduced. At higher concentrations, an increased activity of electron transport was observed, which is attributed to the typical uncoupler effect of protonophores. Indeed, acridones accelerate the decay of the electrochromic absorbance change at 515 nm and also inhibit the generation of the transmembrane proton gradient, measured as an absorbance transient of neutral red. Variable fluorescence induction was quenched even at low concentrations of acridones but was restored by either a long-term illumination or high light intensity. Acridones, similarly to other protonophores, promoted the autooxidation of the high-potential form of cytochrome b559 and partially converted it to lower potential forms. These results suggest that acridones, acting as typical protonophores, uncouple electron transport, accelerate the deactivation of the S2 and S3 states on the donor side, and facilitate the oxidation of cytochrome b559 on the acceptor side of photosystem II.

Episodic star formation in a group of LAEs at z=5.07

We are undertaking a search for high-redshift low-luminosity Lyman Alpha sources in the SHARDS (Survey for High-z Absorption Red and Dead Sources) survey. Among the pre-selected Lyman Alpha sources two candidates were spotted, located 3.19 arcsec apart, and tentatively at the same redshift. Here, we report on the spectroscopic confirmation with Gran Telescopio Canarias of the Lyman Alpha emission from this pair of galaxies at a confirmed spectroscopic redshifts of z=5.07. Furthermore, one of the sources is interacting/merging with another close companion that looks distorted. Based on the analysis of the spectroscopy and additional photometric data, we infer that most of the stellar mass of these objects was assembled in a burst of star formation 100 Myr ago. A more recent burst (2 Myr old) is necessary to account for the measured Lyman Alpha flux. We claim that these two galaxies are good examples of Lyman Alpha sources undergoing episodic star formation. Besides, these sources very likely constitute a group of interacting Lyman Alpha emitters (LAEs).

Factors Affecting Women Leaders in the Denver Group of the Colorado Mountain Club

A study of women leaders in the Colorado Mountain Club (CMC) demonstrated that this group perceived pace as an impediment to leadership growth. This study is an exploratory-quantitative inquiry that assessed the views of 20 of the active women hike leaders in the Denver group. The author designed a survey of factors women hike leaders would rate according to their CMC experiences. Although there are more women members of the Denver group, women leaders comprise only 30% of the leadership group The results from this first ever survey of CMC's women leaders provides a knowledge base for CMC and other interested parties. This study clearly demonstrated the need for more research into its topic of women in leadership positions.

A note on the periodic orbits of a self excited rigid body

The aim of the present paper is to study the periodic orbits of a perturbed self excited rigid body with a fixed point. For studying these periodic orbits we shall use averaging theory of first order.

Constructing an Indigenous Model of the Self to Address Cultural and Mental Health Issues in the Canadian Subarctic

Since the last decades, academic research has paid much attention to the phenomenon of revitalizing indigenous cultures and, more precisely, the use of traditional indigenous healing methods both to deal with individuals' mental health problems and with broader cultural issues. The re-evaluation of traditional indigenous healing practices as a mode of psychotherapeutic treatment has been perhaps one of the most interesting sociocultural processes in the postmodern era. In this regard, incorporating indigenous forms of healing in a contemporary framework of indigenous mental health treatment should be interpreted not simply as an alternative therapeutic response to the clinical context of Western psychiatry, but also constitutes a political response on the part of ethno-cultural groups that have been stereotyped as socially inferior and culturally backward. As a result, a postmodern form of "traditional healing" developed with various forms of knowledge, rites and the social uses of medicinal plants, has been set in motion on many Canadian indigenous reserves over the last two decades.

Ptycholepis marshi Newberry : a chondrostean fish from the Newark group of Eastern North America / Bobb Schaeffer --, David H. Dunkle --, Nicholas G. McDonald --.

v.33:no.12(1975)