Activation of Visuomotor Systems during Visually Guided Movements: A Functional MRI Study

The dorsal stream is a dominant visuomotor pathway that connects the striate and extrastriate cortices to posterior parietal areas. In turn, the posterior parietal areas send projections to the frontal primary motor and premotor areas. This cortical pathway is hypothesized to be involved in the transformation of a visual input into the appropriate motor output. In this study we used functional magnetic resonance imaging (fMRI) of the entire brain to determine the patterns of activation that occurred while subjects performed a visually guided motor task. In nine human subjects, fMRI data were acquired on a 4-T whole-body MR system equipped with a head gradient coil and a birdcage RF coil using aT^*₂-weighted EPI sequence. Functional activation was determined for three different tasks: (1) a visuomotor task consisting of moving a cursor on a screen with a joystick in relation to various targets, (2) a hand movement task consisting of moving the joystick without visual input, and (3) a eye movement task consisting of moving the eyes alone without visual input. Blood oxygenation level-dependent (BOLD) contrast-based activation maps of each subject were generated using period cross-correlation statistics. Subsequently, each subject's brain was normalized to Talairach coordinates, and the individual maps were compared on a pixel by pixel basis. Significantly activated pixels common to at least four out of six subjects were retained to construct the final functional image. The pattern of activation during visually guided movements was consistent with the flow of information from striate and extrastriate visual areas, to the posterior parietal complex, and then to frontal motor areas. The extensive activation of this network and the reproducibility among subjects is consistent with a role for the dorsal stream in transforming visual information into motor behavior. Also extensively activated were the medial and lateral cerebellar structures, implicating the cortico–ponto–cerebellar pathway in visually guided movements. Thalamic activation, particularly of the pulvinar, suggests that this nucleus is an important subcortical target of the dorsal stream.     

Conformational analysis of furanoid epsilon-sugar amino acid containing cyclic peptides by NMR spectroscopy,molecular dynamics simulation,and X-ray crystallography: evidence for a novel turn structure

Sugar amino acids (SAAs) are useful building blocks for the design of peptidomimetics and peptide scaffolds. The three-dimensional structures of cyclic hybrid molecules containing the furanoid epsilon-SAA III and several amino acids were elucidated to study the preferred conformation of such an epsilon-SAA and its conformational influence on the backbone of cyclic peptides. NMR-based molecular dynamics simulations and empirical calculations of the cyclic tetramer 1, consisting of two copies of the SAA residue and two amino acids, revealed that it is conformationally restrained. The two SAA residues adopt different conformations. One of them forms an unusual turn, stabilized by an intraresidue nine-member hydrogen bond. The methylene functionalities of the other SAA residue are positioned in such a way that an intraresidue H bond is not possible. The X-ray crystal structure of 1 strongly resembles the solution conformation. Molecular dynamics calculations in combination with NMR analysis were also performed for compounds 2 and 3, which contain the RGD (Arg-Gly-Asp) consensus sequence and were previously shown to inhibit alpha(IIb)beta(3)-receptor-mediated platelet aggregation. The biologically most active compound 2 adopts a preferred conformation with the single SAA residue folded into the nine-member H bond-containing turn. Compound 3, containing an additional valine residue, as compared with compound 2, is conformational flexible. Our studies demonstrate that the furanoid epsilon-SAA III is able to introduce an unusual intraresidue hydrogen bond-stabilized beta-turn-like conformation in two of the three cyclic structures.     

Development of a dual cell, flow-injection sample holder, and NMR probe for comparative ligand-binding studies

NMR based ligand screening is becoming increasingly important for the very early stages of drug discovery. We have proposed a method that makes highly efficient use of a single sample of a scarce target, or one with poor or limited solubility, to screen an entire compound library. This comparative method is based on immobilizing the target for the screening procedure. In order to support the method, a dual cell, flow injection probe with a single receiver coil has been constructed. The flow injection probe has been mated to a single high performance pump and sample handling system to enable the automated analysis of large numbers of compound mixes for binding to the target. The probe, having an 8 mm 1H/2H dual tuned coil and triple axis gradients, is easily shimmed and yields NMR spectra of comparable quality to a standard 5 mm high-resolution probe. The lineshape in the presence of a solid support is identical to that in glass NMR tubes in a 5 mm probe. Control spectra of each cell are identical and well separated, while ligand binding in a complex mixture can be readily detected in 20-30 min, thus paving the way for use of the probe for actual drug discovery efforts.     

Serum Levels of 25‐Hydroxy‐Vitamin D3 Among Sun‐protected Outdoor Workers in Israel

The objective of this study was to evaluate the effect of reduced sun exposure of outdoor workers on vitamin D status using different modalities of sun protection, for primary prevention of skin cancer. 25‐OH‐D3 measurements were performed in two successive winters, 8 (interim) and 20 months after initiation of the study, in three groups of male outdoor workers, enrolled in either a complete, partial or minimal sun protection program. Ambient solar UVB radiation was monitored simultaneously. No intragroup or intergroup differences were observed between the interim‐ and postintervention measurements of mean 25‐OH‐D3, which were close to 30 ng mL^?1. Significant risk factors for postintervention 25‐OH‐D3 levels >33.8 ng mL^?1 (a surrogate for reduced sun protection) were: previous sunburn episodes (OR 2.5; 95% CI 1.01–6.3; P = 0.05) and younger age (OR 0.92; 95 CI 0.86–0.98; P = 0.009). Outdoor workers of Western, compared with those of Eastern paternal origin had a borderline significant risk (OR 2.4; 95% CI 0.9–6.3; P = 0.07). A borderline significant effect (OR 2.9; 95% CI 0.97–10.1; P = 0.085) was also noted for those in the minimal intervention group. In conclusion, sun protection among outdoor workers following a successful intervention did not suppress mean winter 25‐OH‐D3.