Citations

ABSTRACT The accumulation of filamentous a‐synuclein (α‐S) is associated with Parkinson's disease. It remains controversial as to the mode (antiparallel or parallel) of α‐S self‐assembly and whether an exact alignment of the central hydrophobic region is essential. In the present study, we performed in vitro assembly using α‐S with or without the attachment of artificial leucine zippers (Zips) capable of forming either parallel or antiparallel coiled coils and included a spacer in one derivative. Results showed that Zips accelerate filament assembly in both the parallel and antiparallel fashions, that a precise alignment of the central hydrophobic region is not essential, and that the antiparallel pairs displayed the highest thioflavin T signals. More importantly, cells expressing Zip‐fused α‐S, but not α‐S alone, formed α‐S immunopositive and thioflavin S‐positive inclusions in 7 days. The results suggest that α‐S can assemble in both parallel and antiparallel modes but have a higher tendency to assemble in the latter mode and that cells overexpressing Zip‐fused α‐S may be used to screen α‐S assembly inhibitors due to enhanced ability to form inclusions.—Jiang, P., Ko, L., Jansen, K. R., Golde, T. E., Yen, S.‐H. Using leucine zipper to facilitate α‐synuclein assembly. FASEB J. 22, 3165–3174 (2008)

The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.

Purpose Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non–small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. Patients and Methods Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m 2 on days 1 and 8 plus etoposide 50 mg/m 2 on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m 2 . Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. Results Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. Conclusion In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

Activation of γ-aminobutyric acid (GABA) A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABA A receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABA A agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABA A receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.