† People involved in the organization of the challenge. ‡ People contributing data from their institutions.§ Equal senior authors.

Objective: To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association. Methods: In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies. Results: We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test. Interpretation: Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloidrelated cognitive impairment.

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N'G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth.

Antibody-associated paraneoplastic cerebellar degeneration (the Yo syndrome) is an uncommon disorder in which an immune response is specifically directed against tumor tissue and the cerebellum. Screening of a A expression library has resulted in the isolation of cDNA clones that encode the major antigen recognized by serum from these patients. The fusion protein produced by the cDNA clones provides the basis of a simple diagnostic assay for this neurological syndrome. The occurrence of leucine-zipper and zinc-finger motifs in the predicted open reading frame suggests that this protein plays a role in the regulation of gene expression.Paraneoplastic cerebellar degeneration is a disorder of the cerebellum found in association with neoplasms of lung, ovary, breast, or Hodgkin disease (1). Neuropathological analysis of affected brains has revealed extensive loss of Purkinje cells, variable loss of granule and basket neurons, and proliferation of Bergman glia (2). The relationship between the primary tumor and the resultant cerebellar dysfunction is not clearly understood. The presence of infiltrating lymphocytes in some of the affected brains has suggested an immune mechanism (3).A clinically definable subset of patients with paraneoplastic cerebellar degeneration harbor a characteristic antibody that has been called anti-Yo (4). Sera from these patients react with antigens expressed in the Purkinje cells of the normal cerebellum and in the tumor tissue of affected individuals (5). There is also evidence of increased antibody synthesis in the affected brains (6). These observations suggest a model for the neurological dysfunction in which an immune response primarily directed against a tumor antigen is misdirected against similar antigens peculiar to the cerebellum. On Western blot analysis of Purkinje cells and tumor tissue, the anti-Yo sera react with at least two antigens, a major species of 62 kDa (CDR-62) and a minor species of 34 kDa (CDR-34) (where CDR is cerebellar degeneration related) (7). The gene encoding the minor antigen (CDR-34) has been isolated and characterized (8,9). We now report the isolation of cDNAs that encode the major Yo paraneoplastic antigen. Sequence analysis § revealed CDR-62 to be a member of a family of the leucine-zipper DNA binding proteins. The availability of the recombinant protein has provided a simple diagnostic assay for the presence of anti-Yo antibodies.MATERIALS AND METHODS Sera from patients with antibody-associated paraneoplastic cerebellar degeneration was obtained from their physicians.A HeLa cell A ZAP expression library was obtained from Stratagene.Screening of A HeLa Expression Library. Recombinant phage were screened at a density of 2 x 104 plaque-forming units per 150-mm plate of Escherichia coli XLI-Blue. After incubation for 6 hr at 370C, the plates were overlaid with filters soaked in isopropyl 8-D-thiogalactopyranoside (10 mM) and incubated for a further 12 hr at 370C. The filters were then removed and incubated with anti-Yo sera (IgG, 2 tug/ml) for 2 ...

Eukaryotic circadian clocks include interconnected positive and negative feedback loops. The clock-cycle dimer (CLK-CYC) and its homolog, CLK-BMAL1, are key transcriptional activators of central components of the Drosophila and mammalian circadian networks, respectively. In Drosophila, negative loops include period-timeless and vrille; positive loops include par domain protein 1. Clockwork orange (CWO) is a recently discovered negative transcription factor with unusual effects on period, timeless, vrille, and par domain protein 1. To understand the actions of this protein, we introduced a new system of ordinary differential equations to model regulatory networks. The model is faithful in the sense that it replicates biological observations. CWO loop actions elevate CLK-CYC; the transcription of direct targets responds by integrating opposing signals from CWO and CLK-CYC. Loop regulation and integration of opposite transcriptional signals appear to be central mechanisms as they also explain paradoxical effects of period gain-of-function and null mutations.