Retinal degeneration is associated with brain volume reduction and prognosis in radiologically isolated syndrome.

BACKGROUND: The extent of neurodegeneration in the earliest stages of central nervous system (CNS) demyelination is not known. Optical coherence tomography (OCT) is a powerful tool to study neurodegeneration in demyelinating disorders. OBJECTIVES: To study neuroaxonal loss in the retina of individuals with radiologically isolated syndrome (RIS) and investigate whether OCT measurements are associated with brain volumetrics and clinical conversion to multiple sclerosis (MS). METHODS: Subjects fulfilling the Okuda criteria for RIS (n = 15 patients, 30 eyes) and age- and sex-matched healthy controls (HC) underwent spectral-domain OCT and magnetic resonance imaging for volumetric measurement of brain structures. RESULTS: Macular ganglion cell-inner plexiform layer (mGCIPL), macular retinal nerve fiber layer (mRNFL), and temporal peripapillary RNFL (pRNFL) thickness; normalized total brain volume (nTBV); and normalized thalamic volume (nTV) were reduced in RIS compared to HC. mGCIPL, mRNFL, and pRNFL measurements were associated with nTBV, nTV, and normalized gray and white matter volumes in the RIS group. pRNFL was thinner in individuals with RIS who converted to MS in 5 years. CONCLUSIONS: Retinal neurodegeneration can be detected in the papillomacular region in the earliest stages of CNS demyelination and reflects global disease processes in the brain. OCT can be potentially useful for predicting prognosis in RIS.

Predictors of progression in primary progressive multiple sclerosis in a large Turkish cohort.

BACKGROUND: Studies on the predictors of progression for primary progressive multiple sclerosis (PPMS) are limited and there is no information in the literature for populations outside Europe and North America. In this study, we aimed to identify predictors of progression in a large Turkish PPMS cohort. METHODS: We analyzed a cohort of 157 PPMS patients to investigate the effect of age of onset, gender, onset symptoms, presence or absence of relapses, and baseline gadolinium-enhancing lesions on the rate of progression to EDSS6 by using Kaplan-Meier analysis and multivariate Cox regression. RESULTS: Older age of onset and presence of spinal motor symptoms at onset were associated with a shorter time to EDSS6 and presence of supratentorial signs at onset was associated with a longer time to EDSS6 according to Kaplan-Meier analysis. These factors remained significant after multivariate Cox-regression analysis. Clinical relapses were present in 22.3% and gadolinium-enhancing lesions on baseline MRI were present in 28% of patients, but these factors were not predictive of time to EDSS6. CONCLUSION: We identified age of onset and symptom at onset as predictors of progression in Turkish PPMS patients. Presence of clinical relapses or baseline gadolinium-enhancing lesions did not affect PPMS progression rate.

Receptors and other signaling proteins required for serotonin control of locomotion in Caenorhabditis elegans.

A better understanding of the molecular mechanisms of signaling by the neurotransmitter serotonin is required to assess the hypothesis that defects in serotonin signaling underlie depression in humans. Caenorhabditis elegans uses serotonin as a neurotransmitter to regulate locomotion, providing a genetic system to analyze serotonin signaling. From large-scale genetic screens we identified 36 mutants of C. elegans in which serotonin fails to have its normal effect of slowing locomotion, and we molecularly identified eight genes affected by 19 of the mutations. Two of the genes encode the serotonin-gated ion channel MOD-1 and the G-protein-coupled serotonin receptor SER-4. mod-1 is expressed in the neurons and muscles that directly control locomotion, while ser-4 is expressed in an almost entirely non-overlapping set of sensory and interneurons. The cells expressing the two receptors are largely not direct postsynaptic targets of serotonergic neurons. We analyzed animals lacking or overexpressing the receptors in various combinations using several assays for serotonin response. We found that the two receptors act in parallel to affect locomotion. Our results show that serotonin functions as an extrasynaptic signal that independently activates multiple receptors at a distance from its release sites and identify at least six additional proteins that appear to act with serotonin receptors to mediate serotonin response.

Structures of triacetyloleandomycin and mycalamide A bind to the large ribosomal subunit of Haloarcula marismortui.

Structures have been obtained for the complexes that triacetyloleandomycin and mycalamide A form with the large ribosomal subunit of Haloarcula marismortui. Triacetyloleandomycin binds in the nascent peptide tunnel and inhibits the activity of ribosomes by blocking the growth of the nascent peptide chain. Mycalamide A binds to the E site and inhibits protein synthesis by occupying the space normally occupied by the CCA end of E-site-bound tRNAs.

U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome.

Structures have been obtained for the complexes that tiamulin, homoharringtonine, and bruceantin form with the large ribosomal subunit of Haloarcula marismortui at resolutions ranging from 2.65 to 3.2 A. They show that all these inhibitors block protein synthesis by competing with the amino acid side chains of incoming aminoacyl-tRNAs for binding in the A-site cleft in the peptidyl-transferase center, which is universally conserved. In addition, these structures support the hypothesis that the species specificity exhibited by the A-site cleft inhibitors is determined by the interactions they make, or fail to make, with a single nucleotide, U2504 (Escherichia coli). In the ribosome, the position of U2504 is controlled by its interactions with neighboring nucleotides, whose identities vary among kingdoms.

Mutations outside the anisomycin-binding site can make ribosomes drug-resistant.

Eleven mutations that make Haloarcula marismortui resistant to anisomycin, an antibiotic that competes with the amino acid side chains of aminoacyl tRNAs for binding to the A-site cleft of the large ribosomal unit, have been identified in 23S rRNA. The correlation observed between the sensitivity of H. marismortui to anisomycin and the affinity of its large ribosomal subunits for the drug indicates that its response to anisomycin is determined primarily by the binding of the drug to its large ribosomal subunit. The structures of large ribosomal subunits containing resistance mutations show that these mutations can be divided into two classes: (1) those that interfere with specific drug-ribosome interactions and (2) those that stabilize the apo conformation of the A-site cleft of the ribosome relative to its drug-bound conformation. The conformational effects of some mutations of the second kind propagate through the ribosome for considerable distances and are reversed when A-site substrates bind to the ribosome.