Crystal Structure of Reovirus Attachment Protein σ1 in Complex with Sialylated Oligosaccharides

Many viruses attach to target cells by binding to cell-surface glycans. To gain a better understanding of strategies used by viruses to engage carbohydrate receptors, we determined the crystal structures of reovirus attachment protein σ1 in complex with α-2,3-sialyllactose, α-2,6-sialyllactose, and α-2,8-di-siallylactose. All three oligosaccharides terminate in sialic acid, which serves as a receptor for the reovirus serotype studied here. The overall structure of σ1 resembles an elongated, filamentous trimer. It contains a globular head featuring a compact β-barrel, and a fibrous extension formed by seven repeating units of a triple β-spiral that is interrupted near its midpoint by a short α -helical coiled coil. The carbohydrate-binding site is located between β-spiral repeats two and three, distal from the head. In all three complexes, the terminal sialic acid forms almost all of the contacts with σ1 in an identical manner, while the remaining components of the oligosaccharides make little or no contacts. We used this structural information to guide mutagenesis studies to identify residues in σ1 that functionally engage sialic acid by assessing hemagglutination capacity and growth in murine erythroleukemia cells, which require sialic acid binding for productive infection. Our studies using σ1 mutant viruses reveal that residues 198, 202, 203, 204, and 205 are required for functional binding to sialic acid by reovirus. These findings provide insight into mechanisms of reovirus attachment to cell-surface glycans and contribute to an understanding of carbohydrate binding by viruses. They also establish a filamentous, trimeric carbohydrate-binding module that could potentially be used to endow other trimeric proteins with carbohydrate-binding properties

Meta-analysis of genome-wide association studies for extraversion:Findings from the Genetics of Personality Consortium

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion

Long-term administration of butoctamide hydrogen succinate on nocturnal sleep of mentally retarded subjects: a polygraphic study versus placebo

Butoctamide hydrogen succinate (BAHS) has been proved to increase REM sleep in patients with reduced REM sleep. Following previous experiments on the effects of BAHS on nocturnal sleep of mentally retarded (MR) subjects, a polygraphic study was conducted on 20 MR subjects (age 8-14 years) to verify the effects of BAHS, 1) after long-term administration and 2) in different etiologies of MR. Subjects were divided into two balanced groups receiving placebo or 400 mg BAHS before sleep for a 6-month period. Basal sleep did not differ substantially in the two groups, both presenting reduced REM sleep. Low amounts of REM sleep were partially reversed by BAHS administration, which caused a significant increase in the REM sleep stage. Post-treatment sleep modifications found in the experimental group were not observed in the control group. BAHS produced its effects on REM sleep immediately after the first administration of the drug, but they became more apparent after long-term treatment. Our findings indicate that long-term administration of BAHS at low dosage maintains its effects on REM sleep of mentally retarded children, causing modifications similar to those previously obtained with single administration at higher dosages in cats, in healthy young and elderly volunteers and in Down's syndrome children. In addition, our observations demonstrate the effectiveness of BAHS on REM sleep, when utilized in mental retardation of etiologies other than Down's syndrome

EEG changes induced by carbamazepine therapy at rest and during mental processes

The effects of carbamazepine (CBZ) on EEG background activity have been studied, at rest and during mental processes, in 18 epileptic patients suffering from focal epilepsy and starting antiepileptic treatment for the first time. The EEGs were recorded before and after CBZ therapy, at rest with eyes closed (EC), during blocking reaction (BR), fixation (FIX) and mental arithmetic (MA) tasks, and then evaluated by spectral analysis. All data underwent statistical evaluation utilizing the ANOVA and correlation coefficient. The following parameters were evaluated: mean absolute and relative power and mean frequency. The results have shown that CBZ induced a significant increase of slow activity at rest with EC, which was represented by delta potentials, and was correlated with CBZ plasma levels. In evaluating the different cortical activation patterns, a decrease of the alpha reactivity was noted during BR and FIX, while a significant increase of beta activity was observed during the performance of all tasks. The relationship between the increased beta power, possibly reflecting an increase of cognitive activity for processing information, and the lack of a significant decrease of alpha activity are discussed

Sodium valproate and mental processes in newly referred epileptic patients. A computerized EEG study

Seventeen epileptic patients suffering from generalized idiopathic epilepsy who underwent antiepileptic treatment with sodium valproate (NaVPA) for the first time were studied. The EEG was recorded at rest with eyes closed (EC), during blocking reaction, fixation and mental arithmetic tasks. The computerized EEG study, performed before and after therapy, utilized spectral analysis; data underwent statistical evaluation including ANOVA and correlation analysis. Before NaVPA therapy, a significant decrease of beta 1 and beta 2 relative power, compared with control subjects, was observed in epileptic patients at rest with EC, whereas fast activity increased during mental tasks. After treatment, no significant variations in fast activity were observed during tasks, with a pattern similar to that observed in the control population. Therefore, considering the effect of NaVPA primarily on fast activity, which reflects rather well preserved mental functioning processes, it is possible to hypothesize that the drug interferes positively with mental activities

Effect of carbamazepine on EEG background activity and on interictal epileptiform abnormalities in focal epilepsy

The effect of carbamazepine (CBZ) on EEG background activity and on interictal epileptiform abnormalities (IEA) was studied in 15 patients with focal epilepsy who started antiepileptic drug treatment (AED) for the first time. A computerized EEG study, performed before and two months after starting therapy, utilized spectral analysis and automatic recognition of IEA. The occurrence of seizures was considered in order to clarify the relationship between IEA and the seizures themselves. Statistical evaluation of EEG spectral values was calculated through analysis of variance (ANOVA), while for IEA the non parametric Wilcoxon test was utilized. In 13 patients who remained seizure-free during the two month-period of observation, IEA was unchanged or decreased. In one of the two patients who continued to have seizures, IEA significantly increased. During therapy, the background activity presented significant increase of slow activity in approximately half the patients. This increase was more evident in those patients showing active epileptic foci before treatment, rather than in those with rare or no spikes. The changes in IEA seem to be related to the occurrence of seizures rather than to a direct action of CBZ on spikes

Lateralization of the epileptogenic focus by computerized EEG study and neuropsychological evaluation

The localization of the epileptogenic focus relies on different factors. In patients with partial seizures, asymmetries in EEG background activity were measured by a statistical evaluation of spectral data. Neurophysiological results were compared with neuropsychological findings and MRI. Fifteen of 22 patients showed asymmetries in EEG background activity. The most prominent abnormality was a statistically significant increase of slow activity observed in 59% of cases. Delta asymmetry coincided with the site of lesions, evidenced by MRI, in 83% of patients; with the site of decreased beta activity in 60% and with the maximum level of spiking activity in 58% of cases. Neuropsychological tests showed a lateralization of the hemispheric function which coincided with delta asymmetry in 33% of patients. These results suggest that the EEG background activity, when compared with other parameters, may represent a useful method in lateralizing the epileptogenic focus

Spastic paraplegia, epilepsy, and mental retardation in several members of a family: a novel genetic disorder

We report on a family in which an association between spastic paraplegia and epilepsy has been observed. This disorder is an autosomal dominant trait with incomplete penetrance and variable expressivity. The onset was limited to the first four decades of life; the symptoms were typically those of progressive weakness and spasticity of lower limbs. Epilepsy was present in members of three of the four generations on whom we have information. The concomitance of spastic paraplegia and epilepsy in several members of the same family is unlikely to be fortuitous and probably represents the pleiotropic effect of a single mutant gene