Local sharing as a predominant determinant of synaptic matrix molecular dynamics

Recent studies suggest that central nervous system synapses can persist for weeks, months, perhaps lifetimes, yet little is known as to how synapses maintain their structural and functional characteristics for so long. As a step toward a better understanding of synaptic maintenance we examined the loss, redistribution, reincorporation, and replenishment dynamics of Synapsin I and ProSAP2/Shank3, prominent presynaptic and postsynaptic matrix molecules, respectively. Fluorescence recovery after photobleaching and photoactivation experiments revealed that both molecules are continuously lost from, redistributed among, and reincorporated into synaptic structures at time-scales of minutes to hours. Exchange rates were not affected by inhibiting protein synthesis or proteasome-mediated protein degradation, were accelerated by stimulation, and greatly exceeded rates of replenishment from somatic sources. These findings indicate that the dynamics of key synaptic matrix molecules may be dominated by local protein exchange and redistribution, whereas protein synthesis and degradation serve to maintain and regulate the sizes of local, shared pools of these proteins.     

RNA secondary structure prediction from sequence alignments using a network of k-nearest neighbor classifiers

We present a machine learning method (a hierarchical network of k-nearest neighbor classifiers) that uses an RNA sequence alignment in order to predict a consensus RNA secondary structure. The input to the network is the mutual information, the fraction of complementary nucleotides, and a novel consensus RNAfold secondary structure prediction of a pair of alignment columns and its nearest neighbors. Given this input, the network computes a prediction as to whether a particular pair of alignment columns corresponds to a base pair. By using a comprehensive test set of 49 RFAM alignments, the program KNetFold achieves an average Matthews correlation coefficient of 0.81. This is a significant improvement compared with the secondary structure prediction methods PFOLD and RNAalifold. By using the example of archaeal RNase P, we show that the program can also predict pseudoknot interactions.     

Bassoon speeds vesicle reloading at a central excitatory synapse

Sustained rate-coded signals encode many types of sensory modalities. Some sensory synapses possess specialized ribbon structures, which tether vesicles, to enable high-frequency signaling. However, central synapses lack these structures, yet some can maintain signaling over a wide bandwidth. To analyze the underlying molecular mechanisms, we investigated the function of the active zone core component Bassoon in cerebellar mossy fiber to granule cell synapses. We show that short-term synaptic depression is enhanced in Bassoon knockout mice during sustained high-frequency trains but basal synaptic transmission is unaffected. Fluctuation and quantal analysis as well as quantification with constrained short-term plasticity models revealed that the vesicle reloading rate was halved in the absence of Bassoon. Thus, our data show that the cytomatrix protein Bassoon speeds the reloading of vesicles to release sites at a central excitatory synapse.     

Grandma plays favourites: X-chromosome relatedness and sex-specific childhood mortality

Biologists use genetic relatedness between family members to explain the evolution of many behavioural and developmental traits in humans, including altruism, kin investment and longevity. Women''s post-menopausal longevity in particular is linked to genetic relatedness between family members. According to the ‘grandmother hypothesis’, post-menopausal women can increase their genetic contribution to future generations by increasing the survivorship of their grandchildren. While some demographic studies have found evidence for this, others have found little support for it. Here, we re-model the predictions of the grandmother hypothesis by examining the genetic relatedness between grandmothers and grandchildren. We use this new model to re-evaluate the grandmother effect in seven previously studied human populations. Boys and girls differ in the per cent of genes they share with maternal versus paternal grandmothers because of differences in X-chromosome inheritance. Here, we demonstrate a relationship between X-chromosome inheritance and grandchild mortality in the presence of a grandmother. With this sex-specific and X-chromosome approach to interpreting mortality rates, we provide a new perspective on the prevailing theory for the evolution of human female longevity. This approach yields more consistent support for the grandmother hypothesis, and has implications for the study of human evolution.     

Identification and Immunocytochemical Characterization of Piccolino,a Novel Piccolo Splice Variant Selectively Expressed at Sensory Ribbon Synapses of the Eye and Ear

Piccolo is one of the largest cytomatrix proteins present at active zones of chemical synapses, where it is suggested to play a role in recruiting and integrating molecules relevant for both synaptic vesicle exo- and endocytosis. Here we examined the retina of a Piccolo-mutant mouse with a targeted deletion of exon 14 in the Pclo gene. Piccolo deficiency resulted in its profound loss at conventional chemical amacrine cell synapses but retinal ribbon synapses were structurally and functionally unaffected. This led to the identification of a shorter, ribbon-specific Piccolo variant, Piccolino, present in retinal photoreceptor cells, bipolar cells, as well as in inner hair cells of the inner ear. By RT-PCR analysis and the generation of a Piccolino-specific antibody we show that non-splicing of intron 5/6 leads to premature translation termination and generation of the C-terminally truncated protein specifically expressed at active zones of ribbon synapse containing cell types. With in situ proximity ligation assays we provide evidence that this truncation leads to the absence of interaction sites for Bassoon, Munc13, and presumably also ELKS/CAST, RIM2, and the L-type Ca^{2 +} channel which exist in the full-length Piccolo at active zones of conventional chemical synapses. The putative lack of interactions with proteins of the active zone suggests a function of Piccolino at ribbon synapses of sensory neurons different from Piccolo’s function at conventional chemical synapses.     

A blood based 12-miRNA signature of Alzheimer disease patients

Background

Alzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples.

Results

We apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies.

Conclusions

The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.     

Spatiotopic visual maps revealed by saccadic adaptation in humans

Saccadic adaptation [1] is a powerful experimental paradigm to probe the mechanisms of eye movement control and spatial vision, in which saccadic amplitudes change in response to false visual feedback. The adaptation occurs primarily in the motor system [2, 3], but there is also evidence for visual adaptation, depending on the size and the permanence of the postsaccadic error [4-7]. Here we confirm that adaptation has a strong visual component and show that the visual component of the adaptation is spatially selective in external, not retinal coordinates. Subjects performed?a memory-guided, double-saccade, outward-adaptation task designed to maximize visual adaptation and to dissociate the visual and motor corrections. When the memorized saccadic target was in the same position (in external space) as that used in the adaptation training, saccade targeting was strongly influenced by adaptation (even if not matched in retinal or cranial position), but when in the same retinal or cranial but different external spatial position, targeting was unaffected by adaptation, demonstrating unequivocal spatiotopic selectivity. These results point to the existence of a spatiotopic neural representation for eye movement control that adapts in response to saccade error signals.     

Perioperative kinetics of the nitric oxide derivatives nitrite/nitrate during orthotopic liver transplantation.

Nitric oxide (NO) is an important mediator in ischemia-reperfusion injury during human orthotopic liver transplantation (OLT). The perioperative kinetics of nitrite/nitrate plasma levels in 25 patients undergoing uncomplicated OLT were studied. A uniform pattern with significant increases of nitrite/nitrate levels immediately after reperfusion was seen in all patients, followed by a decrease to pretransplant levels within 24h. Peak levels 30 min after reperfusion were correlated to the indocyanine green plasma disappearance rate (PDR(ICG)), suggesting an association of early released NO with graft perfusion in OLT.