85,301 research outputs found
Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome
Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O’Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (α-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams
Boosting the concordance index for survival data - a unified framework to derive and evaluate biomarker combinations
The development of molecular signatures for the prediction of time-to-event
outcomes is a methodologically challenging task in bioinformatics and
biostatistics. Although there are numerous approaches for the derivation of
marker combinations and their evaluation, the underlying methodology often
suffers from the problem that different optimization criteria are mixed during
the feature selection, estimation and evaluation steps. This might result in
marker combinations that are only suboptimal regarding the evaluation criterion
of interest. To address this issue, we propose a unified framework to derive
and evaluate biomarker combinations. Our approach is based on the concordance
index for time-to-event data, which is a non-parametric measure to quantify the
discrimatory power of a prediction rule. Specifically, we propose a
component-wise boosting algorithm that results in linear biomarker combinations
that are optimal with respect to a smoothed version of the concordance index.
We investigate the performance of our algorithm in a large-scale simulation
study and in two molecular data sets for the prediction of survival in breast
cancer patients. Our numerical results show that the new approach is not only
methodologically sound but can also lead to a higher discriminatory power than
traditional approaches for the derivation of gene signatures.Comment: revised manuscript - added simulation study, additional result
Gene expression programming approach to event selection in high energy physics
Gene Expression Programming is a new evolutionary algorithm that overcomes many limitations of the more established Genetic Algorithms and Genetic Programming. Its first application to high energy physics data analysis is presented. The algorithm was successfully used for event selection on samples with both low and high background level. It allowed automatic identification of selection rules that can be interpreted as cuts applied on the input variables. The signal/background classification accuracy was over 90% in all cases
Conservative and disruptive modes of adolescent change in human brain functional connectivity
Adolescent changes in human brain function are not entirely understood. Here, we used multiecho functional MRI (fMRI) to measure developmental change in functional connectivity (FC) of resting-state oscillations between pairs of 330 cortical regions and 16 subcortical regions in 298 healthy adolescents scanned 520 times. Participants were aged 14 to 26 y and were scanned on 1 to 3 occasions at least 6 mo apart. We found 2 distinct modes of age-related change in FC: “conservative” and “disruptive.” Conservative development was characteristic of primary cortex, which was strongly connected at 14 y and became even more connected in the period from 14 to 26 y. Disruptive development was characteristic of association cortex and subcortical regions, where connectivity was remodeled: connections that were weak at 14 y became stronger during adolescence, and connections that were strong at 14 y became weaker. These modes of development were quantified using the maturational index (MI), estimated as Spearman’s correlation between edgewise baseline FC (at 14 y, FC14) and adolescent change in FC (ΔFC14−26), at each region. Disruptive systems (with negative MI) were activated by social cognition and autobiographical memory tasks in prior fMRI data and significantly colocated with prior maps of aerobic glycolysis (AG), AG-related gene expression, postnatal cortical surface expansion, and adolescent shrinkage of cortical thickness. The presence of these 2 modes of development was robust to numerous sensitivity analyses. We conclude that human brain organization is disrupted during adolescence by remodeling of FC between association cortical and subcortical areas
Systems Biology and the Development of Vaccines and Drugs for Malaria Treatments
The sequencing race has ended and the functional race has already begun. Microarray technology enables
simultaneous gene expression analysis of thousands of genes, enabling a snapshot of an organisms’
transcriptome at an unprecedented resolution. The close correlation between gene transcription and
function, allow the inference of biological processes from the assessed transcriptome profile. Among the
sophisticated analytical problems in microarray technology at the front and back ends respectively, are the
selection of optimal DNA oligos and computational analysis of the genes expression. In this review paper,
we analyse important methods in use today in customized oligos design. In the course of executing this,
we discovered that the oligos designer algorithm hanged on gene PFA0135w of chromosome 1, while
designing oligos for the gene sequences of Plasmodium falciparum. We do not know the reason for this
yet, as the algorithm runs on other sequences like the yeast (Saccharomyces cervisiae) and Neurospora
crassa. We conclude the paper highlighting the procedures encompassing the back end phase and discuss
their application to the development of vaccines and drugs for malaria treatment. Note that, malaria is the
cause of significant global morbidity and mortality with 300-500 million cases annually. Our aims are not
ends, but a means to achieve the following: Iterate the need for experimental biologists to (i) know how to
design their customized oligos and (ii) have some idea about gene expression analysis and the need for
cooperation between experimental biologists and their counterpart, the computational biologists. These
will help experimental biologists to coordinate very well the front and the back ends of the system
biology analysis of the whole genome effectively
Natural Variation and Neuromechanical Systems
Natural variation plays an important but subtle and often ignored role in neuromechanical systems. This is especially important when designing for living or hybrid systems \ud
which involve a biological or self-assembling component. Accounting for natural variation can be accomplished by taking a population phenomics approach to modeling and analyzing such systems. I will advocate the position that noise in neuromechanical systems is partially represented by natural variation inherent in user physiology. Furthermore, this noise can be augmentative in systems that couple physiological systems with technology. There are several tools and approaches that can be borrowed from computational biology to characterize the populations of users as they interact with the technology. In addition to transplanted approaches, the potential of natural variation can be understood as having a range of effects on both the individual's physiology and function of the living/hybrid system over time. Finally, accounting for natural variation can be put to good use in human-machine system design, as three prescriptions for exploiting variation in design are proposed
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