Reconstructing visual experiences from brain activity evoked by natural movies

Quantitative modeling of human brain activity can provide crucial insights about cortical representations [1, 2] and can form the basis for brain decoding devices [3-5]. Recent functional magnetic resonance imaging (fMRI) studies have modeled brain activity elicited by static visual patterns and have reconstructed these patterns from brain activity [6-8]. However, blood oxygen level-dependent (BOLD) signals measured via fMRI are very slow [9], so it has been difficult to model brain activity elicited by dynamic stimuli such as natural movies. Here we present a new motion-energy [10, 11] encoding model that largely overcomes this limitation. The model describes fast visual information and slow hemodynamics by separate components. We recorded BOLD signals in occipitotemporal visual cortex of human subjects who watched natural movies and fit the model separately to individual voxels. Visualization of the fit models reveals how early visual areas represent the information in movies. To demonstrate the power of our approach, we also constructed a Bayesian decoder [8] by combining estimated encoding models with a sampled natural movie prior. The decoder provides remarkable reconstructions of the viewed movies. These results demonstrate that dynamic brain activity measured under naturalistic conditions can be decoded using current fMRI technology.     

Integrative Analysis of Epigenetic Modulation in Melanoma Cell Response to Decitabine: Clinical Implications

Decitabine, an epigenetic modifier that reactivates genes otherwise suppressed by DNA promoter methylation, is effective for some, but not all cancer patients, especially those with solid tumors. It is commonly recognized that to overcome resistance and improve outcome, treatment should be guided by tumor biology, which includes genotype, epigenotype, and gene expression profile. We therefore took an integrative approach to better understand melanoma cell response to clinically relevant dose of decitabine and identify complementary targets for combined therapy. We employed eight different melanoma cell strains, determined their growth, apoptotic and DNA damage responses to increasing doses of decitabine, and chose a low, clinically relevant drug dose to perform whole-genome differential gene expression, bioinformatic analysis, and protein validation studies. The data ruled out the DNA damage response, demonstrated the involvement of p21^Cip1 in a p53-independent manner, identified the TGFβ pathway genes CLU and TGFBI as markers of sensitivity to decitabine and revealed an effect on histone modification as part of decitabine-induced gene expression. Mutation analysis and knockdown by siRNA implicated activated β-catenin/MITF, but not BRAF, NRAS or PTEN mutations as a source for resistance. The importance of protein stability predicted from the results was validated by the synergistic effect of Bortezomib, a proteasome inhibitor, in enhancing the growth arrest of decitabine in otherwise resistant melanoma cells. Our integrative analysis show that improved therapy can be achieved by comprehensive analysis of cancer cells, identified biomarkers for patient''s selection and monitoring response, as well as targets for improved combination therapy.     

Matching fusion protein systems for affinity analysis of two interacting families of proteins: the cohesin-dockerin interaction

Cellulosomes are multi-enzyme complexes that orchestrate the efficient degradation of cellulose and related plant cell wall polysaccharides. The complex is maintained by the high-affinity protein-protein interaction between two complementary modules: the cohesin and the dockerin. In order to characterize the interaction between different cohesins and dockerins, we have developed matching fusion-protein systems, which harbor either the cohesin or the dockerin component. For this purpose, corresponding plasmid cassettes were designed, which encoded for the following carrier proteins: (i) a thermostable xylanase with an appended His-tag; and (ii) a highly stable cellulose-binding module (CBM). The resultant xylanase-dockerin and CBM-cohesin fusion products exhibited high expression levels of soluble protein. The expressed, affinity-purified proteins were extremely stable, and the functionality of the cohesin or dockerin component was retained. The fusion protein system was used to establish a sensitive and reliable, semi-quantitative enzyme-linked affinity assay for determining multiple samples of cohesin-dockerin interactions in microtiter plates. A variety of cohesin-dockerin systems, which had been examined previously using other methodologies, were revisited applying the affinity-based enzyme assay, the results of which served to verify the validity of the approach.     

Cell signaling and transcription factor genes expressed during whole body regeneration in a colonial chordate

Background  

The restoration of adults from fragments of blood vessels in botryllid ascidians (termed whole body regeneration [WBR]) represents an inimitable event in the chordates, which is poorly understood on the mechanistic level.     

Effects of the olfactory environment and nutrition on the ability of male Mediterranean fruit flies to endure starvation

The Mediterranean fruit fly, Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), is targeted for control using the sterile insect technique (SIT). For this technique to succeed, released males must be able to compete with wild males for copulations. Male success is mediated by survival in the field often in adverse conditions. Manipulation of the postteneral environment experienced by sterile males before release has been shown to affect male sexual success and survival. The objectives of this study were to determine how various diets, combined with exposure to volatiles containing alpha-copaene, affect the ability of male Mediterranean fruit flies (from a wild and two unisexual strains) to withstand starvation. Accordingly, we maintained males on one of eight regimes combing a diet of either sugar, sugar and protein, a protein pulse or apricot, with or without the aroma of the sexual stimulant alpha-copaene. The apricot diet was associated with the lowest ability to resist starvation. The sugar-only diet was associated with the highest ability to resist starvation by sterile males. Exposure to alpha-copaene, in combination with the apricot diet, had a significant negative effect on the ability of males (from all strains) to resist starvation relative to other regimes examined. We conclude that the holding regimes that elicit the best sexual performance from males paradoxically also hasten their demise, probably by initiating an irreversible metabolic cascade. The search for the optimal prerelease regime continues.     

Robust control of nitrogen assimilation by a bifunctional enzyme in E. coli

Bacteria regulate the assimilation of multiple nutrients to enable growth. How is balanced utilization achieved, despite fluctuations in the concentrations of the enzymes that make up the regulatory circuitry? Here we address this question by studying the nitrogen system of E. coli. A mechanism based on the avidity of a bifunctional enzyme, adenylyltransferase (AT/AR), to its multimeric substrate, glutamine synthetase, is proposed to maintain a robust ratio between two key metabolites, glutamine and α-ketoglutarate. This ratio is predicted to be insensitive to variations in protein levels of the core circuit and to the rate of nitrogen utilization. We find using mass spectrometry that the metabolite ratio is robust to variations in protein levels and that this robustness depends on the bifunctional enzyme. Moreover, robustness carries through to the bacteria growth rate. Interrupting avidity by adding a monofunctional AT/AR mutant to the native system abolishes robustness, as predicted by the proposed mechanism.     

Comprehensive Mapping of Regional Expression of the Clock Protein PERIOD2 in Rat Forebrain across the 24-h Day

In mammals, a light-entrainable clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms by synchronizing oscillators throughout the brain and body. Notably, the nature of the relation between the SCN clock and subordinate oscillators in the rest of the brain is not well defined. We performed a high temporal resolution analysis of the expression of the circadian clock protein PERIOD2 (PER2) in the rat forebrain to characterize the distribution, amplitude and phase of PER2 rhythms across different regions. Eighty-four LEW/Crl male rats were entrained to a 12-h: 12-h light/dark cycle, and subsequently perfused every 30 min across the 24-h day for a total of 48 time-points. PER2 expression was assessed with immunohistochemistry and analyzed using automated cell counts. We report the presence of PER2 expression in 20 forebrain areas important for a wide range of motivated and appetitive behaviors including the SCN, bed nucleus, and several regions of the amygdala, hippocampus, striatum, and cortex. Eighteen areas displayed significant PER2 rhythms, which peaked at different times of day. Our data demonstrate a previously uncharacterized regional distribution of rhythms of a clock protein expression in the brain that provides a sound basis for future studies of circadian clock function in animal models of disease.     

Shelf-life extension program (SLEP) as a significant contributor to Strategic National Stockpile Maintenance: the Israeli experience with ciprofloxacin

In the past decade, the 2001 anthrax incident in the U.S. and the 2003 SARS epidemic have highlighted the biological threat to civilian populations. The risk posed by the natural or manmade spread of biological agents among the population dictates a need for better national preparedness. One key component of this preparation is the establishment of a Strategic National Stockpile (SNS) of pharmaceuticals that would provide appropriate medical countermeasures in case of an outbreak. However, to reduce the expense of such a stockpile and to make it worthwhile, there is also a need for a shelf-life extension program (SLEP) through which pharmaceuticals could be extended beyond manufacturer-ascribed shelf life, as long as they meet regulation standards. In this article, we review the Israeli experience with the national ciprofloxacin stockpile procurement and shelf-life extension program.     

VDA, a method of choosing a better algorithm with fewer validations

The multitude of bioinformatics algorithms designed for performing a particular computational task presents end-users with the problem of selecting the most appropriate computational tool for analyzing their biological data. The choice of the best available method is often based on expensive experimental validation of the results. We propose an approach to design validation sets for method comparison and performance assessment that are effective in terms of cost and discrimination power.Validation Discriminant Analysis (VDA) is a method for designing a minimal validation dataset to allow reliable comparisons between the performances of different algorithms. Implementation of our VDA approach achieves this reduction by selecting predictions that maximize the minimum Hamming distance between algorithmic predictions in the validation set. We show that VDA can be used to correctly rank algorithms according to their performances. These results are further supported by simulations and by realistic algorithmic comparisons in silico.VDA is a novel, cost-efficient method for minimizing the number of validation experiments necessary for reliable performance estimation and fair comparison between algorithms.Our VDA software is available at http://sourceforge.net/projects/klugerlab/files/VDA/