An Integrated Neural Framework for Dynamic and Static Face Processing.

Faces convey rich information including identity, gender and expression. Current neural models of face processing suggest a dissociation between the processing of invariant facial aspects such as identity and gender, that engage the fusiform face area (FFA) and the processing of changeable aspects, such as expression and eye gaze, that engage the posterior superior temporal sulcus face area (pSTS-FA). Recent studies report a second dissociation within this network such that the pSTS-FA, but not the FFA, shows much stronger response to dynamic than static faces. The aim of the current study was to test a unified model that accounts for these two functional characteristics of the neural face network. In an fMRI experiment, we presented static and dynamic faces while subjects judged an invariant (gender) or a changeable facial aspect (expression). We found that the pSTS-FA was more engaged in processing dynamic than static faces and changeable than invariant aspects, whereas the OFA and FFA showed similar response across all four conditions. These findings support an integrated neural model of face processing in which the ventral areas extract form information from both invariant and changeable facial aspects whereas the dorsal face areas are sensitive to dynamic and changeable facial aspects

RNA-editing-mediated exon evolution

BACKGROUND: Alu retroelements are specific to primates and abundant in the human genome. Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization. It was recently shown that Alu elements are also heavily changed by RNA editing in the human genome. RESULTS: Here we show that the human nuclear prelamin A recognition factor contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization. We demonstrate that RNA editing regulates the exonization in a tissue-dependent manner, through both the creation of a functional AG 3' splice site, and alteration of functional exonic splicing enhancers within the exon. Furthermore, a premature stop codon within the Alu-exon is eliminated by an exceptionally efficient RNA editing event. The sequence surrounding this editing site is important not only for editing of that site but also for editing in other neighboring sites as well. CONCLUSION: Our results show that the abundant RNA editing of Alu sequences can be recruited as a mechanism supporting the birth of new exons in the human genome

Oscillations and variability in the p53 system

Understanding the dynamics and variability of protein circuitry requires accurate measurements in living cells as well as theoretical models. To address this, we employed one of the best-studied protein circuits in human cells, the negative feedback loop between the tumor suppressor p53 and the oncogene Mdm2. We measured the dynamics of fluorescently tagged p53 and Mdm2 over several days in individual living cells. We found that isogenic cells in the same environment behaved in highly variable ways following DNA-damaging gamma irradiation: some cells showed undamped oscillations for at least 3 days (more than 10 peaks). The amplitude of the oscillations was much more variable than the period. Sister cells continued to oscillate in a correlated way after cell division, but lost correlation after about 11 h on average. Other cells showed low-frequency fluctuations that did not resemble oscillations. We also analyzed different families of mathematical models of the system, including a novel checkpoint mechanism. The models point to the possible source of the variability in the oscillations: low-frequency noise in protein production rates, rather than noise in other parameters such as degradation rates. This study provides a view of the extensive variability of the behavior of a protein circuit in living human cells, both from cell to cell and in the same cell over time

The E3 Ubiquitin-Ligase Bmi1/Ring1A Controls the Proteasomal Degradation of Top2α Cleavage Complex – A Potentially New Drug Target

The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha.We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2alpha degradation, increases the persistence of Top2alpha-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2alpha in-vitro and cellular overexpression of Bmi1 increases drug induced Top2alpha ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2alpha ubiquitination and drug-induced Top2alpha degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.The discovery that poisoned Top2alpha is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1

Intronic Alus Influence Alternative Splicing

Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. A large fraction of Alus are found in intronic sequences, implying extensive Alu-Alu dsRNA formation in mRNA precursors. Yet, the effect of these intronic Alus on splicing of the flanking exons is largely unknown. Here, we show that more Alus flank alternatively spliced exons than constitutively spliced ones; this is especially notable for those exons that have changed their mode of splicing from constitutive to alternative during human evolution. This implies that Alu insertions may change the mode of splicing of the flanking exons. Indeed, we demonstrate experimentally that two Alu elements that were inserted into an intron in opposite orientation undergo base-pairing, as evident by RNA editing, and affect the splicing patterns of a downstream exon, shifting it from constitutive to alternative. Our results indicate the importance of intronic Alus in influencing the splicing of flanking exons, further emphasizing the role of Alus in shaping of the human transcriptom

Monitoring Attention in ADHD with an Easy-to-Use Electrophysiological Index

Attention deficit hyperactivity disorder (ADHD) involves characteristic electroencephalographic (EEG) activity. We developed a single-channel EEG marker for attention: the Brain Engagement Index (BEI’). In this study, we evaluated the use of BEI’ for distinguishing between ADHD patients and controls, and for monitoring the effect of pharmacological treatment on ADHD patients. The BEI’ values of 20 ADHD patients and 10 controls were measured using a 1-min auditory oddball paradigm and a continuous performance test (CPT) task. We showed that CPT BEI’ is trait-specific and separates controls from ADHD patients. At the same time, oddball BEI’ is state-specific and identifies differences in attention level within the two groups of ADHD participants and controls. The oddball BEI’ also associates with response to treatment, after distinguishing between treatment effect and learning/time effect. The combined use of this marker with common computerized tests holds promise for research and clinical use in ADHD. Further work is required to confirm the results of the present study