Tune Deafness: Processing Melodic Errors Outside of Conscious Awareness as Reflected by Components of the Auditory ERP

Tune deafness (TD) is a central auditory processing disorder characterized by the inability to discriminate pitch, reproduce melodies or to recognize deviations in melodic structure, in spite of normal hearing. The cause of the disorder is unknown. To identify a pathophysiological marker, we ascertained a group of severely affected TD patients using the Distorted Tunes Test, an ecologically valid task with a longstanding history, and used electrophysiological methods to characterize the brain's responses to correct and incorrect melodic sequences. As expected, we identified a neural correlate of patients' unawareness of melodic distortions: deviant notes modulated long-latency auditory evoked potentials and elicited a mismatch negativity in controls but not in affected subjects. However a robust P300 was elicited by deviant notes, suggesting that, as in blindsight, TD subjects process stimuli that they cannot consciously perceive. Given the high heritability of TD, these patients may make it possible to use genetic methods to study cellular and molecular mechanisms underlying conscious awareness

The Mechanism of Release of P-TEFb and HEXIM1 from the 7SK snRNP by Viral and Cellular Activators Includes a Conformational Change in 7SK

The positive transcription elongation factor, P-TEFb, is required for the production of mRNAs, however the majority of the factor is present in the 7SK snRNP where it is inactivated by HEXIM1. Expression of HIV-1 Tat leads to release of P-TEFb and HEXIM1 from the 7SK snRNP in vivo, but the release mechanisms are unclear.We developed an in vitro P-TEFb release assay in which the 7SK snRNP immunoprecipitated from HeLa cell lysates using antibodies to LARP7 was incubated with potential release factors. We found that P-TEFb was directly released from the 7SK snRNP by HIV-1 Tat or the P-TEFb binding region of the cellular activator Brd4. Glycerol gradient sedimentation analysis was used to demonstrate that the same Brd4 protein transfected into HeLa cells caused the release of P-TEFb and HEXIM1 from the 7SK snRNP in vivo. Although HEXIM1 binds tightly to 7SK RNA in vitro, release of P-TEFb from the 7SK snRNP is accompanied by the loss of HEXIM1. Using a chemical modification method, we determined that concomitant with the release of HEXIM1, 7SK underwent a major conformational change that blocks re-association of HEXIM1.Given that promoter proximally paused polymerases are present on most human genes, understanding how activators recruit P-TEFb to those genes is critical. Our findings reveal that the two tested activators can extract P-TEFb from the 7SK snRNP. Importantly, we found that after P-TEFb is extracted a dramatic conformational change occurred in 7SK concomitant with the ejection of HEXIM1. Based on our findings, we hypothesize that reincorporation of HEXIM1 into the 7SK snRNP is likely the regulated step of reassembly of the 7SK snRNP containing P-TEFb

Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown.

A central hurdle in developing small interfering RNAs (siRNAs) as therapeutics is the inefficiency of their delivery across the plasma and endosomal membranes to the cytosol, where they interact with the RNA interference machinery. With the aim of improving endosomal release, a poorly understood and inefficient process, we studied the uptake and cytosolic release of siRNAs, formulated in lipoplexes or lipid nanoparticles, by live-cell imaging and correlated it with knockdown of a target GFP reporter. siRNA release occurred invariably from maturing endosomes within ∼5-15 min of endocytosis. Cytosolic galectins immediately recognized the damaged endosome and targeted it for autophagy. However, inhibiting autophagy did not enhance cytosolic siRNA release. Gene knockdown occurred within a few hours of release and required <2,000 copies of cytosolic siRNAs. The ability to detect cytosolic release of siRNAs and understand how it is regulated will facilitate the development of rational strategies for improving the cytosolic delivery of candidate drugs

The Algebraic Group Model and its Applications

International audienceOne of the most important and successful tools for assessing hardness assumptions in cryptography is the Generic Group Model (GGM). Over the past two decades, numerous assumptions and protocols have been analyzed within this model. While a proof in the GGM can certainly provide some measure of confidence in an assumption, its scope is rather limited since it does not capture group-specific algorithms that make use of the representation of the group.To overcome this limitation, we propose the Algebraic Group Model (AGM), a model that lies in between the Standard Model and the GGM. It is the first restricted model of computation covering group-specific algorithms yet allowing to derive simple and meaningful security statements. To prove its usefulness, we show that several important assumptions, among them the Computational Diffie-Hellman, the Strong Diffie-Hellman, and the interactive LRSW assumptions, are equivalent to the Discrete Logarithm (DLog) assumption in the AGM. On the more practical side, we prove tight security reductions for two important schemes in the AGM to DLog or a variant thereof: the BLS signature scheme and Groth’s zero-knowledge SNARK (EUROCRYPT 2016), which is the most efficient SNARK for which only a proof in the GGM was known. Our proofs are quite simple and therefore less prone to subtle errors than those in the GGM.Moreover, in combination with known lower bounds on the Discrete Logarithm assumption in the GGM, our results can be used to derive lower bounds for all the above-mentioned results in the GGM