Halogen Bonding Controls Selectivity of FRET Substrate Probes for MMP-9

SummaryMatrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases that catalyze cleavage of extracellular matrix and nonmatrix proteins. MMPs play a role in tissue remodeling, and their uncontrolled activity is associated with number of diseases, including tumor metastasis. Thus, there is a need to develop methods to monitor MMP activity, and number of probes has been previously described. The key problem many probes encounter is the issue of selectivity, since 23 human MMPs, despite playing different physiological roles, have structurally similar active sites. Here, we introduce the halogen bonding concept into the probe design and show that the probe containing iodine exhibits an unprecedented selectivity for MMP-9. We provide structure-based explanation for the selectivity, confirming that it is due to formation of the halogen bond that supports catalysis, and we highlight the value of exploring halogen bonding in the context of selective probe design

Feeling the Beat: Bouncing Synchronization to Vibrotactile Music in Hearing and Early Deaf People

The ability to dance relies on the ability to synchronize movements to a perceived musical beat. Typically, beat synchronization is studied with auditory stimuli. However, in many typical social dancing situations, music can also be perceived as vibrations when objects that generate sounds also generate vibrations. This vibrotactile musical perception is of particular relevance for deaf people, who rely on non-auditory sensory information for dancing. In the present study, we investigated beat synchronization to vibrotactile electronic dance music in hearing and deaf people. We tested seven deaf and 14 hearing individuals on their ability to bounce in time with the tempo of vibrotactile stimuli (no sound) delivered through a vibrating platform. The corresponding auditory stimuli (no vibrations) were used in an additional condition in the hearing group. We collected movement data using a camera-based motion capture system and subjected it to a phase-locking analysis to assess synchronization quality. The vast majority of participants were able to precisely time their bounces to the vibrations, with no difference in performance between the two groups. In addition, we found higher performance for the auditory condition compared to the vibrotactile condition in the hearing group. Our results thus show that accurate tactile-motor synchronization in a dance-like context occurs regardless of auditory experience, though auditory-motor synchronization is of superior quality

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Conception et synthèse de vecteurs non cationiques pour le transfert de gènes

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Keeping the beat: A large sample study of bouncing and clapping to music

The vast majority of humans move in time with a musical beat. This behaviour has been mostly studied through finger-tapping synchronization. Here, we evaluate naturalistic synchronization responses to music – bouncing and clapping - in 100 university students. Their ability to match the period of their bounces and claps to those of a metronome and musical clips varying in beat saliency was assessed. In general, clapping was better synchronized with the beat than bouncing, suggesting that the choice of a specific movement type is an important factor to consider in the study of sensorimotor synchronization processes. Performance improved as a function of beat saliency, indicating that beat abstraction plays a significant role in synchronization. Fourteen percent of the population exhibited marked difficulties with matching the beat. Yet, at a group level, poor synchronizers showed similar sensitivity to movement type and beat saliency as normal synchronizers. These results suggest the presence of quantitative rather than qualitative variations when losing the beat

Keeping the Beat: A Large Sample Study of Bouncing and Clapping to Music

<div><p>The vast majority of humans move in time with a musical beat. This behaviour has been mostly studied through finger-tapping synchronization. Here, we evaluate naturalistic synchronization responses to music–bouncing and clapping–in 100 university students. Their ability to match the period of their bounces and claps to those of a metronome and musical clips varying in beat saliency was assessed. In general, clapping was better synchronized with the beat than bouncing, suggesting that the choice of a specific movement type is an important factor to consider in the study of sensorimotor synchronization processes. Performance improved as a function of beat saliency, indicating that beat abstraction plays a significant role in synchronization. Fourteen percent of the population exhibited marked difficulties with matching the beat. Yet, at a group level, poor synchronizers showed similar sensitivity to movement type and beat saliency as normal synchronizers. These results suggest the presence of quantitative rather than qualitative variations when losing the beat.</p></div

Musical and dance experience of participants.

<p>Musical and dance experience of participants.</p

Produced metrical levels.

<p>Produced metrical levels.</p

Characteristics of stimuli.

<p>Characteristics of stimuli.</p