Cracking the social code of speech prosody using reverse correlation

Human listeners excel at forming high-level social representations about each other, even from the briefest of utterances. In particular, pitch is widely recognized as the auditory dimension that conveys most of the information about a speaker's traits, emotional states, and attitudes. While past research has primarily looked at the influence of mean pitch, almost nothing is known about how intonation patterns, i.e., finely tuned pitch trajectories around the mean, may determine social judgments in speech. Here, we introduce an experimental paradigm that combines state-of-the-art voice transformation algorithms with psychophysical reverse correlation and show that two of the most important dimensions of social judgments, a speaker's perceived dominance and trustworthiness, are driven by robust and distinguishing pitch trajectories in short utterances like the word "Hello," which remained remarkably stable whether male or female listeners judged male or female speakers. These findings reveal a unique communicative adaptation that enables listeners to infer social traits regardless of speakers' physical characteristics, such as sex and mean pitch. By characterizing how any given individual's mental representations may differ from this generic code, the method introduced here opens avenues to explore dysprosody and social-cognitive deficits in disorders like autism spectrum and schizophrenia. In addition, once derived experimentally, these prototypes can be applied to novel utterances, thus providing a principled way to modulate personality impressions in arbitrary speech signals

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial

Atezolizumab; Ovarian cancer; PlatinumAtezolizumab; Càncer d'ovari; PlatíAtezolizumab; Cáncer de ovario; PlatinoPURPOSE Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1–positive populations (alpha .025 for each population). RESULTS Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1–positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1–positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1–positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC

Specificity determinants for the two tRNA substrates of the cyclodipeptide synthase AlbC from Streptomyces noursei

International audienceCyclodipeptide synthases (CDPSs) use two aminoacyl-tRNA substrates in a sequential ping-pong mechanism to form a cyclodipeptide. The crystal structures of three CDPSs have been determined and all show a Rossmann-fold domain similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs). Structural features and mutational analyses however suggest that CDPSs and aaRSs interact differently with their tRNA substrates. We used AlbC from Streptomyces noursei that mainly produces cyclo(l-Phe-l-Leu) to investigate the interaction of a CDPS with its substrates. We demonstrate that Phe-tRNA Phe is the first substrate accommodated by AlbC. Its binding to AlbC is dependent on basic residues located in the helix ␣4 that form a basic patch at the surface of the protein. AlbC does not use all of the Leu-tRNA Leu isoacceptors as a second substrate. We show that the G 1-C 72 pair of the acceptor stem is essential for the recognition of the second substrate. Substitution of D163 located in the loop ␣6–␣7 or D205 located in the loop ␤6–␣8 affected Leu-tRNA Leu isoacceptors specificity, suggesting the involvement of these residues in the binding of the second substrate. This is the first demonstration that the two substrates of CDPSs are accommodated in different binding sites

Unravelling the mechanism of non-ribosomal peptide synthesis by cyclodipeptide synthases.

International audienceCyclodipeptide synthases form cyclodipeptides from two aminoacyl transfer RNAs. They use a ping-pong mechanism that begins with transfer of the aminoacyl moiety of the first aminoacyl tRNA onto a conserved serine, yielding an aminoacyl enzyme. Combining X-ray crystallography, site-directed mutagenesis and affinity labelling of the cyclodipeptide synthase AlbC, we demonstrate that the covalent intermediate reacts with the aminoacyl moiety of the second aminoacyl tRNA, forming a dipeptidyl enzyme, and identify the aminoacyl-binding sites of the aminoacyl tRNAs

Notes de lecture

"CINéMAS: Le temps au cinéma", par Jacques Polet; "Jan BAETENS: L'éthique de la contrainte (Essai sur la poésie moderne)", par Marc Lits; "étienne BOURGEOIS et Jean NIZET: Pression et légitimation", par Emmanuel Belin; "Jacques BRES: La narrativité", par Benoît Grevisse; "Anne-Marie CHRISTIN: L'image écrite ou la déraison graphique", par Jan Baetens; "Boris LIBOIS: éthique de l'information. Essai sur la déontologie journalistique", par André Berten; "Maryse SOUCHARD et Stéphane WARNICH: La communication politique", par Axel GRYSPEERDT"CINéMAS: Le temps au cinéma", par Jacques Polet; "Jan BAETENS: L'éthique de la contrainte (Essai sur la poésie moderne)", par Marc Lits; "étienne BOURGEOIS et Jean NIZET: Pression et légitimation", par Emmanuel Belin; "Jacques BRES: La narrativité", par Benoît Grevisse; "Anne-Marie CHRISTIN: L'image écrite ou la déraison graphique", par Jan Baetens; "Boris LIBOIS: éthique de l'information. Essai sur la déontologie journalistique", par André Berten; "Maryse SOUCHARD et Stéphane WARNICH: La communication politique", par Axel GRYSPEERD

A Family of Plasmodesmal Proteins with Receptor-Like Properties for Plant Viral Movement Proteins

Plasmodesmata (PD) are essential but poorly understood structures in plant cell walls that provide symplastic continuity and intercellular communication pathways between adjacent cells and thus play fundamental roles in development and pathogenesis. Viruses encode movement proteins (MPs) that modify these tightly regulated pores to facilitate their spread from cell to cell. The most striking of these modifications is observed for groups of viruses whose MPs form tubules that assemble in PDs and through which virions are transported to neighbouring cells. The nature of the molecular interactions between viral MPs and PD components and their role in viral movement has remained essentially unknown. Here, we show that the family of PD-located proteins (PDLPs) promotes the movement of viruses that use tubule-guided movement by interacting redundantly with tubule-forming MPs within PDs. Genetic disruption of this interaction leads to reduced tubule formation, delayed infection and attenuated symptoms. Our results implicate PDLPs as PD proteins with receptor-like properties involved the assembly of viral MPs into tubules to promote viral movement

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Genome-wide association study of copy number variations in Parkinson's disease

Objective: Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD. Methods: We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium. Results: We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C, but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation: This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.R-AGR-0382 - INTER/JPND/13/01 COURAGE-PD - BALLING Rudolf3. Good health and well-bein