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"Gauthier, D"
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Coastal wetlands of the world : geology, ecology, distribution and applications
\"Salt marshes and mangrove forests, the intertidal wetlands of the world's coastlines, provide key ecological services to all areas of the globe, and are vital sinks and sources in carbon budgets\"-- Provided by publisher.
Book
Altered auditory feature discrimination in a rat model of Fragile X Syndrome
Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.
Journal Article
Tunable orbital angular momentum in high-harmonic generation
Optical vortices are currently one of the most intensively studied topics in optics. These light beams, which carry orbital angular momentum (OAM), have been successfully utilized in the visible and infrared in a wide variety of applications. Moving to shorter wavelengths may open up completely new research directions in the areas of optical physics and material characterization. Here, we report on the generation of extreme-ultraviolet optical vortices with femtosecond duration carrying a controllable amount of OAM. From a basic physics viewpoint, our results help to resolve key questions such as the conservation of angular momentum in highly nonlinear light–matter interactions, and the disentanglement and independent control of the intrinsic and extrinsic components of the photon’s angular momentum at short-wavelengths. The methods developed here will allow testing some of the recently proposed concepts such as OAM-induced dichroism, magnetic switching in organic molecules and violation of dipolar selection rules in atoms.
The controlled generation of extreme-ultraviolet beams with controllable topological charge has not been demonstrated. Here, Gauthier
et al
. report on the generation of extreme-ultraviolet optical vortices with femtosecond duration carrying a controllable amount of orbital angular momentum.
Journal Article
GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data
Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications.
GATK-gCNV uses a probabilistic model and inference framework to discover rare copy number variants (CNVs) from sequencing read-depth information. This algorithm is used to generate a reference catalog of rare coding CNVs in exome sequencing data from UK Biobank.
Journal Article
Two-stage seeded soft-X-ray free-electron laser
We report the first generation of coherent, tunable, variable-polarization, soft X-ray femtosecond pulses, generated by a seeded free-electron laser (FEL) operating in the fresh bunch, two-stage harmonic upshift configuration. Characterization of the radiation proves this FEL configuration can produce single-transverse-mode, narrow-spectral-bandwidth output pulses of several tens of microjoules energy and low pulse-to-pulse wavelength jitter at final wavelengths of 10.8 nm and below. The fresh bunch configuration enhances the FEL emission at high harmonic orders by avoiding a gain depression due to the energy spread induced by the first-stage FEL interaction. Coherent signals measured down to 4.3 nm suggest this configuration is directly scalable to photon energies that will enable scientific investigations below the carbon K-edge, including access to the L-edges of many magnetic materials, with an energy per pulse unlocking the gate for experiments in the soft X-ray region with close to Fourier-transform-limited pulses.
A seeded free-electron laser with a two-stage harmonic upshift configuration provided tunable and coherent soft-X-ray pulses. The configuration produced single-transverse-mode, narrow-spectral-bandwidth femtosecond pulses with energies of several tens of microjoules and a low pulse-to-pulse wavelength jitter at wavelengths of 10.8 nm and below.
Journal Article
Genomic data in the All of Us Research Program
Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics
1
–
4
. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health
5
,
6
. Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.
A study describes the release of clinical-grade whole-genome sequence data for 245,388 diverse participants by the All of Us Research Program and characterizes the properties of the dataset.
Journal Article
A genomic mutational constraint map using variation in 76,156 human genomes
The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders
1
–
4
, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)—the largest public open-access human genome allele frequency reference dataset—and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.
Journal Article
PD-L1+ and XCR1+ dendritic cells are region-specific regulators of gut homeostasis
The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1
+
DC in the duodenal LP and XCR1
+
DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1
+
and XCR1
+
DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1
+
and XCR1
+
DC as region-specific physiologic regulators of intestinal homeostasis.
Dendritic cells initiate and regulate adaptive immunity and differ according to gut anatomical location. Here the authors show that DC residing in the upper and lower intestines show differential PD-L1 and XCR1 expression and drive specific T cell responses to prevent gut inflammation.
Journal Article
Coherent control with a short-wavelength free-electron laser
Researchers demonstrate correlation of two colours (63.0 and 31.5 nm wavelengths) in a free-electron laser and control photoelectron angular distribution by adjusting phase with 3 attosecond resolution.
Extreme ultraviolet and X-ray free-electron lasers (FELs) produce short-wavelength pulses with high intensity, ultrashort duration, well-defined polarization and transverse coherence, and have been utilized for many experiments previously possible only at long wavelengths: multiphoton ionization
1
, pumping an atomic laser
2
and four-wave mixing spectroscopy
3
. However one important optical technique, coherent control, has not yet been demonstrated, because self-amplified spontaneous emission FELs have limited longitudinal coherence
4
,
5
,
6
,
7
. Single-colour pulses from the FERMI seeded FEL are longitudinally coherent
8
,
9
, and two-colour emission is predicted to be coherent. Here, we demonstrate the phase correlation of two colours, and manipulate it to control an experiment. Light of wavelengths 63.0 and 31.5 nm ionized neon, and we controlled the asymmetry of the photoelectron angular distribution
10
,
11
by adjusting the phase, with a temporal resolution of 3 as. This opens the door to new short-wavelength coherent control experiments with ultrahigh time resolution and chemical sensitivity.
Journal Article