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result(s) for
"Grimm, A"
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Stabilization and operation of a Kerr-cat qubit
Quantum superpositions of macroscopically distinct classical states—so-called Schrödinger cat states—are a resource for quantum metrology, quantum communication and quantum computation. In particular, the superpositions of two opposite-phase coherent states in an oscillator encode a qubit protected against phase-flip errors
1
,
2
. However, several challenges have to be overcome for this concept to become a practical way to encode and manipulate error-protected quantum information. The protection must be maintained by stabilizing these highly excited states and, at the same time, the system has to be compatible with fast gates on the encoded qubit and a quantum non-demolition readout of the encoded information. Here we experimentally demonstrate a method for the generation and stabilization of Schrödinger cat states based on the interplay between Kerr nonlinearity and single-mode squeezing
1
,
3
in a superconducting microwave resonator
4
. We show an increase in the transverse relaxation time of the stabilized, error-protected qubit of more than one order of magnitude compared with the single-photon Fock-state encoding. We perform all single-qubit gate operations on timescales more than sixty times faster than the shortest coherence time and demonstrate single-shot readout of the protected qubit under stabilization. Our results showcase the combination of fast quantum control and robustness against errors, which is intrinsic to stabilized macroscopic states, as well as the potential of these states as resources in quantum information processing
5
–
8
.
A qubit generated and stabilized in a superconducting microwave resonator by encoding it into Schrödinger cat states produced by Kerr nonlinearity and single-mode squeezing shows intrinsic robustness to phase-flip errors.
Journal Article
Catalytic asymmetric synthesis of cannabinoids and menthol from neral
The selective conversion of natural or synthetic neral to (1
R
,6
S
)-
trans
-isopiperitenol would enable and expedite sustainable routes to menthol
1
,
2
and cannabinoids
3
–
5
. However, this reaction has been considered impossible because its product is more reactive to the required acid catalysts than its starting material, resulting in several side products
6
–
9
. We now show that an unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses this process with excellent efficiency and selectivity. Expanding the method to other α,β-unsaturated aldehydes could enable access to new cannabinoids and menthol derivatives not readily accessible previously. Mechanistic studies suggest that the confined catalyst accomplishes this reaction by binding the product in an unreactive conformation, thereby preventing its decomposition. We also show how (1
R
,6
S
)-
trans
-isopiperitenol can be readily converted to pharmaceutically useful cannabinoids and menthol, each in the shortest and most atom-economic routes so far.
An unsymmetric, strong and confined chiral acid, a highly fluorinated imino-imidodiphosphate, catalyses the selective conversion of neral to (1
R
,6
S
)-
trans
-isopiperitenol, enabling sustainable routes to menthol and cannabinoids.
Journal Article
Coherent Oscillations inside a Quantum Manifold Stabilized by Dissipation
Manipulating the state of a logical quantum bit (qubit) usually comes at the expense of exposing it to decoherence. Fault-tolerant quantum computing tackles this problem by manipulating quantum information within a stable manifold of a larger Hilbert space, whose symmetries restrict the number of independent errors. The remaining errors do not affect the quantum computation and are correctable after the fact. Here we implement the autonomous stabilization of an encoding manifold spanned by Schrödinger cat states in a superconducting cavity. We show Zeno-driven coherent oscillations between these states analogous to the Rabi rotation of a qubit protected against phase flips. Such gates are compatible with quantum error correction and hence are crucial for fault-tolerant logical qubits.
Journal Article
CD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation
Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b
+
DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C
+
, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C
+
Ly-6A/E
+
cDC2 to mature Ly-6C
–
CD301b
+
lung resident cDC2 lacking
Ccr7
expression, which then further mature into CD200
+
migratory cDC2 expressing
Ccr7
. Partially mature Ly-6C
+
Ly-6A/E
–
CD301b
–
cDC2, which express
Il1b
, promote Th17 differentiation. By contrast, CD200
+
mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.
Dendritic cells in the lung may be specialised to mediate specific types of immune function. Here the authors show that subpopulations of mouse CD11b
+
lung DC at different stages of maturation and phenotype can promote Th17 or Th2 CD4
+
T cell differentiation.
Journal Article
ToxPi Graphical User Interface 2.0: Dynamic exploration, visualization, and sharing of integrated data models
Background
Drawing integrated conclusions from diverse source data requires synthesis across multiple types of information. The ToxPi (Toxicological Prioritization Index) is an analytical framework that was developed to enable integration of multiple sources of evidence by transforming data into integrated, visual profiles. Methodological improvements have advanced ToxPi and expanded its applicability, necessitating a new, consolidated software platform to provide functionality, while preserving flexibility for future updates.
Results
We detail the implementation of a new graphical user interface for ToxPi (Toxicological Prioritization Index) that provides interactive visualization, analysis, reporting, and portability. The interface is deployed as a stand-alone, platform-independent Java application, with a modular design to accommodate inclusion of future analytics. The new ToxPi interface introduces several features, from flexible data import formats (including legacy formats that permit backward compatibility) to similarity-based clustering to options for high-resolution graphical output.
Conclusions
We present the new ToxPi interface for dynamic exploration, visualization, and sharing of integrated data models. The ToxPi interface is freely-available as a single compressed download that includes the main Java executable, all libraries, example data files, and a complete user manual from
http://toxpi.org
.
Journal Article
An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression
Background
The gut microbiome, a key constituent of the colonic environment, has been implicated as an important modulator of human health. The eukaryotic epigenome is postulated to respond to environmental stimuli through alterations in chromatin features and, ultimately, gene expression. How the host mediates epigenomic responses to gut microbiota is an emerging area of interest. Here, we profile the gut microbiome and chromatin characteristics in colon epithelium from mice fed either an obesogenic or control diet, followed by an analysis of the resultant changes in gene expression.
Results
The obesogenic diet shapes the microbiome prior to the development of obesity, leading to altered bacterial metabolite production which predisposes the host to obesity. This microbiota–diet interaction leads to changes in histone modification at active enhancers that are enriched for binding sites for signal responsive transcription factors. These alterations of histone methylation and acetylation are associated with signaling pathways integral to the development of colon cancer. The transplantation of obesogenic diet-conditioned microbiota into germ free mice, combined with an obesogenic diet, recapitulates the features of the long-term diet regimen. The diet/microbiome-dependent changes are reflected in both the composition of the recipient animals’ microbiome as well as in the set of transcription factor motifs identified at diet-influenced enhancers.
Conclusions
These findings suggest that the gut microbiome, under specific dietary exposures, stimulates a reprogramming of the enhancer landscape in the colon, with downstream effects on transcription factors. These chromatin changes may be associated with those seen during colon cancer development.
Journal Article
MBD3 Localizes at Promoters, Gene Bodies and Enhancers of Active Genes
The Mi-2/nucleosome remodeling and histone deacetylase (NuRD) complex is a multiprotein machine proposed to regulate chromatin structure by nucleosome remodeling and histone deacetylation activities. Recent reports describing localization of NuRD provide new insights that question previous models on NuRD action, but are not in complete agreement. Here, we provide location analysis of endogenous MBD3, a component of NuRD complex, in two human breast cancer cell lines (MCF-7 and MDA-MB-231) using two independent genomic techniques: DNA adenine methyltransferase identification (DamID) and ChIP-seq. We observed concordance of the resulting genomic localization, suggesting that these studies are converging on a robust map for NuRD in the cancer cell genome. MBD3 preferentially associated with CpG rich promoters marked by H3K4me3 and showed cell-type specific localization across gene bodies, peaking around the transcription start site. A subset of sites bound by MBD3 was enriched in H3K27ac and was in physical proximity to promoters in three-dimensional space, suggesting function as enhancers. MBD3 enrichment was also noted at promoters modified by H3K27me3. Functional analysis of chromatin indicated that MBD3 regulates nucleosome occupancy near promoters and in gene bodies. These data suggest that MBD3, and by extension the NuRD complex, may have multiple roles in fine tuning expression for both active and silent genes, representing an important step in defining regulatory mechanisms by which NuRD complex controls chromatin structure and modification status.
Journal Article
Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms
Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with
DNMT3B
mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.
In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.
Journal Article
Interaction of the pioneer transcription factor GATA3 with nucleosomes
During cellular reprogramming, the pioneer transcription factor GATA3 binds chromatin, and in a context-dependent manner directs local chromatin remodeling and enhancer formation. Here, we use high-resolution nucleosome mapping in human cells to explore the impact of the position of GATA motifs on the surface of nucleosomes on productive enhancer formation, finding productivity correlates with binding sites located near the nucleosomal dyad axis. Biochemical experiments with model nucleosomes demonstrate sufficiently stable transcription factor-nucleosome interaction to empower cryo-electron microscopy structure determination of the complex at 3.15 Å resolution. The GATA3 zinc fingers efficiently bind their target 5′-GAT-3′ sequences in the nucleosome when they are located in solvent accessible, consecutive major grooves without significant changes in nucleosome structure. Analysis of genomic loci bound by GATA3 during reprogramming suggests a correlation of recognition motif sequence and spacing that may distinguish productivity of new enhancer formation.
GATA 3 functions as a pioneer factor during cellular reprogramming. Here the authors delineate nucleosome positioning relative to GATA3 binding motifs and describe the structure of a GATA3–nucleosome complex; providing insight into how a pioneer factor interacts with nucleosomes and catalyze their local remodelling to produce an accessible enhancer.
Journal Article