Fast and accurate circularization of a Rydberg atom

Preparation of a so-called circular state in a Rydberg atom where the projection of the electron angular momentum takes its maximum value is challenging due to the required amount of angular momentum transfer. Currently available protocols for circular state preparation are either accurate but slow or fast but error-prone. Here, we show how to use quantum optimal control theory to derive pulse shapes that realize fast and accurate circularization of a Rydberg atom. In particular, we present a theoretical proposal for optimized radio-frequency pulses that achieve high fidelity in the shortest possible time, given current experimental limitations on peak amplitudes and spectral bandwidth. We also discuss the fundamental quantum speed limit for circularization of a Rydberg atom, when lifting these constraints.Comment: 10 pages, 6 figure

Fast Navigation in a Large Hilbert Space Using Quantum Optimal Control

The precise engineering of quantum states, a basic prerequisite for technologies such as quantum-enhanced sensing or quantum computing, becomes more challenging with increasing dimension of the system Hilbert space. Standard preparation techniques then require a large number of operations or slow adiabatic evolution and give access to only a limited set of states. Here, we use quantum optimal control theory to overcome this problem and derive shaped radio-frequency pulses to experimentally navigate the Stark manifold of a Rydberg atom. We demonstrate that optimal control, beyond improving the fidelity of an existing protocol, also enables us to accurately generate a nonclassical superposition state that cannot be prepared with reasonable fidelity using standard techniques. Optimal control thus substantially enlarges the range of accessible states. Our joint experimental and theoretical work establishes quantum optimal control as a key tool for quantum engineering in complex Hilbert spaces

Yeast poly(A)-binding protein Pab1 shuttles between the nucleus and the cytoplasm and functions in mRNA export

Pab1 is the major poly(A)-binding protein in yeast. It is a multifunctional protein that mediates many cellular functions associated with the 3′-poly(A)-tail of messenger RNAs. Here, we characterize Pab1 as an export cargo of the protein export factor Xpo1/Crm1. Pab1 is a major Xpo1/Crm1-interacting protein in yeast extracts and binds directly to Xpo1/Crm1 in a RanGTP-dependent manner. Pab1 shuttles rapidly between the nucleus and the cytoplasm and partially accumulates in the nucleus when the function of Xpo1/Crm1 is inhibited. However, Pab1 can also be exported by an alternative pathway, which is dependent on the MEX67-mRNA export pathway. Import of Pab1 is mediated by the import receptor Kap108/Sxm1 through a nuclear localization signal in its fourth RNA-binding domain. Interestingly, inhibition of Pab1’s nuclear import causes a kinetic delay in the export of mRNA. Furthermore, the inviability of a pab1 deletion strain is suppressed by a mutation in the 5′–3′ exoribonuclease RRP6, a component of the nuclear exosome. Therefore, nuclear Pab1 may be required for efficient mRNA export and may function in the quality control of mRNA in the nucleus

A glucose-starvation response regulates the diffusion of macromolecules

International audienceThe organization and biophysical properties of the cytosol implicitly govern molecular interactions within cells. However, little is known about mechanisms by which cells regulate cytosolic properties and intracellular diffusion rates. Here, we demonstrate that the intracellular environment of budding yeast undertakes a startling transition upon glucose starvation in which macromolecular mobility is dramatically restricted, reducing the movement of both chromatin in the nucleus and mRNPs in the cytoplasm. This confinement cannot be explained by an ATP decrease or the physiological drop in intracellular pH. Rather, our results suggest that the regulation of diffusional mobility is induced by a reduction in cell volume and subsequent increase in molecular crowding which severely alters the biophysical properties of the intracellular environment. A similar response can be observed in fission yeast and bacteria. This reveals a novel mechanism by which cells globally alter their properties to establish a unique homeostasis during starvatio

Abstract CT034: Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study

International audienceAbstract Background: Gamma9 Delta2 (γ9δ2) T cells function at the crossroad of innate and adaptive immunity with important roles in immune responses against pathogens and carcinogenesis, making them an attractive target for cancer immunotherapy. Butyrophilin (BTN) 3A (CD277) is an immune checkpoint molecule expressed on tumors and cells of the immune system that is required for γ9δ2 T cell activation. These observations led to the design and development of ICT01, a humanized, monoclonal antibody that binds the extracellular domain of all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation and killing of multiple tumors in nonclinical settings. Methods: EVICTION (www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, open-label clinical study to assess the safety, tolerability, and activity of a range of IV doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Regulatory and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, the UK and USA. Following signed informed consent, patients received ICT01 every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping by flow cytometry and cytokine analysis (IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13). Tumor biopsies are collected at baseline and on Day 28 for immunohistochemistry (e.g., BTN3A, γ9δ2 T cells) and expression profiling of cancer- and immunity-related genes. Results: Solid tumor (ST) dose cohorts 1-4 (total n=20) were enrolled and treated with ICT01 doses ranging from 20 μg to 20 mg, and dose cohort 1 of hematologic cancer patients (n=3, 200 μg) has been enrolled. ICT01 was well-tolerated, with no dose-limiting toxicities or related SAEs reported. Target occupancy on T cells at 30 min or 4 hours post first dose ranged from 34% (700 μg, n=2), 79% (2 mg, n=5), 93% (7 mg, n=4) and 100% (20 mg, n=1), with activated γ9δ2 T cells (CD69+) migrating from the blood within 30 min of dosing that led to a > 95% decrease from baseline in the number of circulating γ9δ2 T cells for all 4 doses by 24hrs. The 2nd dose of ICT01 induced a similar activation & migration of γ9δ2 T cells from the circulation. There were no effects on CD4/CD8 T cells, NK, or B cells. Available cytokine data from ST cohorts 1 & 2 showed no CRS although transient 2-3x increases in IFNγ, TNFα, & IL-2 were observed 4 hours post dose in patients with higher baseline γ9δ2 T cell counts. A 5-10x increase of IFNγ was observed on Days 7 & 28 in ST cohort 2, consistent with γ9δ2 T cell activation. Digital pathology analysis of tumor biopsies of a cohort 1 melanoma pt demonstrated a 25x and 8x increase of CD3-TCRgamma delta++ and CD3+ cell densities, respectively, as compared to baseline. Analyses of additional cohorts are ongoing and will be presented. Conclusion: The preliminary results demonstrate that ICT01 safely and potently activates the anti-tumor immune response of γ9δ2 T cells mediated by BTN3A. Citation Format: Aurelien Marabelle, Christiane Jungels, Johann De Bono, Norbert Vey, Martin Wermke, Elena Garralda, Steven Le Gouill, Patricia LoRusso, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iche, Daniel Olive, Paul A. Frohna. Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT034

EMMA 2-A MAGE-compliant system for the collaborative analysis and integration of microarray data

Dondrup M, Albaum S, Griebel T, et al. EMMA 2-A MAGE-compliant system for the collaborative analysis and integration of microarray data. BMC Bioinformatics. 2009;10(1): 50.Background: Understanding transcriptional regulation by genome-wide microarray studies can contribute to unravel complex relationships between genes. Attempts to standardize the annotation of microarray data include the Minimum Information About a Microarray Experiment (MIAME) recommendations, the MAGE-ML format for data interchange, and the use of controlled vocabularies or ontologies. The existing software systems for microarray data analysis implement the mentioned standards only partially and are often hard to use and extend. Integration of genomic annotation data and other sources of external knowledge using open standards is therefore a key requirement for future integrated analysis systems. Results: The EMMA 2 software has been designed to resolve shortcomings with respect to full MAGE-ML and ontology support and makes use of modern data integration techniques. We present a software system that features comprehensive data analysis functions for spotted arrays, and for the most common synthesized oligo arrays such as Agilent, Affymetrix and NimbleGen. The system is based on the full MAGE object model. Analysis functionality is based on R and Bioconductor packages and can make use of a compute cluster for distributed services. Conclusion: Our model-driven approach for automatically implementing a full MAGE object model provides high flexibility and compatibility. Data integration via SOAP-based web-services is advantageous in a distributed client-server environment as the collaborative analysis of microarray data is gaining more and more relevance in international research consortia. The adequacy of the EMMA 2 software design and implementation has been proven by its application in many distributed functional genomics projects. Its scalability makes the current architecture suited for extensions towards future transcriptomics methods based on high-throughput sequencing approaches which have much higher computational requirements than microarrays