Rydberg exciton-polaritons in a Cu2O microcavity.

Giant Rydberg excitons with principal quantum numbers as high as n = 25 have been observed in cuprous oxide (Cu2O), a semiconductor in which the exciton diameter can become as large as ∼1 µm. The giant dimension of these excitons results in excitonic interaction enhancements of orders of magnitude. Rydberg exciton-polaritons, formed by the strong coupling of Rydberg excitons to cavity photons, are a promising route to exploit these interactions and achieve a scalable, strongly correlated solid-state platform. However, the strong coupling of these excitons to cavity photons has remained elusive. Here, by embedding a thin Cu2O crystal into a Fabry-Pérot microcavity, we achieve strong coupling of light to Cu2O Rydberg excitons up to n = 6 and demonstrate the formation of Cu2O Rydberg exciton-polaritons. These results pave the way towards realizing strongly interacting exciton-polaritons and exploring strongly correlated phases of matter using light on a chip.

Using enhanced development tools offered by analytical Quality by Design to support switching of a quality control method.

Quality by Design (QbD) principles play an increasingly important role in the pharmaceutical industry. Here, we used an analytical QbD (AQbD) approach to develop a capillary electrophoresis sodium dodecyl sulfate under reducing conditions (rCE-SDS), with the aim of replacing SDS-polyacrylamide gel electrophoresis (SDS-PAGE) as release and stability test method for a commercialized monoclonal antibody product. Method development started with defining analytical method performance requirements as part of an analytical target profile, followed by a systematic risk assessment of method input parameters and their relation to defined method outputs. Based on this, design of experiments studies were performed to identify a method operable design region (MODR). The MODR could be leveraged to improve method robustness. In a bridging study, it was demonstrated that the rCE-SDS method is more sensitive than the legacy SDS-PAGE method, and a conversion factor could be established to compensate for an off-set due to the higher sensitivity, without losing the correlation to the historical data acquired with the former method. Overall, systematic application of analytical Quality by Design principles for designing and developing a new analytical method helped to elucidate the complex dependency of method outputs on its input parameters. The link of the method to product quality attributes and the definition of method performance requirements were found to be most relevant for derisking the analytical method switch, regarding impact on the control strategy.

Symmetry-protected collisions between strongly interacting photons.

Realizing robust quantum phenomena in strongly interacting systems is one of the central challenges in modern physical science. Approaches ranging from topological protection to quantum error correction are currently being explored across many different experimental platforms, including electrons in condensed-matter systems, trapped atoms and photons. Although photon-photon interactions are typically negligible in conventional optical media, strong interactions between individual photons have recently been engineered in several systems. Here, using coherent coupling between light and Rydberg excitations in an ultracold atomic gas, we demonstrate a controlled and coherent exchange collision between two photons that is accompanied by a π/2 phase shift. The effect is robust in that the value of the phase shift is determined by the interaction symmetry rather than the precise experimental parameters, and in that it occurs under conditions where photon absorption is minimal. The measured phase shift of 0.48(3)π is in excellent agreement with a theoretical model. These observations open a route to realizing robust single-photon switches and all-optical quantum logic gates, and to exploring novel quantum many-body phenomena with strongly interacting photons.

Deterministic Photon Sorting in Waveguide QED Systems.

Sorting quantum fields into different modes according to their Fock-space quantum numbers is a highly desirable quantum operation. In this Letter, we show that a pair of two-level emitters, chirally coupled to a waveguide, may scatter single- and two-photon components of an input pulse into orthogonal temporal modes with a fidelity ≳0.9997. We develop a general theory to characterize and optimize this process and reveal that such a high fidelity is enabled by an interesting two-photon scattering dynamics: while the first emitter gives rise to a complex multimode field, the second emitter recombines the field amplitudes, and the net two-photon scattering induces a self-time reversal of the input pulse mode. The presented scheme can be employed to construct logic elements for propagating photons, such as a deterministic nonlinear-sign gate with a fidelity ≳0.9995.

Strongly Correlated States of Light and Repulsive Photons in Chiral Chains of Three-Level Quantum Emitters.

We study the correlated transport of photons through a chain of three-level emitters that are coupled chirally to a photonic mode of a waveguide. It is found that this system can transfer a weak classical input into a strongly correlated state of light in a unitary manner. Our analysis reveals two-photon scattering eigenstates, that are akin to Fano resonances or shape resonances in particle collisions and facilitate the emergence of antibunched light with long-range correlations upon crossing a critical length of the chain. By operating close to conditions of electromagnetically induced transparency of the three-level medium, a high degree of antibunching and photon transmission can be maintained in the presence of moderate losses. These features suggest a promising mechanism for single-photon generation and may open the door to exploring correlated quantum many-body states of light with repulsively interacting photons.

Estimating Inert Gas Bubbling from Simple SCUBA Diving Parameters.

Inert gas bubbles frequently occur in SCUBA divers' vascular systems, eventually leading to decompression accidents. Only in professional settings, dive profiles can be adjusted on individual basis depending on bubble grades detected through ultrasonography. A total of 342 open-circuit air dives following sports diving profiles were assessed using echocardiography. Subsequently, (Eftedal-Brubakk) bubble grades were correlated with dive and individual parameters. Post-dive cardiac bubbles were observed in 47% of all dives and bubble grades were significantly correlated with depth (r=0.46), air consumption (r=0.41), age (r=0.25), dive time (r=0.23), decompression diving (r=0.19), surface time (r=- 0.12). Eftedal-Brubakk categorical bubble grades for sports diving with compressed air can be approximated by bubble grade = (age*50-1 - surface time*150-1+maximum depth*45-1+air consumption*4500-1)2 (units in years, hours, meter, and bar*liter; R2=0.31). Thus, simple dive and individual parameters allow reasonable estimation of especially relevant medium to higher bubble grades for information on relevant decompression stress after ascent. Echo bubble grade 0 is overestimated by the formula derived. However, echo might fail to detect minor bubbling only. The categorical prediction of individual decompression stress with simple bio and dive data should be evaluated further to be developed towards dive computer included automatic ex-post information for decision-making on individual safety measures.

Plasma-Enhanced Interaction and Optical Nonlinearities of Cu_{2}O Rydberg Excitons.

We theoretically investigate the nonlinear optical transmission through a cuprous oxide crystal for wavelengths that cover the series of highly excited excitons, observed in recent experiments. Since such Rydberg excitons have strong van der Waals interactions, they can dynamically break the conditions for resonant exciton creation and dramatically modify the refractive index of the material in a nonlinear manner. We explore this mechanism theoretically and determine its effects on the optical properties of a semiconductor for the case of degenerate pair-state asymptotes of Rydberg excitons in Cu_{2}O. Upon analyzing the additional effects of a dilute residual electron-hole plasma, we find quantitative agreement with previous transmission measurements, which provides strong indications for the enhancement of Rydberg-induced nonlinearities by surrounding free charges.

Defective replication initiation results in locus specific chromosome breakage and a ribosomal RNA deficiency in yeast.

A form of dwarfism known as Meier-Gorlin syndrome (MGS) is caused by recessive mutations in one of six different genes (ORC1, ORC4, ORC6, CDC6, CDT1, and MCM5). These genes encode components of the pre-replication complex, which assembles at origins of replication prior to S phase. Also, variants in two additional replication initiation genes have joined the list of causative mutations for MGS (Geminin and CDC45). The identity of the causative MGS genetic variants strongly suggests that some aspect of replication is amiss in MGS patients; however, little evidence has been obtained regarding what aspect of chromosome replication is faulty. Since the site of one of the missense mutations in the human ORC4 alleles is conserved between humans and yeast, we sought to determine in what way this single amino acid change affects the process of chromosome replication, by introducing the comparable mutation into yeast (orc4Y232C). We find that yeast cells with the orc4Y232C allele have a prolonged S-phase, due to compromised replication initiation at the ribosomal DNA (rDNA) locus located on chromosome XII. The inability to initiate replication at the rDNA locus results in chromosome breakage and a severely reduced rDNA copy number in the survivors, presumably helping to ensure complete replication of chromosome XII. Although reducing rDNA copy number may help ensure complete chromosome replication, orc4Y232C cells struggle to meet the high demand for ribosomal RNA synthesis. This finding provides additional evidence linking two essential cellular pathways-DNA replication and ribosome biogenesis.

Supersolidity around a Critical Point in Dipolar Bose-Einstein Condensates.

We explore spatial symmetry breaking of a dipolar Bose-Einstein condensate in the thermodynamic limit and reveal a critical point in the phase diagram at which crystallization occurs via a second-order phase transition. This behavior is traced back to the significant effects of quantum fluctuations in dipolar condensates, which moreover stabilize a new supersolid phase, namely a regular honeycomb pattern with high modulational contrast and near-perfect superfluidity.

Polariton Exchange Interactions in Multichannel Optical Networks.

We examine the dynamics of Rydberg polaritons with dipolar interactions that propagate in multiple spatial modes. The dipolar excitation exchange between different Rydberg states mediates an effective exchange between polaritons that enables photons to hop across different spatial channels. Remarkably, the efficiency of this photon exchange process can increase with the channel distance and becomes optimal at a finite rail separation. Based on this mechanism, we design a simple photonic network that realizes a two photon quantum gate with a robust π phase, protected by the symmetries of the underlying photon interaction and the geometry of the network. These capabilities expand the scope of Rydberg electromagnetically induced transparency towards multidimensional geometries for nonlinear optical networks and explorations of photonic many-body physics.

Evaluation of a real-time magnetic resonance imaging-guided electrophysiology system for structural and electrophysiological ventricular tachycardia substrate assessment.

AIMS: Potential advantages of real-time magnetic resonance imaging (MRI)-guided electrophysiology (MR-EP) include contemporaneous three-dimensional substrate assessment at the time of intervention, improved procedural guidance, and ablation lesion assessment. We evaluated a novel real-time MR-EP system to perform endocardial voltage mapping and assessment of delayed conduction in a porcine ischaemia-reperfusion model. METHODS AND RESULTS: Sites of low voltage and slow conduction identified using the system were registered and compared to regions of late gadolinium enhancement (LGE) on MRI. The Sorensen-Dice similarity coefficient (DSC) between LGE scar maps and voltage maps was computed on a nodal basis. A total of 445 electrograms were recorded in sinus rhythm (range: 30-186) using the MR-EP system including 138 electrograms from LGE regions. Pacing captured at 103 sites; 47 (45.6%) sites had a stimulus-to-QRS (S-QRS) delay of ≥40 ms. Using conventional (0.5-1.5 mV) bipolar voltage thresholds, the sensitivity and specificity of voltage mapping using the MR-EP system to identify MR-derived LGE was 57% and 96%, respectively. Voltage mapping had a better predictive ability in detecting LGE compared to S-QRS measurements using this system (area under curve: 0.907 vs. 0.840). Using an electrical threshold of 1.5 mV to define abnormal myocardium, the total DSC, scar DSC, and normal myocardium DSC between voltage maps and LGE scar maps was 79.0 ± 6.0%, 35.0 ± 10.1%, and 90.4 ± 8.6%, respectively. CONCLUSION: Low-voltage zones and regions of delayed conduction determined using a real-time MR-EP system are moderately associated with LGE areas identified on MRI.

Long-Range Interactions and Symmetry Breaking in Quantum Gases through Optical Feedback.

We consider a quasi-two-dimensional atomic Bose-Einstein condensate interacting with a near-resonant laser field that is backreflected onto the condensate by a planar mirror. We show that this single-mirror optical feedback leads to an unusual type of effective interaction between the ultracold atoms giving rise to a rich spectrum of ground states. In particular, we find that it can cause the spontaneous contraction of the quasi-two-dimensional condensate to form a self-bound one-dimensional chain of mesoscopic quantum droplets, and demonstrate that the observation of this exotic effect is within reach of current experiments.

Epicardial electroanatomical mapping, radiofrequency ablation, and lesion imaging in the porcine left ventricle under real-time magnetic resonance imaging guidance-an in vivo feasibility study.

Aims: Magnetic resonance imaging (MRI) is the gold standard for defining myocardial substrate in 3D and can be used to guide ventricular tachycardia ablation. We describe the feasibility of using a prototype magnetic resonance-guided electrophysiology (MR-EP) system in a pre-clinical model to perform real-time MRI-guided epicardial mapping, ablation, and lesion imaging with active catheter tracking. Methods and results: Experiments were performed in vivo in pigs (n = 6) using an MR-EP guidance system research prototype (Siemens Healthcare) with an irrigated ablation catheter (Vision-MR, Imricor) and a dedicated electrophysiology recording system (Advantage-MR, Imricor). Following epicardial access, local activation and voltage maps were acquired, and targeted radiofrequency (RF) ablation lesions were delivered. Ablation lesions were visualized in real time during RF delivery using MR-thermometry and dosimetry. Hyper-acute and acute assessment of ablation lesions was also performed using native T1 mapping and late-gadolinium enhancement (LGE), respectively. High-quality epicardial bipolar electrograms were recorded with a signal-to-noise ratio of greater than 10:1 for a signal of 1.5 mV. During epicardial ablation, localized temperature elevation could be visualized with a maximum temperature rise of 35 °C within 2 mm of the catheter tip relative to remote myocardium. Decreased native T1 times were observed (882 ± 107 ms) in the lesion core 3-5 min after lesion delivery and relative location of lesions matched well to LGE. There was a good correlation between ablation lesion site on the iCMR platform and autopsy. Conclusion: The MR-EP system was able to successfully acquire epicardial voltage and activation maps in swine, deliver, and visualize ablation lesions, demonstrating feasibility for intraprocedural guidance and real-time assessment of ablation injury.

Observation of spatially ordered structures in a two-dimensional Rydberg gas.

The ability to control and tune interactions in ultracold atomic gases has paved the way for the realization of new phases of matter. So far, experiments have achieved a high degree of control over short-range interactions, but the realization of long-range interactions has become a central focus of research because it would open up a new realm of many-body physics. Rydberg atoms are highly suited to this goal because the van der Waals forces between them are many orders of magnitude larger than those between ground-state atoms. Consequently, mere laser excitation of ultracold gases can cause strongly correlated many-body states to emerge directly when atoms are transferred to Rydberg states. A key example is a quantum crystal composed of coherent superpositions of different, spatially ordered configurations of collective excitations. Here we use high-resolution, in situ Rydberg atom imaging to measure directly strong correlations in a laser-excited, two-dimensional atomic Mott insulator. The observations reveal the emergence of spatially ordered excitation patterns with random orientation, but well-defined geometry, in the high-density components of the prepared many-body state. Together with a time-resolved analysis, this supports the description of the system in terms of a correlated quantum state of collective excitations delocalized throughout the gas. Our experiment demonstrates the potential of Rydberg gases to realize exotic phases of matter, thereby laying the basis for quantum simulations of quantum magnets with long-range interactions.

Quantum nonlinear optics with single photons enabled by strongly interacting atoms.

The realization of strong nonlinear interactions between individual light quanta (photons) is a long-standing goal in optical science and engineering, being of both fundamental and technological significance. In conventional optical materials, the nonlinearity at light powers corresponding to single photons is negligibly weak. Here we demonstrate a medium that is nonlinear at the level of individual quanta, exhibiting strong absorption of photon pairs while remaining transparent to single photons. The quantum nonlinearity is obtained by coherently coupling slowly propagating photons to strongly interacting atomic Rydberg states in a cold, dense atomic gas. Our approach paves the way for quantum-by-quantum control of light fields, including single-photon switching, all-optical deterministic quantum logic and the realization of strongly correlated many-body states of light.

Functional centromeres determine the activation time of pericentric origins of DNA replication in Saccharomyces cerevisiae.

The centromeric regions of all Saccharomyces cerevisiae chromosomes are found in early replicating domains, a property conserved among centromeres in fungi and some higher eukaryotes. Surprisingly, little is known about the biological significance or the mechanism of early centromere replication; however, the extensive conservation suggests that it is important for chromosome maintenance. Do centromeres ensure their early replication by promoting early activation of nearby origins, or have they migrated over evolutionary time to reside in early replicating regions? In Candida albicans, a neocentromere contains an early firing origin, supporting the first hypothesis but not addressing whether the new origin is intrinsically early firing or whether the centromere influences replication time. Because the activation time of individual origins is not an intrinsic property of S. cerevisiae origins, but is influenced by surrounding sequences, we sought to test the hypothesis that centromeres influence replication time by moving a centromere to a late replication domain. We used a modified Meselson-Stahl density transfer assay to measure the kinetics of replication for regions of chromosome XIV in which either the functional centromere or a point-mutated version had been moved near origins that reside in a late replication region. We show that a functional centromere acts in cis over a distance as great as 19 kb to advance the initiation time of origins. Our results constitute a direct link between establishment of the kinetochore and the replication initiation machinery, and suggest that the proposed higher-order structure of the pericentric chromatin influences replication initiation.

Patient-centric Comparability Assessment of Biopharmaceuticals.

The comparability assessment of a biological product after implementing a manufacturing process change should involve a risk-based approach. Process changes may occur at any stage of the product lifecycle: early development, clinical manufacture for pivotal trials, or post-approval. The risk of the change to impact product quality varies. The design of the comparability assessment should be adapted accordingly. A working group reviewed and consolidated industry approaches to assess comparability of traditional protein-based biological products during clinical development and post-approval. The insights compiled in this review article encompass topics such as a risk-evaluation strategy, the design of comparability studies, definition of assessment criteria for comparability, holistic evaluation of data, and the regulatory submission strategy. These practices can be leveraged across the industry to help companies in design and execution of comparability assessments, and to inform discussions with global regulators.

A next-generation Fab library platform directly yielding drug-like antibodies with high affinity, diversity, and developability.

We previously described an in vitro single-chain fragment (scFv) library platform originally designed to generate antibodies with excellent developability properties. The platform design was based on the use of clinical antibodies as scaffolds into which replicated natural complementarity-determining regions purged of sequence liabilities were inserted, and the use of phage and yeast display to carry out antibody selection. In addition to being developable, antibodies generated using our platform were extremely diverse, with most campaigns yielding sub-nanomolar binders. Here, we describe a platform advancement that incorporates Fab phage display followed by single-chain antibody-binding fragment Fab (scFab) yeast display. The scFab single-gene format provides balanced expression of light and heavy chains, with enhanced conversion to IgG, thereby combining the advantages of scFvs and Fabs. A meticulously engineered, quality-controlled Fab phage library was created using design principles similar to those used to create the scFv library. A diverse panel of binding scFabs, with high conversion efficiency to IgG, was isolated against two targets. This study highlights the compatibility of phage and yeast display with a Fab semi-synthetic library design, offering an efficient approach to generate drug-like antibodies directly, facilitating their conversion to potential therapeutic candidates.

Disruption of individual nuo-genes leads to the formation of partially assembled NADH:ubiquinone oxidoreductase (complex I) in Escherichia coli.

The proton-pumping NADH:ubiquinone oxidoreductase, respiratory complex I, couples the electron transfer from NADH to ubiquinone with the translocation of protons across the membrane. In Escherichia coli the complex is made up of 13 different subunits encoded by the so-called nuo-genes. Mutants, in which each of the nuo-genes was individually disrupted by the insertion of a resistance cartridge were unable to assemble a functional complex I. Each disruption resulted in the loss of complex I-mediated activity and the failure to extract a structurally intact complex. Thus, all nuo-genes are required either for the assembly or the stability of a functional E. coli complex I. The three subunits comprising the soluble NADH dehydrogenase fragment of the complex were detected in the cytoplasm of several nuo-mutants as one distinct band after BN-PAGE. It is discussed that the fully assembled NADH dehydrogenase fragment represents an assembly intermediate of the E. coli complex I. A partially assembled complex I bound to the membrane was detected in the nuoK and nuoL mutants, respectively. Overproduction of the ΔNuoL variant resulted in the accumulation of two populations of a partially assembled complex in the cytoplasmic membranes. Both populations are devoid of NuoL. One population is enzymatically active, while the other is not. The inactive population is missing cluster N2 and is tightly associated with the inducible lysine decarboxylase. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes.

Dissipative many-body quantum optics in Rydberg media.

We develop a theoretical framework for the dissipative propagation of quantized light under conditions of electromagnetically induced transparency in atomic media involving strongly interacting Rydberg states. The theory allows us to determine the peculiar spatiotemporal structure of the output of the recently demonstrated single-photon filter and the recently proposed single-photon subtractor, which, respectively, let through and absorb a single photon. In addition to being crucial for applications of these and other optical quantum devices, the theory opens the door to the study of exotic dissipative many-body dynamics of strongly interacting photons in nonlinear nonlocal media.