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Delicate engineering of integrated nonlinear structures is required for developing scalable sources of non-classical light to be deployed in quantum information processing systems. In this work, we demonstrate a photonic molecule composed of two coupled microring resonators on an integrated nanophotonic chip, designed to generate strongly squeezed light uncontaminated by noise from unwanted parasitic nonlinear processes. By tuning the photonic molecule to selectively couple and thus hybridize only the modes involved in the unwanted processes, suppression of parasitic parametric fluorescence is accomplished. This strategy enables the use of microring resonators for the efficient generation of degenerate squeezed light: without it, simple single-resonator structures cannot avoid contamination from nonlinear noise without significantly compromising pump power efficiency. We use this device to generate 8(1) dB of broadband degenerate squeezed light on-chip, with 1.65(1) dB directly measured. Integrated sources of nonclassical light are a key component for scalable quantum technologies. Here, the authors work with two coupled microring resonators and show how to detune the resonances involved in unwanted parametric fluorescence, without significantly affecting the pump power efficiency.

Growing interest in quantum computing for practical applications has led to a surge in the availability of programmable machines for executing quantum algorithms 1 , 2 . Present-day photonic quantum computers 3 – 7 have been limited either to non-deterministic operation, low photon numbers and rates, or fixed random gate sequences. Here we introduce a full-stack hardware−software system for executing many-photon quantum circuit operations using integrated nanophotonics: a programmable chip, operating at room temperature and interfaced with a fully automated control system. The system enables remote users to execute quantum algorithms that require up to eight modes of strongly squeezed vacuum initialized as two-mode squeezed states in single temporal modes, a fully general and programmable four-mode interferometer, and photon number-resolving readout on all outputs. Detection of multi-photon events with photon numbers and rates exceeding any previous programmable quantum optical demonstration is made possible by strong squeezing and high sampling rates. We verify the non-classicality of the device output, and use the platform to carry out proof-of-principle demonstrations of three quantum algorithms: Gaussian boson sampling, molecular vibronic spectra and graph similarity 8 . These demonstrations validate the platform as a launchpad for scaling photonic technologies for quantum information processing. A system for realizing many-photon quantum circuits is presented, comprising a programmable nanophotonic chip operating at room temperature, interfaced with a fully automated control system.

Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A ‘drug holiday’ where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.

The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples, we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of LUAD initiation and growth, we identify that Huwe1 is essential for mutant Kras -induced lung tumour development and reveal a novel, p53-independent requirement for Huwe1 in LUAD. Mechanistically, we demonstrate induction of senescence following HUWE1 depletion - characterised by impaired proliferation, an atypical cell cycle distribution, emergence of morphologically abnormal enlarged cells, increased β-galactosidase activity, and transcriptional reprogramming associated with inflammatory senescence-associated secretory phenotype (SASP) signalling and NFκB activation. Together, these data highlight a crucial role for HUWE1 in mutant Kras -induced LUAD tumorigenesis and in the continued growth and proliferation of established LUAD cells, confirming HUWE1 as a rational therapeutic target for LUAD.

Photonics offers a promising platform for quantum computing 1 , 2 , 3 – 4 , owing to the availability of chip integration for mass-manufacturable modules, fibre optics for networking and room-temperature operation of most components. However, experimental demonstrations are needed of complete integrated systems comprising all basic functionalities for universal and fault-tolerant operation 5 . Here we construct a (sub-performant) scale model of a quantum computer using 35 photonic chips to demonstrate its functionality and feasibility. This combines all the primitive components as discrete, scalable rack-deployed modules networked over fibre-optic interconnects, including 84 squeezers 6 and 36 photon-number-resolving detectors furnishing 12 physical qubit modes at each clock cycle. We use this machine, which we name Aurora, to synthesize a cluster state 7 entangled across separate chips with 86.4 billion modes, and demonstrate its capability of implementing the foliated distance-2 repetition code with real-time decoding. The key building blocks needed for universality and fault tolerance are demonstrated: heralded synthesis of single-temporal-mode non-Gaussian resource states, real-time multiplexing actuated on photon-number-resolving detection, spatiotemporal cluster-state formation with fibre buffers, and adaptive measurements implemented using chip-integrated homodyne detectors with real-time single-clock-cycle feedforward. We also present a detailed analysis of our architecture’s tolerances for optical loss, which is the dominant and most challenging hurdle to crossing the fault-tolerant threshold. This work lays out the path to cross the fault-tolerant threshold and scale photonic quantum computers to the point of addressing useful applications. A proof-of-principle study reports a complete photonic quantum computer architecture that can, once appropriate component performance is achieved, deliver a universal and fault-tolerant quantum computer.

BackgroundChimeric Antigen Receptor (CAR)-T cell therapy is very effective in the treatment of B cell leukemia but still inefficient in solid cancer treatment. Immunosuppression in tumor microenvironment (TME), tumor heterogeneity and immune escape dampen the efficacy of CAR-T cells in these tumor types. To overcome these issues, here we propose murine 4th generation CAR-T cells secreting a modified Toll-Like Receptor (TLR) ligand. We assume that this mediator functions as a ‘danger signal’ that can activate immune cells in the TME and promotes the generation of an inflammatory milieu. Thus, we aim to combine direct CAR-dependent antitumor activity and TLR-mediated immunostimulation in one tool.Materials and MethodsMC38 murine cancer cells were engineered to express a truncated form of the human Epidermal Growth Factor Receptor (trEGFR) and used as a target. A second generation CAR was synthetized (cetuximab scFv - CD8 hinge - 4.1BB - CD3z) and cloned in the MSCV retroviral vector. Murine 2nd generation CAR-T cells were engineered and killing and cytokines secretion assessed by luminescence-based assay and ELISA upon co-culture with target cells. Different constructs were tested combining the TLR ligand to different export signals. Colorimetric assays and western blot analyses were performed to evaluate its activity and its production and secretion, respectively. A repetition of the Nuclear Factor of Activated T cells (NFAT) with a synthetic TATA box (synTATA)(1) was tested for the inducible production of the TLR ligand only upon CAR-T cells activation.ResultsEGFR-targetedmurine CAR-T cells recognized and killed target cells after 48 hours of co-culture. Meanwhile, TLR ligand constructs were cloned and expressed in HEK293T cells. Analysis of supernatants and cell lysates revealed high production and secretion of the glycosylated ligand when coupled with the IgK leader sequence, indicating Golgi transport. Whereas, when coupled with the cell penetrating peptides transportan or a repetition of eight arginines, the ligand was produced and released in the supernatant in its non-glycosylated form, bypassing Golgi. All the secreted ligands stimulated TLR-sensor cells, with different intensities and kinetics. TLR activation appeared to be dependent on ligand production and its glycosylation status as well. Finally, murine T cells transduced with the NFAT synTATA promoter expressed GFP upon CD3 activation, indicating inducible protein production.ConclusionsEGFR-targetedCAR-T cells activity, ligand-dependent TLR stimulation and NFAT synTATA inducible protein production represent valuable building blocks for the production of 4th generation CAR-T cells. Next steps contemplate the construction of a vector encoding for both CAR and inducible TLR ligand, and to test its functionality in terms of improved CAR activity and reshaping of immune cell landscape in solid tumors both in vitro and in an immunocompetent mouse tumor model.ReferencesZimmermann K, Kuehle J, Dragon AC, et al. Design and Characterization of an ‘All-in-One’ Lentiviral Vector System Combining Constitutive Anti-GD2 CAR Expression and Inducible Cytokines. Cancers (Basel) 2020;12(2):375.Disclosure Information J. Magri: None. M. Menotti: None. A. Abbati: None. T.L. Haas: None.

The cheetah is unusual among felids in exhibiting near genetic uniformity at a variety of loci previously screened to measure population genetic diversity. It has been hypothesized that a demographic crash or population bottle-neck in the recent history of the species is causal to the observed monomorphic profiles for nuclear coding loci. The timing of a bottleneck is difficult to assess, but certain aspects of the cheetah's natural history suggest it may have occurred near the end of the last ice age (late Pleistocene, approximately 10,000 years ago), when a remarkable extinction of large vertebrates occurred on several continents. To further define the timing of such a bottleneck, the character of genetic diversity for two rapidly evolving DNA sequences, mitochondrial DNA and hypervariable minisatellite loci, was examined. Moderate levels of genetic diversity were observed for both of these indices in surveys of two cheetah subspecies, one from South Africa and one from East Africa. Back calculation from the extent of accumulation of DNA diversity based on observed mutation rates for VNTR (variable number of tandem repeats) loci and mitochondrial DNA supports a hypothesis of an ancient Pleistocene bottleneck that rendered the cheetah depauperate in genetic variation for nuclear coding loci but would allow sufficient time for partial reconstitution of more rapidly evolving genomic DNA segments.

Effective utilization of the domestic cat as an animal model for hereditary and infectious disease requires the development and implementation of high quality gene maps incorporating microsatellites and conserved coding gene markers. Previous feline linkage and radiation hybrid maps have lacked sufficient microsatellite coverage on all chromosomes to make effective use of full genome scans. Here we report the isolation and genomic mapping of 304 novel polymorphic repeat loci in the feline genome. The new loci were mapped in the domestic cat radiation hybrid panel using an automated fluorescent Taq-Man based assay. The addition of these 304 microsatellites brings the total number of microsatellites mapped in the feline genome to 580, and the total number of loci placed onto the RH map to 1,126. Microsatellites now span every autosome with an average spacing of roughly one polymorphic STR every five centimorgans, and full genome coverage of one marker every 2.7 megabases. These loci now provide a useful tool for undertaking full-genome scans to identify genes associated with phenotypes of interest, such as those relating to hereditary disease, coat color, patterning and morphology. These resources can also be extended to the remaining 36 species of the cat family for population genetic and evolutionary genomic analyses.