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We describe the newest generation of the SLAC Microresonator RF (SMuRF) electronics, a warm digital control and readout system for microwave-frequency resonator-based cryogenic detector and multiplexer systems such as microwave SQUID multiplexers (\\(\\)mux) or microwave kinetic inductance detectors (MKIDs). Ultra-sensitive measurements in particle physics and astronomy increasingly rely on large arrays of cryogenic sensors, which in turn necessitate highly multiplexed readout and accompanying room-temperature electronics. Microwave-frequency resonators are a popular tool for cryogenic multiplexing, with the potential to multiplex thousands of detector channels on one readout line. The SMuRF system provides the capability for reading out up to 3328 channels across a 4-8 GHz bandwidth. Notably, the SMuRF system is unique in its implementation of a closed-loop tone-tracking algorithm that minimizes RF power transmitted to the cold amplifier, substantially relaxing system linearity requirements and effective noise from intermodulation products. Here we present a description of the hardware, firmware, and software systems of the SMuRF electronics, comparing achieved performance with science-driven design requirements. We focus in particular on the case of large channel count, low bandwidth applications, but the system has been easily reconfigured for high bandwidth applications. The system described here has been successfully deployed in lab settings and field sites around the world and is baselined for use on upcoming large-scale observatories.

We describe an on-sky demonstration of a microwave-multiplexing readout system in one of the receivers of the Keck Array, a polarimetry experiment observing the cosmic microwave background at the South Pole. During the austral summer of 2018-2019, we replaced the time-division multiplexing readout system with microwave-multiplexing components including superconducting microwave resonators coupled to radio-frequency superconducting quantum interference devices at the sub-Kelvin focal plane, coaxial-cable plumbing and amplification between room temperature and the cold stages, and a SLAC Microresonator Radio Frequency system for the warm electronics. In the range 5-6 GHz, a single coaxial cable reads out 528 channels. The readout system is coupled to transition-edge sensors, which are in turn coupled to 150-GHz slot-dipole phased-array antennas. Observations began in April 2019, and we report here on an initial characterization of the system performance.

The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands: 27, 39, 93, 145, 225 and 280 GHz. The initial configuration of SO will have three small-aperture 0.5-m telescopes (SATs) and one large-aperture 6-m telescope (LAT), with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The SATs will target the largest angular scales observable from Chile, mapping ~10% of the sky to a white noise level of 2 \\(\\)K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, \\(r\\), at a target level of \\((r)=0.003\\). The LAT will map ~40% of the sky at arcminute angular resolution to an expected white noise level of 6 \\(\\)K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the LSST sky region and partially with DESI. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.

The next generation of cryogenic CMB and submillimeter cameras under development require densely instrumented sensor arrays to meet their science goals. The readout of large numbers (\\(\\)10,000--100,000 per camera) of sub-Kelvin sensors, for instance as proposed for the CMB-S4 experiment, will require substantial improvements in cold and warm readout techniques. To reduce the readout cost per sensor and integration complexity, efforts are presently focused on achieving higher multiplexing density while maintaining readout noise subdominant to intrinsic detector noise. Highly-multiplexed cold readout technologies in active development include Microwave Kinetic Inductance Sensors (MKIDs) and microwave rf-SQUIDs. Both exploit the high quality factors of superconducting microwave resonators to densely channelize sub-Kelvin sensors into the bandwidth of a microwave transmission line. We present advancements in the development of a new warm readout system for microwave SQUID multiplexing, the SLAC Superconducting Microresonator RF electronics, or SMuRF. The SMuRF system is unique in its ability to track each tone, minimizing the total RF power required to read out each resonator, thereby significantly reducing the linearity requirements on the cold and warm readout. Here, we present measurements of the readout noise and linearity of the first full SMuRF system, including a demonstration of closed-loop tone tracking on a 528 channel cryogenic microwave SQUID multiplexer. SMuRF is being explored as a potential readout solution for several future CMB projects including Simons Observatory, BICEP Array, CCAT-prime, Ali-CPT, and CMB-S4. Parallel development of the platform is underway to adapt SMuRF to read out both MKID and fast X-ray TES calorimeter arrays.

The Simons Observatory (SO) is a ground-based cosmic microwave background (CMB) experiment sited on Cerro Toco in the Atacama Desert in Chile that promises to provide breakthrough discoveries in fundamental physics, cosmology, and astrophysics. Supported by the Simons Foundation, the Heising-Simons Foundation, and with contributions from collaborating institutions, SO will see first light in 2021 and start a five year survey in 2022. SO has 287 collaborators from 12 countries and 53 institutions, including 85 students and 90 postdocs. The SO experiment in its currently funded form ('SO-Nominal') consists of three 0.4 m Small Aperture Telescopes (SATs) and one 6 m Large Aperture Telescope (LAT). Optimized for minimizing systematic errors in polarization measurements at large angular scales, the SATs will perform a deep, degree-scale survey of 10% of the sky to search for the signature of primordial gravitational waves. The LAT will survey 40% of the sky with arc-minute resolution. These observations will measure (or limit) the sum of neutrino masses, search for light relics, measure the early behavior of Dark Energy, and refine our understanding of the intergalactic medium, clusters and the role of feedback in galaxy formation. With up to ten times the sensitivity and five times the angular resolution of the Planck satellite, and roughly an order of magnitude increase in mapping speed over currently operating (\"Stage 3\") experiments, SO will measure the CMB temperature and polarization fluctuations to exquisite precision in six frequency bands from 27 to 280 GHz. SO will rapidly advance CMB science while informing the design of future observatories such as CMB-S4.

A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 ( GJB3 ) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer. Breast cancer cells interact with neighbouring adipocytes, but the mechanisms are not fully understood. Here, the authors show that triple-negative breast cancer (TNBC) cells transfer cAMP through gap junctions, activating lipolysis in tumour-associated adipocytes to promote TNBC growth.

BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

Introduction Concomitant urinary tract infection (UTI) or invasive bacterial infection (IBI) in previously healthy, well-appearing febrile infants with COVID-19 is low. We sought to review the rates of UTI and IBI in all febrile infants with COVID-19 presenting to community emergency departments (EDs). Methods We retrospectively reviewed infants aged 7-90 days with COVID-19 from July 1, 2020, to August 31, 2022, who had an ED visit. Infants without fever or with COVID-19 more than seven days prior to the index ED visit were excluded. We collected data on blood, urine, and cerebrospinal fluid (CSF) culture results. UTI, bacteremia, and bacterial meningitis were defined by culture review as per prior standards. Results We included 622 infants, of whom 329 were febrile. Older infants and those presenting later in the pandemic had lower rates of complete evaluation. Of the 201 infants with urine collected, four (2%) had a UTI. Of the 184 infants with blood cultures obtained, 19 (10.3%) had contaminated blood cultures. One of the 159 infants (0.6%) with both blood and urine collected had an   bacteremic UTI. Only 12 infants had CSF obtained; however, no infants received treatment for bacterial meningitis. Factors associated with UTI were higher white blood cell (p=0.001) and absolute neutrophil counts (p=0.036), and abnormal urinalysis (UA) and urine microscopy (p<0.001). Conclusions Febrile infants with COVID-19 are at low risk for UTI and even lower risk for IBI. We recommend, at a minimum, that all febrile well-appearing infants aged 7-60 days with COVID-19 be evaluated for concomitant bacterial infections with a UA with microscopy.