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A Genetically Encoded Magnetic Resonance Imaging Reporter Enables Sensitive Detection and Tracking of Spontaneous Metastases in Deep Tissues
No full textMetastasis is the leading cause of cancer-related death. However, it remains a poorly understood aspect of cancer biology, and most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Here, our objective was to develop an imaging reporter system that offers sensitive three-dimensional (3D) detection of cancer cells at high resolutions in live mice. An organic anion-transporting polypeptide 1b3 (oatp1b3) was used as an MRI reporter gene, and its sensitivity was systematically optimized for in vivo tracking of viable cancer cells in a spontaneous metastasis model. Metastases with oatp1b3-MRI could be observed at the single lymph node level and tracked over time as cancer cells spread to multiple lymph nodes and different organ systems in individual animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were largely obscured by light scatter from the initial node. Importantly, MRI could detect micrometastases in lung tissue comprised on the order of 1,000 cancer cells. In summary, oatp1b3-MRI enables longitudinal tracking of cancer cells with combined high resolution and high sensitivity that provides 3D spatial information and the surrounding anatomical context.
Significance: An MRI reporter gene system optimized for tracking metastasis in deep tissues at high resolutions and able to detect spontaneous micrometastases in lungs of mice provides a useful tool for metastasis research
Extreme differences in SARS-CoV-2 viral loads among respiratory specimen types during presumed pre-infectious and infectious periods
No full textSARS-CoV-2 viral-load measurements from a single-specimen type are used to establish diagnostic strategies, interpret clinical-trial results for vaccines and therapeutics, model viral transmission, and understand virus–host interactions. However, measurements from a single-specimen type are implicitly assumed to be representative of other specimen types. We quantified viral-load timecourses from individuals who began daily self-sampling of saliva, anterior-nares (nasal), and oropharyngeal (throat) swabs before or at the incidence of infection with the Omicron variant. Viral loads in different specimen types from the same person at the same timepoint exhibited extreme differences, up to 109 copies/mL. These differences were not due to variation in sample self-collection, which was consistent. For most individuals, longitudinal viral-load timecourses in different specimen types did not correlate. Throat-swab and saliva viral loads began to rise as many as 7 days earlier than nasal-swab viral loads in most individuals, leading to very low clinical sensitivity of nasal swabs during the first days of infection. Individuals frequently exhibited presumably infectious viral loads in one specimen type while viral loads were low or undetectable in other specimen types. Therefore, defining an individual as infectious based on assessment of a single-specimen type underestimates the infectious period, and overestimates the ability of that specimen type to detect infectious individuals. For diagnostic COVID-19 testing, these three single-specimen types have low clinical sensitivity, whereas a combined throat–nasal swab, and assays with high analytical sensitivity, was inferred to have significantly better clinical sensitivity to detect presumed pre-infectious and infectious individuals
Index Cases First Identified by Nasal-Swab Rapid COVID-19 Tests Had More Transmission to Household Contacts Than Cases Identified by Other Test Types
No full textImportance. At-home rapid COVID-19 tests utilize nasal-swab specimens and require high viral loads to reliably give positive results. Longitudinal studies from the onset of infection have found infectious virus can present in oral specimens days before nasal. Detection and initiation of infection-control practices may therefore be delayed when nasal-swab rapid tests are used, resulting in greater exposure and transmission to contacts.
Objective. We assessed whether index cases first identified by rapid nasal-swab COVID-19 tests had more transmission to household contacts than index cases who used other test types (tests with higher analytical sensitivity but longer turnaround times, and/or that utilize non-nasal specimen types).
Design. In this observational cohort study, members of households with a recent COVID-19 case were screened for infection at least daily by RT-qPCR on one or more self-collected upper-respiratory specimen types. Participants reported demographic/medical information (including COVID-19 testing), symptom and exposure information, and household infection-control practices. A two-level random intercept model was used to assess the association between the infection outcome of household contacts and each covariable (household size, race/ethnicity, age, vaccination status, viral variant, infection-control practices, and whether a rapid nasal-swab test was used to initially identify the household index case).
Setting. Southern California, September 2020—June 2021 and November 2021—March 2022.
Participants. Cohort of 370 individuals from 85 households.
Main Outcome(s) and Measure(s)Transmission was quantified by adjusted secondary attack rates (aSAR) and adjusted odds ratios (aOR).
Results. An aSAR of 53.6% (95% CI 38.8–68.3%) was observed among households where the index case first tested positive by a rapid nasal-swab COVID-19 test, which was significantly higher than the aSAR for households where the index case utilized another test type (27.2% 95% CI 19.5– 35.0%,P=0.003 pairwise comparisons of predictive margins). We observed an aOR of 4.90 (95% CI 1.65–14.56) for transmission to household contacts when a nasal-swab rapid test was used to identify the index case, compared to other test types.
Conclusions and Relevance. Use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may not limit transmission as well as other test types.
Key Points:
Question: Does identification of index cases by rapid nasal-swab tests limit household transmission of SARS-CoV-2 as well as other test types?
Finding. Significantly higher adjusted secondary attack rates and adjusted odds ratios for transmission were observed in households where the index case used a nasal rapid COVID-19 test for initial detection versus other test types.
Meaning. The use of nasal-swab rapid COVID-19 tests for initial detection of infection and initiation of infection control may not limit transmission as well as other test types
Structure and Function of the Dot/Icm T4SS
No full textThe Legionella pneumophila Dot/Icm type IV secretion system (T4SS) delivers effector proteins into host cells during infection. Despite its significance as a potential drug target, our current understanding of its atomic structure is limited to isolated subcomplexes. In this study, we used subtomogram averaging and integrative modeling to construct a nearly-complete model of the Dot/Icm T4SS accounting for seventeen protein components. We locate and provide insights into the structure and function of six new components including DotI, DotJ, DotU, IcmF, IcmT, and IcmX. We find that the cytosolic N-terminal domain of IcmF, a key protein forming a central hollow cylinder, interacts with DotU, providing insight into previously uncharacterized density. Furthermore, our model, in combination with analyses of compositional heterogeneity, explains how the cytoplasmic ATPase DotO is connected to the periplasmic complex via interactions with membrane-bound DotI/DotJ proteins. Coupled with in situ infection data, our model offers new insights into the T4SS-mediated secretion mechanism
Probing metabolism in an E. coli-based cell-free system reveals a trade-off between transcription and translation
No full textCell-free transcription-translation (TX-TL) systems have been used for diverse applications, from prototyping gene circuits to providing a platform for the development of synthetic life, but their performance is limited by issues such as batch-to-batch variability, poor predictability, and limited lifetime. These issues stem largely from the fact that cell lysate contains an active and complex metabolism whose effect on TX-TL has remained largely uncharacterized.
Motivated by a minimal model of cell-free metabolism, this work explored the effects of energy molecules, which power TX-TL, and fuel molecules, which regenerate energy by harnessing core metabolism, on anE. coli-based TX-TL system. This work reports a compensatory interaction between TX-TL components Mg⁺² and 3-phosphoglyceric acid (3-PGA, used to regenerate ATP), where if one component’s concentration is increased, the other’s must likewise be increased to maintain optimal translation. Furthermore, maximum total mRNA and protein production occur in different and opposite concentration regimes of Mg⁺² and 3-PGA. To explore the observed phenomenon, transcription and translation were decoupled. Under translation inhibition, transcriptional output was uniform across Mg⁺² and 3-PGA concentrations, but in a translation-only system, maximum protein production occurred in the previously found optimal regime of Mg⁺² and 3-PGA, suggesting a TX-TL trade-off. Using alternative fuels to regenerate energy, this work found that the trade-off is universal across the different fuel sources, and that a system’s position along the trade-off is determined strongly by Mg⁺² and DNA concentrations. In systems where additional energy is supplied and where a fuel source is absent, the trade-off is absent, suggesting the trade-off arises from limitations in the regulation of translation and efficient energy regeneration. This work represents a significant advancement in understanding the effects of fuel and energy metabolism on TX-TL in cell-free systems and lays the foundation for improving TX-TL performance, lifetime, standardization, and prediction
Magnetic Signature of Vertically Migrating Aggregations in the Ocean
No full textThe significance of fluid transport in the ocean due to migrating aggregations of zooplankton remains poorly understood due to practical challenges associated with predicting, identifying, and quantifying instances of enhanced biogenic mixing. We present a new approach to overcome these limitations by quantifying the biogenic transport via its distinct magnetic signatures. This present approach can be accomplished potentially without a priori knowledge of the precise location of the aggregation and without triggering animal avoidance caused by the introduction of instruments into the migration
A Distance Measurement to M33 Using Optical Photometry of Mira Variables
No full textWe present a systematic analysis to determine and improve the pulsation periods of 1637 known long-period Mira variables in M33 using gri-band light curves spanning ∼18 yr from several surveys, including the M33 variability survey, Panoramic Survey Telescope and Rapid Response System, Palomar Transient Factory (PTF), intermediate PTF, and Zwicky Transient Facility. Based on these collections of light curves, we found that optical-band light curves that are as complete as possible are crucial to determine the periods of distant Miras. We demonstrated that the machine-learning techniques can be used to classify Miras into O-rich and C-rich based on the (J − Kₛ) period–color plane. Finally, We derived the distance modulus to M33 using O-rich Miras at maximum light together with our improved periods as 24.67 ± 0.06 mag, which is in good agreement with the recommended value given in the literature
Real-time evolution of Anderson impurity models via tensor network influence functionals
No full textIn this work, we present and analyze two tensor network-based influence functional approaches for simulating the real-time dynamics of quantum impurity models such as the Anderson model. Via comparison with recent numerically exact simulations, we show that such methods accurately capture the long-time nonequilibrium quench dynamics. The two parameters that must be controlled in these tensor network influence functional approaches are a time discretization (Trotter) error and a bond dimension (tensor network truncation) error. We show that the actual numerical uncertainties are controlled by an intricate interplay of these two approximations, which we demonstrate in different regimes. Our work opens the door to using these tensor network influence functional methods as general impurity solvers
Characterization of a Set of Small Planets with TESS and CHEOPS and an Analysis of Photometric Performance
No full textThe radius valley carries implications for how the atmospheres of small planets form and evolve, but this feature is visible only with highly precise characterizations of many small planets. We present the characterization of nine planets and one planet candidate with both NASA TESS and ESA CHEOPS observations, which adds to the overall population of planets bordering the radius valley. While five of our planets—TOI 118 b, TOI 262 b, TOI 455 b, TOI 560 b, and TOI 562 b—have already been published, we vet and validate transit signals as planetary using follow-up observations for four new TESS planets, including TOI 198 b, TOI 244 b, TOI 444 b, and TOI 470 b. While a three times increase in primary mirror size should mean that one CHEOPS transit yields an equivalent model uncertainty in transit depth as about nine TESS transits in the case that the star is equally as bright in both bands, we find that our CHEOPS transits typically yield uncertainties equivalent to between two and 12 TESS transits, averaging 5.9 equivalent transits. Therefore, we find that while our fits to CHEOPS transits provide overall lower uncertainties on transit depth and better precision relative to fits to TESS transits, our uncertainties for these fits do not always match expected predictions given photon-limited noise. We find no correlations between number of equivalent transits and any physical parameters, indicating that this behavior is not strictly systematic, but rather might be due to other factors such as in-transit gaps during CHEOPS visits or nonhomogeneous detrending of CHEOPS light curves
Simulations of light distribution on new instrumented baffles surrounding Virgo end mirrors
No full textAs part of the second phase of Advanced Virgo upgrade program, instrumented baffles are being constructed to be installed around the end mirrors (EMs) in the main arms, in continuation of what has been implemented for the input mode cleaner EM during phase I. These baffles will be equipped with photosensors, allowing for real-time monitoring of the stray light around the mirrors. In this paper, we present optical simulations of the light distribution in the detector’s main cavities to assess the ability of the sensors to effectively monitor misalignment and defects on the mirrors’ surface and to play a role in the pre-alignment of the interferometer