The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between ...remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/sqrtHz at Fourier frequencies above 100 mHz.
The Portable Radio Science Receiver (PRSR) is a suitcase-sized open-loop digital receiver designed to be small and easy to transport so that it can be deployed quickly and easily anywhere in the ...world. The PRSR digitizes, down-converts, and filters using custom hardware, firmware, and software. Up to 16 channels can be independently configured and recorded with a total data rate of up to 256 Mbps. The design and implementation of the system's hardware, firmware, and software is described. To minimize costs and time to deployment, our design leveraged elements of the hardware, firmware, and software designs from the existing full-sized operational (non-portable) Radio Science Receivers (RSR) and Wideband VLBI Science Receivers (WVSR), which have successfully supported flagship NASA deep space missions at all Deep Space Network (DSN) sites. We discuss a demonstration of the PRSR using VLBI, with one part per billion angular resolution: 1 nano-radian / 200 μas. This is the highest resolution astronomical instrument ever operated solely from the Southern Hemisphere. Preliminary results from two sites are presented, including the European Space Agency (ESA) sites at Cebreros, Spain and Malargüe, Argentina. Malargüe's South American location is of special interest because it greatly improves the geometric coverage for spacecraft navigation in the Southern Hemisphere and will for the first time provide coverage to the 1/4 of the range of declination that has been excluded from reference frame work at Ka-band.
Isolated, short dispersed pulses of radio emission of unknown origin have been reported and there is strong interest in wide-field, sensitive searches for such events. To achieve high sensitivity, ...large collecting area is needed and dispersion due to the interstellar medium should be removed. To survey a large part of the sky in reasonable time, a telescope that forms multiple simultaneous beams is desirable. We have developed a novel FPGA-based transient search engine that is suitable for these circumstances. It accepts short-integration-time spectral power measurements from each beam of the telescope, performs incoherent de-dispersion simultaneously for each of a wide range of dispersion measure (DM) values, and automatically searches the de-dispersed time series for pulse-like events. If the telescope provides buffering of the raw voltage samples of each beam, then our system can provide trigger signals to allow data in those buffers to be saved when a tentative detection occurs; this can be done with a latency of tens of ms, and only the buffers for beams with detections need to be saved. In one version of our implementation, intended for the ASKAP array of 36 antennas (currently under construction in Australia), 36 beams are simultaneously de-dispersed for 448 different DMs with an integration time of 1.0 ms. In the absence of such a multi-beam telescope, we have built a second version that handles up to 6 beams at 0.1 ms integration time and 512 DMs. We have deployed and tested this at a 34-m antenna of the Deep Space Network in Goldstone, California. A third version that processes up to 6 beams at an integration time of 2.0 ms and 1,024 DMs has been built and deployed at the Murchison Widefield Array telescope.
Isolated, short pulses of radio emission of unknown origin have been reported and there is strong interest in wide and sensitive searches for such events. To achieve high sensitivity, large ...collecting area is needed and dispersion due to the interstellar medium should be removed. To survey a large part of the sky in reasonable time, a telescope that forms multiple simultaneous beams is desirable. We have developed an FPGA-based transient search engine that is suitable for these circumstances. It accepts short-integration-time spectral power measurements from each beam of the telescope, performs incoherent de-dispersion simultaneously for each of a wide range of dispersion measure (DM) values, and automatically searches the de-dispersed time series for pulse-like events. If the telescope provides buffering of the raw voltage samples of each beam, then our system can provide trigger signals to allow data in those buffers to be saved when a tentative detection occurs; this can be done with a latency of tens of ms, and only the buffers for beams with detections need be saved.
We report the detection of an ultra-bright fast radio burst (FRB) from a modest, 3.4-day pilot survey with the Australian Square Kilometre Array Pathfinder. The survey was conducted in a wide-field ...fly's-eye configuration using the phased-array-feed technology deployed on the array to instantaneously observe an effective area of \(160\) deg\(^2\), and achieve an exposure totaling \(13200\) deg\(^2\) hr. We constrain the position of FRB 170107 to a region \(8'\times8'\) in size (90% containment) and its fluence to be \(58\pm6\) Jy ms. The spectrum of the burst shows a sharp cutoff above \(1400\) MHz, which could be either due to scintillation or an intrinsic feature of the burst. This confirms the existence of an ultra-bright (\(>20\) Jy ms) population of FRBs.
Ultralight materials present an opportunity to dramatically increase the efficiency of load-bearing aerostructures. To date, however, these ultralight materials have generally been confined to the ...laboratory bench-top, due to dimensional constraints of the manufacturing processes. We show a programmable material system applied as a large-scale, ultralight, and conformable aeroelastic structure. The use of a modular, lattice-based, ultralight material results in stiffness typical of an elastomer (2.6 MPa) at a mass density typical of an aerogel 5.6 mg cm 3 . This, combined with a building block based manufacturing and configuration strategy, enables the rapid realization of new adaptive structures and mechanisms. The heterogeneous design with programmable anisotropy allows for enhanced elastic and global shape deformation in response to external loading, making it useful for tuned fluid-structure interaction. We demonstrate an example application experiment using two building block types for the primary structure of a 4.27 m wingspan aircraft, where we spatially program elastic shape morphing to increase aerodynamic efficiency and improve roll control authority, demonstrated with full-scale wind tunnel testing.
Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and ...uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.
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•Macrophages mobilize classical epithelial modules during granuloma formation•Macrophage reprogramming shares features of mesenchymal-epithelial transitions•Inhibition of macrophage epithelialization leads to disordered granulomas•Granuloma disruption increases immune access and promotes host survival
A hallmark of tuberculosis is aggregation of macrophages into a structure termed the granuloma. Cronan et al. show that macrophages deploy classical epithelialization pathways to construct mycobacterial granulomas. This reprogramming is host detrimental, as macrophage-specific inhibition of the process enhances host survival and immune cell access and reduces bacterial burden.
Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), ...where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid—PS—controls the movement of another lipid—cholesterol—between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.
Abstract Tuberculous meningitis (TBM) is the most lethal form of tuberculosis. Clinical features, such as coma, can predict death, but they are insufficient for the accurate prognosis of other ...outcomes, especially when impacted by co-morbidities such as HIV infection. Brain magnetic resonance imaging (MRI) characterises the extent and severity of disease and may enable more accurate prediction of complications and poor outcomes. We analysed clinical and brain MRI data from a prospective longitudinal study of 216 adults with TBM; 73 (34%) were HIV-positive, a factor highly correlated with mortality. We implemented an end-to-end framework to model clinical and imaging features to predict disease progression. Our model used state-of-the-art machine learning models for automatic imaging feature encoding, and time-series models for forecasting, to predict TBM progression. The proposed approach is designed to be robust to missing data via a novel tailored model optimisation framework. Our model achieved a 60% balanced accuracy in predicting the prognosis of TBM patients over the six different classes. HIV status did not alter the performance of the models. Furthermore, our approach identified brain morphological lesions caused by TBM in both HIV and non-HIV-infected, associating lesions to the disease staging with an overall accuracy of 96%. These results suggest that the lesions caused by TBM are analogous in both populations, regardless of the severity of the disease. Lastly, our models correctly identified changes in disease symptomatology and severity in 80% of the cases. Our approach is the first attempt at predicting the prognosis of TBM by combining imaging and clinical data, via a machine learning model. The approach has the potential to accurately predict disease progression and enable timely clinical intervention.
The impact of proteins and peptides on the treatment of various conditions including ocular diseases over the past few decades has been advanced by substantial breakthroughs in structural ...biochemistry, genetic engineering, formulation and delivery approaches. Formulation and delivery of proteins and peptides, such as monoclonal antibodies, aptamers, recombinant proteins and peptides to ocular tissues poses significant challenges owing to their large size, poor permeation and susceptibility to degradation. A wide range of advanced drug delivery systems including polymeric controlled release systems, cell-based delivery and nanowafers are being exploited to overcome the challenges of frequent administration to ocular tissues. The next generation systems integrated with new delivery technologies are anticipated to generate improved efficacy and safety through the expansion of the therapeutic target space. This review will highlight recent advances in formulation and delivery strategies of protein and peptide based biopharmaceuticals. We will also describe the current state of proteins and peptides based ocular therapy and future therapeutic opportunities.
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