Tolerogenic dendritic cells protect against acute kidney injury

Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. The phenotypic and genomic signatures of bone marrow–derived syngeneic or allogeneic, Vitamin-D3/IL-10–conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes

The influence of the atmospheric refractive index on radio Xmax measurements of air showers

The refractive index of the atmosphere, which is n ≈ 1:0003 at sea level, varies with altitude and with local temperature, pressure and humidity. When performing radio measurements of air showers, natural variations in n will change the radio lateral intensity distribution, by changing the Cherenkov angle. Using CoREAS simulations, we have evaluated the systematic error on measurements of the shower maximum Xmax due to variations in n. It was found that a 10% increase in refractivity (n - 1) leads to an underestimation of Xmax between 8 and 22 g/cm2 for proton-induced showers at zenith angles from 15 to 45 degrees, respectively

Cosmic Ray Mass Measurements with LOFAR

In the dense core of LOFAR individual air showers are detected by hundreds of dipole antennas simultaneously. We reconstruct Xmax by using a hybrid technique that combines a two-dimensional fit of the radio profile to CoREAS simulations and a one-dimensional fit of the particle density distribution. For high-quality detections, the statistical uncertainty on Xmax is smaller than 20 g/cm2. We present results of cosmic-ray mass analysis in the energy regime of 1017 - 1017.5 eV. This range is of particular interest as it may harbor the transition from a Galactic to an extragalactic origin of cosmic rays

Extending enzyme molecular recognition with an expanded amino acid alphabet

Natural enzymes are constructed from the twenty proteogenic amino acids, which may then require post-translational modification or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range of non-canonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity. Specifically, 13 different non-canonical side chains were incorporated at 12 different positions within the active site of N-acetylneuraminic acid lyase (NAL), and the resulting chemically-modified enzymes were screened for activity with a range of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity was not achievable with any of the 20 proteogenic amino acids. Structural and modelling studies revealed that the unique shape and functionality of the non-canonical side chain enabled the active site to be remodelled to enable more efficient stabilisation of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions of protein engineers wishing to develop enzymes with new catalytic properties

Towards real-time identification of cosmic rays with LOw-Frequency ARray radio antennas

Contains fulltext : 173576.pdf (publisher's version ) (Open Access

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery