The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity.

Inflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1 <sup>C284A</sup> , we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1 <sup>C284A</sup> , we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis

Excitation and relaxation in atom-cluster collisions

Electronic and vibrational degrees of freedom in atom-cluster collisions are treated simultaneously and self-consistently by combining time-dependent density functional theory with classical molecular dynamics. The gradual change of the excitation mechanisms (electronic and vibrational) as well as the related relaxation phenomena (phase transitions and fragmentation) are studied in a common framework as a function of the impact energy (eV...MeV). Cluster "transparency" characterized by practically undisturbed atom-cluster penetration is predicted to be an important reaction mechanism within a particular window of impact energies.Comment: RevTeX (4 pages, 4 figures included with epsf

Pilot study on the microbial contamination of conventional vs. silver-impregnated uniforms worn by ambulance personnel during one week of emergency medical service

The antimicrobial impregnation of products used everyday, such as surfaces, textiles and clothing – including those used in hospitals – is increasing. In view of potential toxic and environmental risks for users and patients, a careful risk-benefit assessment must be conducted for each newly developed product impregnated or coated with antimicrobial agents, prior to marketing and manufacture

Lidar–radar synergistic method to retrieve ice, supercooled water and mixed-phase cloud properties

Mixed-phase clouds are not well represented in climate and weather forecasting models, due to a lack of the key processes controlling their life cycle. Developing methods to study these clouds is therefore essential, despite the complexity of mixed-phase cloud processes and the difficulty of observing two cloud phases simultaneously. We propose in this paper a new method to retrieve the microphysical properties of mixed-phase clouds, ice clouds and supercooled water clouds using airborne or satellite radar and lidar measurements, called VarPy-mix. This new approach extends an existing variational method developed for ice cloud retrieval using lidar, radar and passive radiometers. We assume that the lidar attenuated backscatter β at 532 nm is more sensitive to particle concentration and is consequently mainly sensitive to the presence of supercooled water. In addition, radar reflectivity Z at 95 GHz is sensitive to the size of hydrometeors and hence more sensitive to the presence of ice particles. Consequently, in the mixed phase the supercooled droplets are retrieved with the lidar signal and the ice particles with the radar signal, meaning that the retrievals rely strongly on a priori and error values. This method retrieves simultaneously the visible extinction for ice αice and liquid αliq particles, the ice and liquid water contents IWC and LWC, the effective radius of ice re,ice and liquid re,liq particles, and the ice and liquid number concentrations Nice and Nliq. Moreover, total extinction αtot, total water content (TWC) and total number concentration Ntot can also be estimated. As the retrieval of ice and liquid is different, it is necessary to correctly identify each phase of the cloud. To this end, a cloud-phase classification is used as input to the algorithm and has been adapted for mixed-phase retrieval. The data used in this study are from DARDAR-MASK v2.23 products, based on the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) and Cloud Profiling Radar (CPR) observations from the CALIPSO and CloudSat satellites, respectively, belonging to the A-Train constellation launched in 2006. Airborne in situ measurements performed on 7 April 2007 during the Arctic Study of Tropospheric Aerosol, Clouds and Radiation (ASTAR) campaign and collected under the track of CloudSat–CALIPSO are compared with the retrievals of the new algorithm to validate its performance. Visible extinctions, water contents, effective radii and number concentrations derived from in situ measurements and the retrievals showed similar trends and are globally in good agreement. The mean percent error between the retrievals and in situ measurements is 39 % for αliq, 398 % for αice, 49 % for LWC and 75 % for IWC. It is also important to note that temporal and spatial collocations are not perfect, with a maximum spatial shift of 1.68 km and a maximum temporal shift of about 10 min between the two platforms. In addition, the sensitivity of remote sensing and that of in situ measurements is not the same, and in situ measurement uncertainties are between 25 % and 60 %.</p

Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolerant nanobodies

Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19. However, their production in mammalian cells is not scalable to meet the global demand. Single-domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein, we isolated 45 infection-blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS-CoV-2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X-ray and cryo-EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune-escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low-picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such “fold-promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape-mutations

Refixation of the Anterior Cruciate Ligament: A Biomechanical Analysis of Suture Techniques in a Porcine Model

Purpose Refixation of acute anterior cruciate ligament (ACL) tears represents an increasingly popular treatment option. Systematic evaluations of various suture technique parameters are still pending. We therefore aimed to evaluate the mechanical pull-out outcomes of various suture methods for optimization of ACL refixation. Methods Sixty fresh knees from mature domestic pigs were dissected and the femoral attachment of the ACL was peeled off. The 60 knees were divided in 10 groups and sutured as follows: (A) one suture (1, 2, 4 and 6 passes), (B) two sutures (2, 4 and 6 passes each; sutures knotted together as a loop) and (C) two sutures (2, 4 and 6 passes each, sutures knotted separately). The pull-out test was conducted using a validated electrodynamic testing machine. First occurrence of failure, maximum pull-out load and stiffness were measured. Suture failure was defined as pull-out of the ACL. Results Two-point fixation, using two sutures, with at least two passes, showed the most favourable biomechanical stability. The maximum pull-out load was significantly higher with two sutures (529.5 N) used compared to one (310.4 N), p < 0.001. No significant differences were found for maximum pull-out loads between two-point fixation versus one-point fixation but stiffness was significantly higher with two-point fixation (107.4 N/mm vs. 79.4 N/mm, p < 0.001). More passes resulted in higher maximum pull-out loads. Conclusion The results suggest using two independent sutures, refixed separately and at least two suture passes, is appropriate for ACL refixation. More suture passes provide additional strength but are technically challenging to achieve during surgery. Level of Evidence Level IV

Muon Track Reconstruction and Data Selection Techniques in AMANDA

The Antarctic Muon And Neutrino Detector Array (AMANDA) is a high-energy neutrino telescope operating at the geographic South Pole. It is a lattice of photo-multiplier tubes buried deep in the polar ice between 1500m and 2000m. The primary goal of this detector is to discover astrophysical sources of high energy neutrinos. A high-energy muon neutrino coming through the earth from the Northern Hemisphere can be identified by the secondary muon moving upward through the detector. The muon tracks are reconstructed with a maximum likelihood method. It models the arrival times and amplitudes of Cherenkov photons registered by the photo-multipliers. This paper describes the different methods of reconstruction, which have been successfully implemented within AMANDA. Strategies for optimizing the reconstruction performance and rejecting background are presented. For a typical analysis procedure the direction of tracks are reconstructed with about 2 degree accuracy.Comment: 40 pages, 16 Postscript figures, uses elsart.st

Retrieval of optical and microphysical properties of transported Saharan dust over Athens and Granada based on multi-wavelength Raman lidar measurements: Study of the mixing processes

In this paper we extract the aerosol microphysical properties for a collection of mineral dust cases measured by multi-wavelength depolarization Raman lidar systems located at the National Technical University of Athens (NTUA, Athens, Greece) and the Andalusian Institute for Earth System Research (IISTA-CEAMA, Granada, Spain). The lidar-based retrievals were carried out with the Spheroidal Inversion eXperiments software tool (SphInX) developed at the University of Potsdam (Germany). The software uses regularized inversion of a two-dimensional enhancement of the Mie model based on the spheroid-particle approximation with the aspect ratio determining the particle shape. The selection of the cases was based on the transport time from the source regions to the measuring sites. The aerosol optical depth as measured by AERONET ranged from 0.27 to 0.54 (at 500 nm) depending on the intensity of each event. Our analysis showed the hourly mean particle linear depolarization ratio and particle lidar ratio values at 532 nm ranging from 11 to 34% and from 42 to 79 sr respectively, depending on the mixing status, the corresponding air mass pathways and their transport time. Cases with shorter transport time showed good agreement in terms of the optical and SphInX-retrieved microphysical properties between Athens and Granada providing a complex refractive index value equal to 1.4 + 0.004i. On the other hand, the results for cases with higher transport time deviated from the aforementioned ones as well as from each other, providing, in particular, an imaginary part of the refractive index ranging from 0.002 to 0.005. Reconstructions of two-dimensional shape-size distributions for each selected layer showed that the dominant effective particle shape was prolate with diverse spherical contributions. The retrieved volume concentrations reflect overall the intensity of the episodes.Spanish Ministry of Sciences, Innovation and Universities through project CGL2016-81092,Spanish Ministry of Education, Culture and Sports through grant FPU14/0368