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Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
Despite the implementation of consolidative immune checkpoint inhibition after definitive chemoradiotherapy (CRT), the prognosis for locally advanced non-small-cell lung cancer (NSCLC) remains poor. We assessed the impact of the C-reactive protein (CRP) to albumin ratio (CAR) as an inflammation-based prognostic score in patients with locally advanced NSCLC treated with CRT. We retrospectively identified and analyzed 52 patients with primary unresectable NSCLC (UICC Stage III) treated with definitive/neoadjuvant CRT between 2014 and 2019. CAR was calculated by dividing baseline CRP by baseline albumin levels and correlated with clinicopathologic parameters to evaluate prognostic impact. After dichotomizing patients by the median, univariate and multivariate Cox regression analyses were performed. An increased CAR was associated with advanced T-stage (p = 0.018) and poor performance status (p = 0.004). Patients with pre-therapeutic elevated CAR had significantly lower hemoglobin and higher leukocyte levels (hemoglobin p = 0.001, leukocytes p = 0.018). High baseline CAR was shown to be associated with worse local control (LPFS, p = 0.006), shorter progression-free survival (PFS, p = 0.038) and overall survival (OS, p = 0.022), but not distant metastasis-free survival (DMFS). Multivariate analysis confirmed an impaired outcome in patients with high CAR (LPFS: HR 3.562, 95% CI 1.294–9.802, p = 0.011). CAR is an easily available and independent prognostic marker after CRT in locally advanced NSCLC. CAR may be a useful biomarker for patient stratification to individualize treatment concepts.
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Immersion freezing is the most relevant heterogeneous ice nucleation mechanism through which ice crystals are formed in mixed-phase clouds. In recent years, an increasing number of laboratory experiments utilizing a variety of instruments have examined immersion freezing activity of atmospherically relevant ice-nucleating particles. However, an intercomparison of these laboratory results is a difficult task because investigators have used different ice nucleation (IN) measurement methods to produce these results. A remaining challenge is to explore the sensitivity and accuracy of these techniques and to understand how the IN results are potentially influenced or biased by experimental parameters associated with these techniques.
Within the framework of INUIT (Ice Nuclei Research Unit), we distributed an illite-rich sample (illite NX) as a representative surrogate for atmospheric mineral dust particles to investigators to perform immersion freezing experiments using different IN measurement methods and to obtain IN data as a function of particle concentration, temperature (T), cooling rate and nucleation time. A total of 17 measurement methods were involved in the data intercomparison. Experiments with seven instruments started with the test sample pre-suspended in water before cooling, while 10 other instruments employed water vapor condensation onto dry-dispersed particles followed by immersion freezing. The resulting comprehensive immersion freezing data set was evaluated using the ice nucleation active surface-site density, ns, to develop a representative ns(T) spectrum that spans a wide temperature range (−37 °C < T < −11 °C) and covers 9 orders of magnitude in ns.
In general, the 17 immersion freezing measurement techniques deviate, within a range of about 8 °C in terms of temperature, by 3 orders of magnitude with respect to ns. In addition, we show evidence that the immersion freezing efficiency expressed in ns of illite NX particles is relatively independent of droplet size, particle mass in suspension, particle size and cooling rate during freezing. A strong temperature dependence and weak time and size dependence of the immersion freezing efficiency of illite-rich clay mineral particles enabled the ns parameterization solely as a function of temperature. We also characterized the ns(T) spectra and identified a section with a steep slope between −20 and −27 °C, where a large fraction of active sites of our test dust may trigger immersion freezing. This slope was followed by a region with a gentler slope at temperatures below −27 °C. While the agreement between different instruments was reasonable below ~ −27 °C, there seemed to be a different trend in the temperature-dependent ice nucleation activity from the suspension and dry-dispersed particle measurements for this mineral dust, in particular at higher temperatures. For instance, the ice nucleation activity expressed in ns was smaller for the average of the wet suspended samples and higher for the average of the dry-dispersed aerosol samples between about −27 and −18 °C. Only instruments making measurements with wet suspended samples were able to measure ice nucleation above −18 °C. A possible explanation for the deviation between −27 and −18 °C is discussed. Multiple exponential distribution fits in both linear and log space for both specific surface area-based ns(T) and geometric surface area-based ns(T) are provided. These new fits, constrained by using identical reference samples, will help to compare IN measurement methods that are not included in the present study and IN data from future IN instruments.
Recently significant advances have been made in the collection, detection, and characterization of ice nucleating particles (INP). Ice nuclei are particles that facilitate the heterogeneous formation of ice within the atmospheric aerosol by lowering the free energy barrier to spontaneous nucleation and growth of ice from atmospheric water and/or vapor. The Frankfurt isostatic diiffusion chamber (FRIDGE) is an INP collection and offline detection system that has become widely deployed and shows additional potential for ambient measurements. Since its initial development FRIDGE has gone through several iterations and improvements. Here we describe improvements that have been made in the collection and analysis techniques. We detail the uncertainties inherent in the measurement method, and suggest a systematic method of error analysis for FRIDGE measurements. Thus what is presented herein should serve as a foundation for the dissemination of all current and future measurements using FRIDGE instrumentation.
Ice nucleating particles over the eastern mediterranean measured by unmanned aircraft systems
(2017)
During an intensive field campaign on aerosol, clouds, and ice nucleation in the Eastern Mediterranean in April 2016, we measured the abundance of ice nucleating particles (INPs) in the lower troposphere from unmanned aircraft systems (UASs). Aerosol samples were collected by miniaturized electrostatic precipitators onboard the UASs at altitudes up to 2.5 km. The number of INPs in these samples, which are active in the deposition and condensation modes at temperatures from −20 to −30 °C, were analyzed immediately after collection on site using the ice nucleus counter FRIDGE (FRankfurt Ice nucleation Deposition freezinG Experiment). During the 1-month campaign, we encountered a series of Saharan dust plumes that traveled at several kilometers' altitude. Here we present INP data from 42 individual flights, together with aerosol number concentrations, observations of lidar backscattering, dust concentrations derived by the dust transport model DREAM (Dust Regional Atmospheric Model), and results from scanning electron microscopy. The effect of the dust plumes is reflected by the coincidence of INPs with the particulate matter (PM), the lidar signal, and the predicted dust mass of the model. This suggests that mineral dust or a constituent related to dust was a major contributor to the ice nucleating properties of the aerosol. Peak concentrations of above 100 INPs std L−1 were measured at −30 °C. The INP concentration in elevated plumes was on average a factor of 10 higher than at ground level. Since desert dust is transported for long distances over wide areas of the globe predominantly at several kilometers' altitude, we conclude that INP measurements at ground level may be of limited significance for the situation at the level of cloud formation.
Ice nucleating particles over the Eastern Mediterranean measured by unmanned aircraft systems
(2016)
During an intensive field campaign on aerosol, clouds and ice nucleation in the Eastern Mediterranean in April 2016, we have measured the abundance of ice nucleating particles (INP) in the lower troposphere from unmanned aircraft systems (UAS). Aerosol samples were collected by miniaturized electrostatic precipitators onboard the UAS at altitudes up to 2.5 km. The number of INP in these samples, which are active in the deposition and condensation modes at temperatures from −20 to −30 ◦C, were analyzed immediately after collection on site using the ice nucleus counter FRIDGE. During the one month campaign we encountered a series of Saharan dust plumes that traveled at several kilometers altitude. Here we present INP data from 42 individual flights, together with aerosol number concentrations, observations of lidar backscattering, dust concentrations derived by the dust transport model DREAM (Dust Regional Atmospheric Model), and results from scanning electron microscopy. The effect of the dust plumes is reflected by the coincidence of INP with the particulate mass (PM), the lidar signal and with the predicted dust mass of the model. This suggests that mineral dust or a constituent related to dust was a major contributor to the ice nucleating properties of the aerosol. Peak concentrations of above 100 INP std.l -1 were measured at −30 ◦C. The INP concentration in elevated plumes was on average a factor of 10 higher than at ground level. Since desert dust is transported for long distances over wide areas of the globe predominantly at several km altitude we conclude that INP measurements at ground level may be of limited significance for the situation at the level of cloud formation.