Small-Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection

The urokinase receptor (uPAR) is a cell surface receptor that binds to the serine protease urokinase-type plasminogen activator (uPA) with high affinity. This interaction is beneficial for extravascular fibrin clearance, but it has also been associated with a broad range of pathological conditions including cancer, atherosclerosis, and kidney disease. Here, starting with a small molecule that we previously discovered by virtual screening and cheminformatics analysis, we design and synthesize several derivatives that were tested for binding and inhibition of the uPAR ⋅ uPA interaction. To confirm the binding site and establish a binding mode of the compounds, we carried out biophysical studies using uPAR mutants, among them uPAR^H47C−N259C, a mutant previously developed to mimic the structure of uPA-bound uPAR. Remarkably, a substantial increase in potency is observed for inhibition of uPAR^H47C−N259C binding to uPA compared to wild-type uPAR, consistent with our use of the structure of uPAR in its uPA-bound state to design small-molecule uPAR ⋅ uPA antagonists. Combined with the biophysical studies, molecular docking followed by extensive explicit-solvent molecular dynamics simulations and MM-GBSA free energy calculations yielded the most favorable binding pose of the compound. Collectively, these results suggest that potent inhibition of uPAR binding to uPA with small molecules will likely only be achieved by developing small molecules that exhibit high-affinity to solution apo structures of uPAR, rather than uPA-bound structures of the receptor.     

Precipitous weakening of quartz at the α–β phase inversion

Crystalline quartz has long been identified as among the weakest of abundant crustal minerals. This weakness is particularly evident around the α–β phase inversion at 573°C, in which Si–O bonds undergo a displacive structural transformation from trigonal to hexagonal symmetry. Here we present data using indentation testing methodologies that highlight the precipitous extent of the transformational weakening. Although the indentations are localized over relatively small specimen contact areas, the data quantify the essential deformation and fracture properties of quartz in a predominantly (but not exclusively) compressive stress field, at temperatures and pressures pertinent to conditions in the earth's crust.     

Real-time organic aerosol chemical speciation in the indoor environment using extractive electrospray ionization mass spectrometry

Understanding the sources and composition of organic aerosol (OA) in indoor environments requires rapid measurements, since many emissions and processes have short timescales. However, real-time molecular-level OA measurements have not been reported indoors. Here, we present quantitative measurements, at a time resolution of five seconds, of molecular ions corresponding to diverse aerosol-phase species, by applying extractive electrospray ionization mass spectrometry (EESI-MS) to indoor air analysis for the first time, as part of the highly instrumented HOMEChem field study. We demonstrate how the complex spectra of EESI-MS are screened in order to extract chemical information and investigate the possibility of interference from gas-phase semivolatile species. During experiments that simulated the Thanksgiving US holiday meal preparation, EESI-MS quantified multiple species, including fatty acids, carbohydrates, siloxanes, and phthalates. Intercomparisons with Aerosol Mass Spectrometer (AMS) and Scanning Mobility Particle Sizer suggest that EESI-MS quantified a large fraction of OA. Comparisons with FIGAERO-CIMS shows similar signal levels and good correlation, with a range of 100 for the relative sensitivities. Comparisons with SV-TAG for phthalates and with SV-TAG and AMS for total siloxanes also show strong correlation. EESI-MS observations can be used with gas-phase measurements to identify co-emitted gas- and aerosol-phase species, and this is demonstrated using complementary gas-phase PTR-MS observations.     

Skeletal Muscle Health and Cognitive Function: A Narrative Review

Sarcopenia is the loss of skeletal muscle mass and function with advancing age. It involves both complex genetic and modifiable risk factors, such as lack of exercise, malnutrition and reduced neurological drive. Cognitive decline refers to diminished or impaired mental and/or intellectual functioning. Contracting skeletal muscle is a major source of neurotrophic factors, including brain-derived neurotrophic factor, which regulate synapses in the brain. Furthermore, skeletal muscle activity has important immune and redox effects that modify brain function and reduce muscle catabolism. The identification of common risk factors and underlying mechanisms for sarcopenia and cognition may allow the development of targeted interventions that slow or reverse sarcopenia and also certain forms of cognitive decline. However, the links between cognition and skeletal muscle have not been elucidated fully. This review provides a critical appraisal of the literature on the relationship between skeletal muscle health and cognition. The literature suggests that sarcopenia and cognitive decline share pathophysiological pathways. Ageing plays a role in both skeletal muscle deterioration and cognitive decline. Furthermore, lifestyle risk factors, such as physical inactivity, poor diet and smoking, are common to both disorders, so their potential role in the muscle–brain relationship warrants investigation.     

NanoPaint: A Tool for Rapid and Dynamic Imaging of Membrane Structural Plasticity at the Nanoscale

Single‐particle tracking with quantum dots (QDs) constitutes a powerful tool to track the nanoscopic dynamics of individual cell membrane components unveiling their membrane diffusion characteristics. Here, the nano‐resolved population dynamics of QDs is exploited to reconstruct the topography and structural changes of the cell membrane surface with high temporal and spatial resolution. For this proof‐of‐concept study, bright, small, and stable biofunctional QD nanoconstructs are utilized recognizing the endogenous neuronal cannabinoid receptor 1, a highly expressed and fast‐diffusing membrane protein, together with a commercial point‐localization microscope. Rapid QD diffusion on the axonal plasma membrane of cultured hippocampal neurons allows precise reconstruction of the membrane surface in less than 1 min with a spatial resolution of tens of nanometers. Access of the QD nanoconstructs to the synaptic cleft enables rapid 3D topological reconstruction of the entire presynaptic component. Successful reconstruction of membrane nano‐topology and deformation at the second time‐scale is also demonstrated for HEK293 cell filopodia and axons. Named “nanoPaint,” this super‐resolution imaging technique amenable to any endogenous transmembrane target represents a versatile platform to rapidly and accurately reconstruct the cell membrane nano‐topography, thereby enabling the study of the rapid dynamic phenomena involved in neuronal membrane plasticity.     

Bayesian data analysis to quantify the uncertainty of intact rock strength

One of the main difficulties in the geotechnical design process lies in dealing with uncertainty. Uncertainty is associated with natural variation of properties, and the imprecision and unpredictability caused by insufficient information on parameters or models. Probabilistic methods are normally used to quantify uncertainty. However, the frequentist approach commonly used for this purpose has some drawbacks.First, it lacks a formal framework for incorporating knowledge not represented by data. Second, it has limitations in providing a proper measure of the confidence of parameters inferred from data. The Bayesian approach offers a better framework for treating uncertainty in geotechnical design. The advantages of the Bayesian approach for uncertainty quantification are highlighted in this paper with the Bayesian regression analysis of laboratory test data to infer the intact rock strength parameters σ_(ci) and m_i used in the Hoek-Brown strength criterion. Two case examples are used to illustrate different aspects of the Bayesian methodology and to contrast the approach with a frequentist approach represented by the nonlinear least squares(NLLS) method. The paper discusses the use of a Student's t-distribution versus a normal distribution to handle outliers, the consideration of absolute versus relative residuals, and the comparison of quality of fitting results based on standard errors and Bayes factors. Uncertainty quantification with confidence and prediction intervals of the frequentist approach is compared with that based on scatter plots and bands of fitted envelopes of the Bayesian approach. Finally, the Bayesian method is extended to consider two improvements of the fitting analysis. The first is the case in which the Hoek-Brown parameter, a, is treated as a variable to improve the fitting in the triaxial region. The second is the incorporation of the uncertainty in the estimation of the direct tensile strength from Brazilian test results within the overall evaluation of the intact rock strength.     

Elevated temperature impact on performance of Low Temperature Co-fired Ceramic dielectrics

The need for electronics to operate at temperatures of 200°C and above continues to grow. These applications include avionics, aerospace, automotive, downhole drilling, mining, and many others. To satisfy this demand, a significant amount of research and development has been conducted. Despite the efforts, the number of new electronic components designed specifically for high-temperature operation is still relatively limited. In Low Temperature Co-fired Ceramic (LTCC) packages, LTCC materials are generally used as the host media for a number of pre-fabricated semiconductor components. As a result, reliability of the entire LTCC package largely depends on the performance of the least robust component. Ferro A6M-E and Ferro L8 are the two well-established and recognized LTCC dielectrics widely used for mid and high frequency LTCC applications, including several high reliability aerospace and defense applications that require demanding Mil-Spec qualifications. This study is our first attempt to characterize and understand basic high-temperature dielectric properties of these two commercial LTCC materials. The secondary objective is to initiate a dialogue in attempt to establish reliability requirements for LTCC packages dedicated for high-temperature operation.