Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.FWN – Publicaties zonder aanstelling Universiteit Leide

Zero dynamics and stabilization for linear DAEs

We study linear differential-algebraic multi-input multi-output systems which are not necessarily regular and investigate the asymptotic stability of the zero dynamics and stabilizability. To this end, the concepts of autonomous zero dynamics, transmission zeros, right-invertibility, stabilizability in the behavioral sense and detectability in the behavioral sense are introduced and algebraic characterizations are derived. It is then proved, for the class of right-invertible systems with autonomous zero dynamics, that asymptotic stability of the zero dynamics is equivalent to three conditions: stabilizability in the behavioral sense, detectability in the behavioral sense, and the condition that all transmission zeros of the system are in the open left complex half-plane. Furthermore, for the same class, it is shown that we can achieve, by a compatible control in the behavioral sense, that the Lyapunov exponent of the interconnected system equals the Lyapunov exponent of the zero dynamics

Collisional and Radiative Processes in Optically Thin Plasmas

Most of our knowledge of the physical processes in distant plasmas is obtained through measurement of the radiation they produce. Here we provide an overview of the main collisional and radiative processes and examples of diagnostics relevant to the microphysical processes in the plasma. Many analyses assume a time-steady plasma with ion populations in equilibrium with the local temperature and Maxwellian distributions of particle velocities, but these assumptions are easily violated in many cases. We consider these departures from equilibrium and possible diagnostics in detail

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

Factors affecting body temperatures of toads

Factors influencing levels and rates of variation of body temperature ( T b ) in montane Bufo boreas boreas and in lowland Bufo boreas halophilus were investigated as an initial step toward understanding the role of natural thermal variation in the physiology and energetics of these ectothermic animals. Body temperatures of boreas can vary 25–30° C over 24-h periods. Such variation is primarily due to both nocturnal and diurnal activity and the physical characteristics of the montane environment. Bufo boreas halophilus are primarily nocturnal except during breeding and are voluntarily active at body temperatures ranging between 10 and 25° C. Despite variation in T b encountered in the field, boreas select a narrow range of T b in a thermal gradient, averaging 23.5 and 26.2° C for fasted individuals maintained under field conditions or acclimated to 20° C, respectively. In a thermal gradient the mean T b of fasted halophilus acclimated to 20° C is 23.9° C. Skin color of boreas varies in the field from very dark to light. The dark skins absorb approximately 4% more radiation than the light ones. Light colored boreas should absorb approximately 5% more radiation than similarly colored halophilus . Evaporative water losses increase directly with skin temperatures and vapor pressure deficit in both subspecies. Larger individuals heat and cool more slowly than smaller ones. Calculation of an enery budget for boreal toads suggests that they could sit in direct sunlight for long periods without fatally overheating, providing the skin was continually moist.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47722/1/442_2004_Article_BF00344732.pd

Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia:a Multinational Point Prevalence Study of Hospitalised Patients

Pseudornonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP. We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa. Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP. The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases. The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients

Search for jet extinction in the inclusive jet-pT spectrum from proton-proton collisions at s=8 TeV

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published articles title, journal citation, and DOI.The first search at the LHC for the extinction of QCD jet production is presented, using data collected with the CMS detector corresponding to an integrated luminosity of 10.7  fb−1 of proton-proton collisions at a center-of-mass energy of 8 TeV. The extinction model studied in this analysis is motivated by the search for signatures of strong gravity at the TeV scale (terascale gravity) and assumes the existence of string couplings in the strong-coupling limit. In this limit, the string model predicts the suppression of all high-transverse-momentum standard model processes, including jet production, beyond a certain energy scale. To test this prediction, the measured transverse-momentum spectrum is compared to the theoretical prediction of the standard model. No significant deficit of events is found at high transverse momentum. A 95% confidence level lower limit of 3.3 TeV is set on the extinction mass scale

Searches for electroweak neutralino and chargino production in channels with Higgs, Z, and W bosons in pp collisions at 8 TeV

Searches for supersymmetry (SUSY) are presented based on the electroweak pair production of neutralinos and charginos, leading to decay channels with Higgs, Z, and W bosons and undetected lightest SUSY particles (LSPs). The data sample corresponds to an integrated luminosity of about 19.5 fb(-1) of proton-proton collisions at a center-of-mass energy of 8 TeV collected in 2012 with the CMS detector at the LHC. The main emphasis is neutralino pair production in which each neutralino decays either to a Higgs boson (h) and an LSP or to a Z boson and an LSP, leading to hh, hZ, and ZZ states with missing transverse energy (E-T(miss)). A second aspect is chargino-neutralino pair production, leading to hW states with E-T(miss). The decays of a Higgs boson to a bottom-quark pair, to a photon pair, and to final states with leptons are considered in conjunction with hadronic and leptonic decay modes of the Z and W bosons. No evidence is found for supersymmetric particles, and 95% confidence level upper limits are evaluated for the respective pair production cross sections and for neutralino and chargino mass values