Interferon-γ Receptor 1 and GluR1 upregulated in motor neurons of symptomatic hSOD1G93A mice.

Motor neurons are markedly vulnerable to excitotoxicity mostly by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) stimulation and are principal targets in the neurodegenerative disease Amyotrophic Lateral Sclerosis. Interferon-gamma (IFN-γ), a pro-inflammatory cytokine, can independently cause neuronal dysfunction by triggering calcium influx through a calcium-permeable complex of IFN-γ receptor 1(IFNGR1) subunit and AMPAR subunit GluR1. This receptor complex is formed via a non-canonical neuron-specific IFN-γ pathway that involves Jak1/Stat1 and Protein Kinase A. In this study, we explore the expression of the pathway's participants for the first time in the hSOD1G93A Amyotrophic Lateral Sclerosis mouse model. Elevated IFNGR1 and GluR1 are detected in motor neurons of hSOD1G93A symptomatic mice ex vivo, unlike the downstream targets - Jak1, Stat1, and Protein Kinase A. We, also, determine effects of IFN-γ alone or in the presence of an excitotoxic agent, kainate, on motor neuron survival in vitro. IFN-γ induces neuronal damage, but does not influence kainate-mediated excitotoxicity. Increased IFNGR1 can most likely sensitize motor neurons to excitotoxic insults involving GluR1 and/or pathways mediated by IFN-γ, thus, serving as a potential direct link between neurodegeneration and inflammation in Amyotrophic Lateral Sclerosis.

Access and Disclosure of Personal Health Information: A Challenging Privacy Landscape in 2016-2018.

OBJECTIVES: To assess the current health data access and disclosure environment for potential privacy-protecting mechanisms that enable legitimate use of personal health information while preserving the rights of individuals. To identify the gaps and challenges between increasing requests and expanding uses of such information and the regulations, technologies, and management practices that permit appropriate access and disclosure while guarding against harmful misuse of such information. METHODS: A scoping literature review focused on (1) regulations affecting access and disclosure of personal health information, (2) the uses of health information that challenge access and disclosure boundaries, and (3) privacy management practices that may help mitigate gaps in protecting patient privacy. RESULTS: Countries and jurisdictions are developing laws, regulations, and public policies to balance the privacy rights of individuals and the unprecedented opportunities to advance health and health care through expanded uses of health data. Regulations and guidance are evolving, but they are outpaced by the increasing demand for and the challenges of managing access and disclosure. Mechanisms such as consent and authorization may not always be adequate. Mechanisms that advance principled stewardship are more important than ever. CONCLUSIONS: Access and disclosure management are important dimensions of privacy management practices. This is a volatile period in which diverging public policies may reveal how best to balance access and disclosure of personal health information by individuals and by institutional custodians of the information. Approaches to access and disclosure management, including the roles of individuals, should be a focus for research and study in the years ahead.

Challenges in Estimating the Motility Parameters of Single Processive Motor Proteins.

Cytoskeletal motor proteins are essential to the function of a wide range of intracellular mechano-systems. The biophysical characterization of their movement along their filamentous tracks is therefore of large importance. Toward this end, single-molecule, in vitro stepping-motility assays are commonly used to determine motor velocity and run length. However, comparing results from such experiments has proved difficult due to influences from variations in the experimental conditions and the data analysis methods. Here, we investigate the movement of fluorescently labeled, processive, dimeric motor proteins and propose a unified algorithm to correct the measurements for finite filament length as well as photobleaching. Particular emphasis is put on estimating the statistical errors associated with the proposed evaluation method, as knowledge of these values is crucial when comparing measurements from different experiments. Testing our approach with simulated and experimental data from GFP-labeled kinesin-1 motors stepping along immobilized microtubules, we show 1) that velocity distributions should be fitted by a t location-scale probability density function rather than by a normal distribution; 2) that the impossibility to measure events shorter than the image acquisition time needs to be taken into account; 3) that the interaction time and run length of the motors can be estimated independent of the filament length distribution; and 4) that the dimeric nature of the motors needs to be considered when correcting for photobleaching. Moreover, our analysis reveals that controlling the temperature during the experiments with a precision below 1 K is of importance. We believe our method will not only improve the evaluation of experimental data, but also allow for better statistical comparisons between different populations of motor proteins (e.g., with distinct mutations or linked to different cargos) and filaments (e.g., in distinct nucleotide states or with different posttranslational modifications). Therefore, we include a detailed workflow for image processing and analysis (including MATLAB code), serving as a tutorial for the estimation of motility parameters in stepping-motility assays.

Prediction of micelle/water and liposome/water partition coefficients based on molecular dynamics simulations, COSMO-RS, and COSMOmic.

Liposomes and micelles find various applications as potential solubilizers in extraction processes or in drug delivery systems. Thermodynamic and transport processes governing the interactions of different kinds of solutes in liposomes or micelles can be analyzed regarding the free energy profiles of the solutes in the system. However, free energy profiles in heterogeneous systems such as micelles are experimentally almost not accessible. Therefore, the development of predictive methods is desirable. Molecular dynamics (MD) simulations reliably simulate the structure and dynamics of lipid membranes and micelles, whereas COSMO-RS accurately reproduces solvation free energies in different solvents. For the first time, free energy profiles in micellar systems, as well as mixed lipid bilayers, are investigated, taking advantage of both methods: MD simulations and COSMO-RS, referred to as COSMOmic (Klamt, A.; Huniar, U.; Spycher, S.; Keldenich, J. COSMOmic: A Mechanistic Approach to the Calculation of Membrane-Water Partition Coefficients and Internal Distributions within Membranes and Micelles. J. Phys. Chem. B 2008, 112, 12148-12157). All-atom molecular dynamics simulations of the system SDS/water and CTAB/water have been applied in order to retrieve representative micelle structures for further analysis with COSMOmic. For the system CTAB/water, different surfactant concentrations were considered, which results in different micelle sizes. Free energy profiles of more than 200 solutes were predicted and validated by means of experimental partition coefficients. To our knowledge, these are the first quantitative predictions of micelle/water partition coefficients, which are based on whole free energy profiles from molecular methods. Further, the partitioning in lipid bilayer systems containing different hydrophobic tail groups (DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), SOPC (stearoyl-oleoylphosphatidylcholine), DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)) as well as mixed bilayers was calculated. Experimental partition coefficients (log P) were reproduced with a root-mean-square error (RMSE) of 0.62. To determine the influence of cholesterol as an important component of cellular membranes, free energy profiles in the presence of cholesterol were calculated and shown to be in good agreement with experimental data.

COSMO-RS for the prediction of the retention behavior in micellar liquid chromatography based on partition coefficients of non-dissociated and dissociated solutes.

Several methods for the description of the retention behavior in micellar liquid chromatography (MLC) were described previously. Thereby, the most common are the linear solvation energy relationships (LSER). However, for the evaluation of the LSER, a number of experimental data are necessary. In this work, the retention data are predicted based on a single data point for a given solute/surfactant combination. The prediction of micelle/water partition coefficients with the COSMO-RS model was evaluated for the nonionic surfactant Brij 35 and the cationic CTAB for 21 solutes. The predicted partition coefficients along with the retention data of a single measurement were combined with a common retention model for the evaluation of partition coefficients. Thus, the description of the retention data based on a minimum of experimental data was realized in this work. The COSMO-RS model appears to be suitable for the flexible and qualitative prediction of the retention data, which is of special benefit, when a large number of solutes are studied. Furthermore, the introduced method is a promising alternative to describe the retention behavior of ionizable solutes, which is of great interest for e.g. pharmaceutical processes and analyses. To evaluate the method, lipophilicity profiles of several solutes were determined with MLC. While for the nonionic surfactant the lipophilicity is similar to the octanol/water system, a contrary phenomenon, namely a significant increase of the partition coefficient with progressive dissociation can be observed with the ionic surfactant. The MLC method proved to be an efficient method for the determination of micelle/water partition coefficients, excluding non-binding and "overbinding" solutes. The introduced COSMO-RS based approach for the estimation of the retention in MLC is especially promising for highly retarding solutes, since it is time and cost saving compared to the experimental determination.

Partition coefficients of ionizable solutes in mixed nonionic/ionic micellar systems.

Surfactant solutions in practical applications usually are mixtures of ionic and nonionic surfactants. Because of synergistic effects, the solubilization of hydrophobic compounds can be enhanced while decreasing the needed amount of surfactant at the same time. In this work, the influence of the composition of Brij 35/CTAB and Brij 35/SDS mixed micelles on the partition coefficient log D(MW) of various acids and bases over the entire pH range was investigated. Two experimental methods (MLC, micellar liquid chromatography; MEUF, micellar enhanced ultrafiltration) are evaluated for the determination of partition coefficients in mixed-micelle systems. Although MLC stands out because of its automation and easy handling, MEUF is applicable to a broader log D(MW) range. It is shown that the partitioning can be influenced dramatically by the two investigated parameters. By adjusting the pH value and the composition of the micelles, we can tailor the partition behavior of solutes for virtually any application. The thermodynamic model COSMO-RS gives valuable predictions of the partition coefficients if the composition of the micelle is available. Different approaches for the description of the micellar composition are evaluated in this work. On the basis of the cmc value of the single surfactants and the mixture only, it is shown that the regular solution approximation gives reasonable micellar compositions. The partition coefficients between water and the mixed micelles are predicted with the COSMO-RS model, in good agreement with the experimental data. Moreover, the micellar composition can be evaluated by fitting the prediction to the experimentally determined partition coefficients.

Unsuspected lower extremity deep venous thrombosis simulating musculoskeletal pathology.

OBJECTIVE: The purpose of this study was to highlight the critical role that MRI may play in diagnosing unsuspected lower extremity deep venous thrombosis and to stress the importance of scrutinizing MRI studies of the lower extremity showing apparently non-specific muscle edema for any evidence of intramuscular venous thrombosis. DESIGN AND PATIENTS: The imaging studies of four patients in whom deep venous thrombosis was unsuspected on clinical grounds, and first diagnosed on the basis of MRI findings, were reviewed by two musculoskeletal radiologists in consensus. In all four patients the initial clinical suspicion was within the scope of musculoskeletal injuries (gastrocnemius strain, n=3; ruptured Baker cyst, n=1), explaining the choice of MRI over ultrasound as the first diagnostic modality. RESULTS: All patients showed marked reactive edema in the surrounding soft tissues or muscles. Three patients showed MR evidence of branching rim-enhancing structures within intramuscular plexuses characteristic of venous thrombosis (gastrocnemius, n=1; sural, n=2); one patient showed a distended popliteal vein. Ultrasound was able to duplicate the MRI findings in three patients: one patient showed above-the-knee extension on ultrasound; neither of the two patients with intramuscular thrombosis demonstrated on ultrasound showed extension to the deep venous trunks. CONCLUSION: Intramuscular venous thrombosis can present as marked edema-like muscle changes on MRI, simulating primary musculoskeletal conditions. In the absence of clinical suspicion for deep venous thrombosis, only the identification of rim-enhancing branching intramuscular tubular structures will allow the correct diagnosis to be made.

Flexor carpi radialis tendinopathy: spectrum of imaging findings and association with triscaphe arthritis.

OBJECTIVE: To present the spectrum of pathology affecting the flexor carpi radialis (FCR), and its anatomical, functional and clinical relationship with conditions affecting the triscaphe or scapho-trapezium-trapezoid (STT) compartment, and particularly osteoarthritis. DESIGN: The study comprised two men and four women aged between 23 and 79 years (mean age, 49 years). Two musculoskeletal radiologists in consensus evaluated MRI findings. RESULTS: Five of the patients showed evidence of triscaphe osteoarthritis. One of the patients showed synovitis and reactive marrow edema at the triscaphe joint without more specific findings of osteoarthritis. Five patients showed evidence of FCR tenosynovitis. Partial-thickness tears were noted in three patients. Two patients showed complete discontinuity of the FCR; one of them had undergone prior tendon harvesting for interposition arthroplasty after trapezectomy. One patient showed a ganglion cyst in connection to the FCR tendon sheath. CONCLUSION: The FCR tendon courses over the volar surfaces of the scaphoid and trapezium in a separate fibro-osseous tunnel. This anatomical and functional relationship explains the coexistence of FCR tendinopathy and STT arthritis demonstrated by MR imaging.