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Blood vessels in the central nervous system (CNS) form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells to peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizures, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB-dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.

SUMMARYTraumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair1,2. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining 5 different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis3 (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 hrs after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target.

This study demonstrates how gene expression profiles of white blood cells in acute spinal cord injury patients can be utilized for the diagnosis of the injury severity and the neurological level of injury., Diagnosis of spinal cord injury (SCI) severity at the ultra-acute stage is of great importance for emergency clinical care of patients as well as for potential enrollment into clinical trials. The lack of a diagnostic biomarker for SCI has played a major role in the poor results of clinical trials. We analyzed global gene expression in peripheral white blood cells during the acute injury phase and identified 197 genes whose expression changed after SCI compared with healthy and trauma controls and in direct relation to SCI severity. Unsupervised coexpression network analysis identified several gene modules that predicted injury severity (AIS grades) with an overall accuracy of 72.7% and included signatures of immune cell subtypes. Specifically, for complete SCIs (AIS A), ROC analysis showed impressive specificity and sensitivity (AUC: 0.865). Similar precision was also shown for AIS D SCIs (AUC: 0.938). Our findings indicate that global transcriptomic changes in peripheral blood cells have diagnostic and potentially prognostic value for SCI severity.

The prime condition for the virtual design of mechatronic railway vehicles is a software environment comprising the different computational engineering tools being interconnected by efficient interfaces. The paper presents such an environment with a multibody system software in its centre and a couple of interfaces to other engineering software tools around. Especially in view of mechatronics, the different types of coupling to control engineering software are of interest. The simulation of railway vehicles calls for a specific module describing, besides others, the highly nonlinear contact between wheel and rail. The state-of-the-art of such a simulation tool chain is illustrated for the complex analysis and design issue of a “Mechatronic Train”.

Ein mannlicher 72 jahriger Patient mit Pra-Sezary Syndrom, der auf PUVA nicht ansprach, wurde systemisch mit einer low-dose Methotrexat (MTX)-Therapie (12,5 mg bis 25 mg/ Woche i. v.) behandelt. Das klinische Bild mit Erythrodermie, Lichenifikation, Schuppung, odematoser Schwellung der Extremitaten und einem qualenden Juckreiz besserte sich durch MTX rasch. Parallel dazu lies sich ein Ruckgang der Eosinophilie im peripheren Blut feststellen. Alle ubrigen hamatologischen Parameter incl. flowzytometrisch analysierter T-Zell-Subsets blieben im Normbereich. Eine Immunsuppression trat nicht auf. Der Patient tolerierte die MTX-Therapie subjektiv sehr gut, objektive Nebenwirkungen wurden nicht beobachtet. Nach Erzielung der kompletten Remission wurde die MTX-Therapie abgesetzt. In der Nachsorgephase von 27 Monaten trat bislang kein Rezidiv auf. Anhand unserer Kasuistik scheint die low-dose MTX-Therapie im Fruhstadium des Sezary-Syndroms (Pra-Sezary Syndrom) eine ausgezeichnete Behandlungsstrategie zu sein, was anhand groserer Patientenkollektive systematisch uberpruft werden muste.

The development of advanced railway vehicles requires an efficient modelling and simulation of wheel-rail systems under complex conditions and maneuvers. For that reason, the multibody system simulation software SIMPACK was enhanced recently with a generally applicable wheel-rail contact module to be outlined in this paper. This module comprises the possibility of applying a constrained or an elastic contact model, single or multiple contact locations per wheel-rail element, analytic or measured track geometries including irregularities and rail profiles, varying in longitudinal direction (switches). A simulation study of a passenger car running through a switch demonstrates the efficiency of the constrained wheel-rail contact model extended for the simulation of multiple contacts. As a second example a freight train is investigated and its simulation results are compared to measurements in order to validate the simulation tool as well as the model.

We have carried out numerous experiments with supersources having intensities in the 100 Curie range. These sources usually require massive shielding, and are not easily moved to carry out Mossbauer spectroscopy. Several of these sources can be used with microfoil conversion electron (MICE) detectors, but they cannot be moved easily either because of the delicate microfoils used, which ideally have thicknesses less than the range of the internally converted electrons. Here, we describe a technique for doing Mossbauer spectroscopy by oscillating a monochromating crystal parallel to the reciprocal lattice vector of the Bragg reflection, this being used to filter out extraneous photons from the beam. Specifically, an LiF crystal is used in diffraction experiments as a filter to scatter the 46.5-keV Mossbauer gamma rays from183Ta by setting it at the (200) Bragg reflection. In the present measurements, the LiF crystal was mounted in the transmission mode and oscillated with a crank along the scattering vectorQ to produce the velocity modulation, with the source, sample and absorber all at rest. The velocity components of the filtering crystal along the incident and scattered beams cause the measured linewidth to be equal to the usual Mossbauer width divided by 2 sinθ, whereθ is the Bragg angle. Measured widths for the (200), (400), (600) and (800) Bragg reflections agreed with the calculated values of 12.08, 6.04, 4.03 and 3.02 cm/s, within our experimental uncertainties. The technique could have applications not only to MICE detectors, but also to very narrow resonances such as67Zn, where the increased velocities required for small Bragg angles could be an advantage and lead to enhanced resolution.

We have been able to prepare Mossbauer sources having intensities ranging from 10 to 100 Ci for several isotopes, using the Missouri University Research Reactor Facility, MURR. These sources offer rich opportunities for carrying out precision Mossbauer experiments as well as high collimation scattering experiments. Using such intense sources, we have been able to measure the interference parameter of the 46.5 keV Mossbauer transition to about 1% accuracy. We find it to be about 10% greater than predicted by theory, which may have significant implications for time reversal violation experiments. We have also been able to show that the Bragg scattered recoilless fraction scattered from (200) planes of sodium chloride crystals is 94% of that found for the (600) reflection, even though the integrated intensity of this reflection is more than a factor of 10 less than that of the (200) reflection. We highlight some of the experiments that we have carried out and discuss some of the enticing possibilities for the future with sources in the 10–1000 Ci range. One of these is the possibility of doing Mossbauer spectroscopy with a stationary source and absorber, moving only a monochromating crystal filter along the direction of the reciprocal lattice vector associated with the Bragg reflection being used.

We discuss our experiences with exceptionally intense Mossbauer sources (of order 100 Ci) and their use in making precision determinations of line shape parameters. We review our measurements of interference and recoilless fraction using conventional transmission geometry. Fitting simultaneous sets of data with known constraints greatly improves the efficiency of line-shape determination. Measurements of interference have been made using a two-absorber technique first introduced by Mossbauer and coworkers. Our results indicate that the method can be useful for determining interference, but that incorrect line shape parameters are obtained if powder samples are used which do not comply well with the assumption of thickness uniformity in the absorber.

We have completed a Mossbauer effect (ME) experiment using two absorbers, one stationary and one Doppler shifted, as a means of enhancing the off-resonant signal, in order to confirm earlier measurements in 183W done using single absorbers. A parameter of particular importance is the interference parameter, β, which is relevant to understanding certain time reversal invariance experiments, and which our previous measurements indicated was larger in magnitude than that predicted by theory. The value for 100β reported here is −0.318 (5), which is in excellent agreement with our earlier value and is larger in magnitude than that predicted by theory.

The analytic description of Mossbauer line shape based on the Fourier-transform method [1] makes it possible to precisely determine the recoil-free fraction,f, of a single absorber over a wide temperature range with a single measurement at each temperature. Most measurements of recoil-free fraction have been done with a Lorentzian representation of the Mossbauer line with semi empirical correction factors of uncertain precision. Our method, based on line shape rather than area, is exact for absorbers of any thickness, limited only by the number of terms taken in the expansion. In fact, our exact line-shape description makes it advantageous to use very thick absorbers. As an example, we report values for an absorber of effective thickness 12. The resonance thickness number of the absorber is an intrinsic parameter, so that a fit yields this quantity directly. The correlations that arise between certain variables may be reduced by fitting, simultaneously and with known constraints, spectra taken with different absorbers or with one absorber at various temperatures. Using this technique, we report precise values forf(T) in tungsten using the 46.5 keV transition in183W atT=297 K and 1067 K; these values are 0.300±0.009 and 0.0123±0.0002, respectively.

A Mossbauer gamma-ray diffraction instrument has been developed which utilizes high intensity sources produced by neutron irradiation. Most of the early work has used 70 Ci, 5.1 d 183Ta sources produced by double neutron capture which yield 12 × 1010 photons/s for the 46.5 keV Mossbauer transition in 183W. A dewar is enclosed in the shielding cask which allows sources to be cooled to 77 K. Samples are located approximately midway between source and detector, which are separated by 155 cm. Collimators in front of the sample and detector commonly limit the beam to 3 mm wide by 25 mm high. A 27% minimum is seen in the velocity spectrum for the 46.5 keV photons scattered from the 200 Bragg reflection in LiF taken in transmission. Enriched, room temperature absorbers mounted on a rotor can be Doppler-shifted up to 17 meV. Q-space resolution of 0.01 A−1 is significantly better than that reported by other groups using Mossbauer scattering. When a microfoil internal conversion electron (MICE) detector is used, the instrument has the potential for directly measuring the energy transferred by the inelastically scattered photons, especially for low energy excitations in solids which require high energy resolution.

The field of gamma-ray scattering is new and only a few of the possible applications of the technique have been pursued. At the University of Missouri Research Reactor (MURR) we are presently completing two instruments to perform studies not previously attempted. The first instrument is a full-circle diffractometer with additional differential ω-motion and linear drive system for the detector which will be used for accurate crystallographic structure measurements at either 0.125 A ( 153 Sm) or 0.03 A ( 198 Au). The reduced absorption and extinction at these wavelengths should permit more accurate structure factor determination than has been possible with either X-rays or neutrons. A unique source irradiation system and shield cask have been designed to permit the utilization of relatively large, extremely intense sources. The cask is self-centering at the instrument and has a built in rotation of the source container to maximize the intensity. A large exit aperture is provided in the vertical direction (∼3″) to give extra intensity when tight collimation is not required in that direction. The second instrument will be using the 103 keV photons from 153 Sm as a Mossbauer source and will detect inelastically scattered photons with a centrifugally driven absorber. Because of the high specific activities attainable in the flux trap at MURR (∼6000 Ci/g for enriched 152 Sm) these experiments should be possible where such studies with traditional sources, e.g., 57 Fe, have not succeeded.

KUKA has been working with a major car manufacturer in Germany to develop a new approach to production.

A Monte Carlo method for generating charged-particle spectra in Si(Li) detectors is presented. Application of these spectra to resolving complex spectra that have been complicated by thick targets, kinematical considerations, and other experimental problems is discussed. An example is shown of the technique applied to resolving the triton and alpha components in a 7 Li(γ, t) 4 He reaction spectrum involving several discrete energies for the gamma rays incident on a 7 LiF target.

The concentrations of metronidazole, clindamycin, chloramphenicol, cefoxitin, ticarcillin, and moxalactam in the serum, femurs, and scapulae of normal rats were measured microbiologically 0.5, 1, 1, and 4 h after intravenous injection of 15-, 15-, 20-, 40-, 75-, and 30-mg/kg doses of the respective drugs. By 0.5 h metronidazole reached levels of 3.0 micrograms/g in compact femoral bone and 2.7 micrograms/g in cancellous scapular bone. Clindamycin and chloramphenicol reached levels of 8.1 and 6.1 micrograms/g, respectively, at 0.5 h. Cefoxitin penetrated bone to a level of 2.6 micrograms/g, whereas ticarcillin and moxalactam failed to reach significant levels in bone after single intravenous doses.