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Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro-BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell-signaling pathways, including prosurvival and cell-death machinery in a receptor-specific manner. Pro-BDNF preferentially binds to the p75 neurotrophin receptor (p75(NTR) ), whereas mBDNF is the major ligand of the tropomyosin-related kinase receptor. To elucidate a potential role for p75(NTR) in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small-molecule ligand that binds to p75(NTR) to promote survival signaling and inhibit neuronal cell death. Modulation of early p75(NTR) signaling and its effects on electrographic SE, SE-induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75(NTR) activation during epileptogenesis and in seizure-induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy.

To achieve a better understanding of the bridging mechanism at the static surface filtration, simulations of particle deposition at a three-dimensional pore model of a filter were performed. The simulations are used to investigate the total filter resistance, which results from interferences between filter medium, particles and fluid. Thereby a CFD (Computational Fluid Dynamics) method for flow simulation was coupled with a Discrete Element Method (DEM) which calculates the particle interactions. The results show that a built particle bridge influences the flow through an unclosed pore. It was concluded that bridging of open pores is hindered at high velocities of approach caused by increasing percentage of closed pores. Moreover, it could be shown, that the total filter resistance depends on the approaching velocity and shape of particles.

In many industrial applications the silo for bulk materials is an important part of an overall process. Silos are used for instance to buffer intermediate products to ensure a continuous supply for the next process step. This study deals with the discharging behaviour of silos containing cohesive bulk solids with particle sizes in the range of 100-500 μm. In this contribution the TOMAS [1,2] model developed for stationary and non-stationary discharging of a convergent hopper is verified with experiments and simulations using the Discrete Element Method. Moreover the influence of the cohesion of the bulk solids on the discharge behaviour is analysed by the simulation. The simulation results showed a qualitative agreement with the analytical model of TOMAS.

Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: We sought to determine joint outcomes relative to impact level of athletic participation among school-aged children who had hemophilia and were taking prophylactic factor replacement, as well as to investigate prognostic factors for joint outcomes., Methods: School-aged boys with severe hemophilia A or B at a single center were included in the study. Clinical data on baseline joint status, BMI, hemophilia treatment, bleeding episodes, joint assessments, athletic participation, and injuries were retrospectively reviewed. Data on athletic participation were supplemented, when incomplete in the medical record, via structured telephone interview., Results: Among 37 children with severe hemophilia A or B receiving factor prophylaxis, 73% participated in high-impact activities, whereas 27% participated in exclusively low-impact activities. The frequency of joint hemorrhages and new injuries did not appreciably differ between high- and low-impact athletics. In most instances, children developed <1 bleed or injury per season. A new target joint developed in 1 (3%) child. Sixteen percent of children met established BMI criteria for overweight, and 3% were obese. In logistic regression analyses with adjustment for prophylaxis frequency, level of athletic participation was not a significant prognostic factor for joint hemorrhage., Conclusions: In the setting of regular prophylaxis and adult coaching and supervision, significant bleeding complications were uncommon and level of impact of athletic participation was not a prognostic factor for joint outcomes. Athletic participation with appropriate supervision and precautions should be encouraged in children with hemophilia receiving prophylaxis, given potential health benefits in an increasingly overweight pediatric population.

We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC(50) = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the above-mentioned methodologies.