Spastin in the human and mouse central nervous system with special reference to its expression in the hippocampus of mouse pilocarpine model of status epilepticus and temporal lobe epilepsy

In the present in situ hybridization and immunocytochemical studies in the mouse central nervous system (CNS), a strong expression of spastin mRNA and protein was found in Purkinje cells and dentate nucleus in the cerebellum, in hippocampal principal cells and hilar neurons, in amygdala, substantia nigra, striatum, in the motor nuclei of the cranial nerves and in different layers of the cerebral cortex except piriform and entorhinal cortices where only neurons in layer II were strongly stained. Spastin protein and mRNA were weakly expressed in most of the thalamic nuclei. In selected human brain regions such as the cerebral cortex, cerebellum, hippocampus, amygdala, substania nigra and striatum, similar results were obtained. Electron microscopy showed spastin immunopositive staining in the cytoplasma, dendrites, axon terminals and nucleus. In the mouse pilocarpine model of status epilepticus and subsequent temporal lobe epilepsy, spastin expression disappeared in hilar neurons as early as at 2h during pilocarpine induced status epilepticus, and never recovered. At 7 days and 2 months after pilocarpine induced status epilepticus, spastin expression was down-regulated in granule cells in the dentate gyrus, but induced expression was found in reactive astrocytes. The demonstration of widespread distribution of spastin in functionally different brain regions in the present study may provide neuroanatomical basis to explain why different neurological, psychological disorders and cognitive impairment occur in patients with spastin mutation. Down-regulation or loss of spastin expression in hilar neurons may be related to their degeneration and may therefore initiate epileptogenetic events, leading to temporal lobe epilepsy.

What can be gained from comprehensive disaggregate surveillance? The Avon Surveillance System for Sexually Transmitted Infections

OBJECTIVE: To describe a new disaggregate surveillance system covering key diagnosed sexually transmitted infections in a UK locality. METHODS: The Avon System for Surveillance of Sexually Transmitted Infections (ASSIST) collects computerised person- and episode-based information about laboratory-diagnosed sexually transmitted infections from genitourinary medicine (GUM) clinics, the Avon Brook Clinic, and the Health Protection Agency and trust laboratories in primary care trusts in Avon. The features of the system are illustrated here, by describing chlamydia-testing patterns according to the source of test, age and sex, and by mapping the distribution of chlamydia across Bristol, UK. RESULTS: Between 2000 and 2004, there were 821,685 records of tests for sexually transmitted infections, with 23,542 positive results. The proportion of tests and positive results for chlamydia and gonorrhoea sent from general practice increased over time. Most chlamydia tests in both GUM and non-specialist settings were performed on women aged >25 years, but positivity rates were highest in women aged <25 years. The positivity rate remained stable between 2000 and 2004. Including data from all diagnostic settings, chlamydia rates were about twice as high as those estimated only from genitourinary clinic cases. CONCLUSIONS: The ASSIST model could be a promising new tool for planning and measuring sexual health services in England if it can become sustainable and provide more timely data using fewer resources. Collecting denominator data and including infections diagnosed in primary care are essential for meaningful surveillance.

Antitumor activity of an epithelial cell adhesion molecule targeted nanovesicular drug delivery system

Site-specific delivery of anticancer agents to tumors represents a promising therapeutic strategy because it increases efficacy and reduces toxicity to normal tissues compared with untargeted drugs. Sterically stabilized immunoliposomes (SIL), guided by antibodies that specifically bind to well internalizing antigens on the tumor cell surface, are effective nanoscale delivery systems capable of accumulating large quantities of anticancer agents at the tumor site. The epithelial cell adhesion molecule (EpCAM) holds major promise as a target for antibody-based cancer therapy due to its abundant expression in many solid tumors and its limited distribution in normal tissues. We generated EpCAM-directed immunoliposomes by covalently coupling the humanized single-chain Fv antibody fragment 4D5MOCB to the surface of sterically stabilized liposomes loaded with the anticancer agent doxorubicin. In vitro, the doxorubicin-loaded immunoliposomes (SIL-Dox) showed efficient cell binding and internalization and were significantly more cytotoxic against EpCAM-positive tumor cells than nontargeted liposomes (SL-Dox). In athymic mice bearing established human tumor xenografts, pharmacokinetic and biodistribution analysis of SIL-Dox revealed long circulation times in the blood with a half-life of 11 h and effective time-dependent tumor localization, resulting in up to 15% injected dose per gram tissue. These favorable pharmacokinetic properties translated into potent antitumor activity, which resulted in significant growth inhibition (compared with control mice), and was more pronounced than that of doxorubicin alone and nontargeted SL-Dox at low, nontoxic doses. Our data show the promise of EpCAM-directed nanovesicular drug delivery for targeted therapy of solid tumors.

Re-evaluation of pulmonary titanium dioxide nanoparticle distribution using the "relative deposition index": Evidence for clearance through microvasculature

ABSTRACT: BACKGROUND: Translocation of nanoparticles (NP) from the pulmonary airways into other pulmonary compartments or the systemic circulation is controversially discussed in the literature. In a previous study it was shown that titanium dioxide (TiO2) NP were "distributed in four lung compartments (air-filled spaces, epithelium/endothelium, connective tissue, capillary lumen) in correlation with compartment size". It was concluded that particles can move freely between these tissue compartments. To analyze whether the distribution of TiO2 NP in the lungs is really random or shows a preferential targeting we applied a newly developed method for comparing NP distributions. METHODS: Rat lungs exposed to an aerosol containing TiO2 NP were prepared for light and electron microscopy at 1 h and at 24 h after exposure. Numbers of TiO2 NP associated with each compartment were counted using energy filtering transmission electron microscopy. Compartment size was estimated by unbiased stereology from systematically sampled light micrographs. Numbers of particles were related to compartment size using a relative deposition index and chi-squared analysis. RESULTS: Nanoparticle distribution within the four compartments was not random at 1 h or at 24 h after exposure. At 1 h the connective tissue was the preferential target of the particles. At 24 h the NP were preferentially located in the capillary lumen. CONCLUSION: We conclude that TiO2 NP do not move freely between pulmonary tissue compartments, although they can pass from one compartment to another with relative ease. The residence time of NP in each tissue compartment of the respiratory system depends on the compartment and the time after exposure. It is suggested that a small fraction of TiO2 NP are rapidly transported from the airway lumen to the connective tissue and subsequently released into the systemic circulation.

Distribution of intracellular and secreted surfactant during postnatal rat lung development

Pulmonary surfactant prevents alveolar collapse via reduction of surface tension. In contrast to human neonates, rats are born with saccular lungs. Therefore, rat lungs serve as a model for investigation of the surfactant system during postnatal alveolar formation. We hypothesized that this process is associated with characteristic structural and biochemical surfactant alterations. We aimed to discriminate changes related to alveolarization from those being either invariable or follow continuous patterns of postnatal changes. Secreted active (mainly tubular myelin (tm)) and inactive (unilamellar vesicles (ulv)) surfactant subtypes as well as intracellular surfactant (lamellar bodies (lb)) in type II pneumocytes (PNII) were quantified before (day (d) 1), during (d 7), at the end of alveolarization (d 14), and after completion of lung maturation (d 42) using electron microscopic methods supplemented by biochemical analyses (phospholipid quantification, immunoblotting for SP-A). Immunoelectron microscopy determined the localization of surfactant protein A (SP-A). (1) At d 1 secreted surfactant was increased relative to d 7-42 and then decreased significantly. (2) Air spaces of neonatal lungs comprised lower fractions of tm and increased ulv, which correlated with low SP-A concentrations in lung lavage fluid (LLF) and increased respiratory rates, respectively. (3) Alveolarization (d 7-14) was associated with decreasing PNII size although volume and sizes of Lb continuously increased. (4) The volume fractions of Lb correlated well with the pool sizes of phospholipids in lavaged lungs. Our study emphasizes differential patterns of developmental changes of the surfactant system relative to postnatal alveolarization.

Differential distribution of stem cells in the auditory and vestibular organs of the inner ear

The adult mammalian cochlea lacks regenerative capacity, which is the main reason for the permanence of hearing loss. Vestibular organs, in contrast, replace a small number of lost hair cells. The reason for this difference is unknown. In this work we show isolation of sphere-forming stem cells from the early postnatal organ of Corti, vestibular sensory epithelia, the spiral ganglion, and the stria vascularis. Organ of Corti and vestibular sensory epithelial stem cells give rise to cells that express multiple hair cell markers and express functional ion channels reminiscent of nascent hair cells. Spiral ganglion stem cells display features of neural stem cells and can give rise to neurons and glial cell types. We found that the ability for sphere formation in the mouse cochlea decreases about 100-fold during the second and third postnatal weeks; this decrease is substantially faster than the reduction of stem cells in vestibular organs, which maintain their stem cell population also at older ages. Coincidentally, the relative expression of developmental and progenitor cell markers in the cochlea decreases during the first 3 postnatal weeks, which is in sharp contrast to the vestibular system, where expression of progenitor cell markers remains constant or even increases during this period. Our findings indicate that the lack of regenerative capacity in the adult mammalian cochlea is either a result of an early postnatal loss of stem cells or diminishment of stem cell features of maturing cochlear cells.

Computational prediction of the influence of crosslink distribution on the thermo-mechanical properties of epoxies

Experimental studies on epoxies report that the microstructure consists of highly crosslinked localized regions connected with a dispersed phase of low crosslink density. The various thermo-mechanical properties of epoxies might be affected by the crosslink distribution. But as experiments cannot report the exact number of crosslinked covalent bonds present in the structure, molecular dynamics is thus being used in this work to determine the influence of crosslink distribution on thermo-mechanical properties. Molecular dynamics and molecular mechanics simulations are used to establish wellequilibrated molecular models of EPON 862-DETDA epoxy system with a range of crosslink densities and various crosslink distributions. Crosslink distributions are being varied by forming differently crosslinked localized clusters and then by forming different number of crosslinks interconnecting the clusters. Simulations are subsequently used to predict the volume shrinkage, thermal expansion coefficients, and elastic properties of each of the crosslinked systems. The results indicate that elastic properties increase with increasing levels of overall crosslink density and the thermal expansion coefficient decreases with overall crosslink density, both above and below the glass transition temperature. Elastic moduli and coefficients of linear thermal expansion values were found to be different for systems with same overall crosslink density but having different crosslink distributions, thus indicating an effect of the epoxy nanostructure on physical properties. The values of thermo-mechanical properties for all the crosslinked systems are within the range of values reported in literature.

DISTRIBUTED APPROACH FOR SOLVING OPTIMAL POWER FLOW PROBLEMS IN THREE-PHASE UNBALANCED DISTRIBUTION NETWORK

The objective of this report is to study distributed (decentralized) three phase optimal power flow (OPF) problem in unbalanced power distribution networks. A full three phase representation of the distribution networks is considered to account for the highly unbalance state of the distribution networks. All distribution network’s series/shunt components, and load types/combinations had been modeled on commercial version of General Algebraic Modeling System (GAMS), the high-level modeling system for mathematical programming and optimization. The OPF problem has been successfully implemented and solved in a centralized approach and distributed approach, where the objective is to minimize the active power losses in the entire system. The study was implemented on the IEEE-37 Node Test Feeder. A detailed discussion of all problem sides and aspects starting from the basics has been provided in this study. Full simulation results have been provided at the end of the report.

Development of Vapor Deposited Silica Sol-Gel Particles for a Bioactive Materials System to Direct Osteoblast Behavior

Tissue engineering and regenerative medicine have emerged in an effort to generate replacement tissues capable of restoring native tissue structure and function, but because of the complexity of biologic system, this has proven to be much harder than originally anticipated. Silica based bioactive glasses are popular as biomaterials because of their ability to enhance osteogenesis and angiogenesis. Sol-gel processing methods are popular in generating these materials because it offers: 1) mild processing conditions; 2) easily controlled structure and composition; 3) the ability to incorporate biological molecules; and 4) inherent biocompatibility. The goal of this work was to develop a bioactive vaporization system for the deposition of silica sol-gel particles as a means to modify the material properties of a substrate at the nano- and micro- level to better mimic the instructive conditions of native bone tissue, promoting appropriate osteoblast attachment, proliferation, and differentiation as a means for supporting bone tissue regeneration. The size distribution, morphology and degradation behavior of the vapor deposited sol-gel particles developed here were found to be dependent upon formulation (H2O:TMOS, pH, Ca/P incorporation) and manufacturing (substrate surface character, deposition time). Additionally, deposition of these particles onto substrates can be used to modify overall substrate properties including hydrophobicity, roughness, and topography. Deposition of Ca/P sol particles induced apatite-like mineral formation on both two- and three-dimensional materials when exposed to body fluids. Gene expression analysis suggests that Ca/P sol particles induce upregulation osteoblast gene expression (Runx2, OPN, OCN) in preosteoblasts during early culture time points. Upon further modification-specifically increasing particle stability-these Ca/P sol particles possess the potential to serve as a simple and unique means to modify biomaterial surface properties as a means to direct osteoblast differentiation.

Developing and Deploying an XML-based Learning Content Management System at the FernUniversität Hagen

This paper is a report about the FuXML project carried out at the FernUniversität Hagen. FuXML is a Learning Content Management System (LCMS) aimed at providing a practical and efficient solution for the issues attributed to authoring, maintenance, production and distribution of online and offline distance learning material. The paper presents the environment for which the system was conceived and describes the technical realisation. We discuss the reasons for specific implementation decisions and also address the integration of the system within the organisational and technical infrastructure of the university.

Theoretical models of planetary system formation: mass vs. semi-major axis

Context. Planet formation models have been developed during the past years to try to reproduce what has been observed of both the solar system and the extrasolar planets. Some of these models have partially succeeded, but they focus on massive planets and, for the sake of simplicity, exclude planets belonging to planetary systems. However, more and more planets are now found in planetary systems. This tendency, which is a result of radial velocity, transit, and direct imaging surveys, seems to be even more pronounced for low-mass planets. These new observations require improving planet formation models, including new physics, and considering the formation of systems. Aims: In a recent series of papers, we have presented some improvements in the physics of our models, focussing in particular on the internal structure of forming planets, and on the computation of the excitation state of planetesimals and their resulting accretion rate. In this paper, we focus on the concurrent effect of the formation of more than one planet in the same protoplanetary disc and show the effect, in terms of architecture and composition of this multiplicity. Methods: We used an N-body calculation including collision detection to compute the orbital evolution of a planetary system. Moreover, we describe the effect of competition for accretion of gas and solids, as well as the effect of gravitational interactions between planets. Results: We show that the masses and semi-major axes of planets are modified by both the effect of competition and gravitational interactions. We also present the effect of the assumed number of forming planets in the same system (a free parameter of the model), as well as the effect of the inclination and eccentricity damping. We find that the fraction of ejected planets increases from nearly 0 to 8% as we change the number of embryos we seed the system with from 2 to 20 planetary embryos. Moreover, our calculations show that, when considering planets more massive than ~5 M⊕, simulations with 10 or 20 planetary embryos statistically give the same results in terms of mass function and period distribution.

Analysis of the 207Bi, 194Hg/Au and 173Lu distribution in the irradiated MEGAPIE target

Samples obtained from different locations within the prototype liquid metal spallation target MEGAPIE irradiated in 2006 at PSI were analysed using γ-spectrometry. A variety of radionuclides formed by reaction of the target material, lead–bismuth eutectic (LBE), with the proton beam and secondary particles were identified. While nuclides representing the target material itself (207Bi) and nuclides of noble metals were found in LBE samples throughout the target, nuclides of electropositive metals were found to be quantitatively deposited on free surfaces and material interfaces within the target system. This behaviour is analysed in more detail based on results obtained for three nuclides representing groups of elements with distinct chemical behaviour, namely 207Bi, 194Hg/Au and 173Lu. Quantitative analysis results are given and compared with predictions obtained using nuclear physics calculations for those nuclides showing rather homogeneous distribution within the target. Possible reasons for the separation of radionuclides from the liquid metal and their deposition on surfaces are given, and consequences arising for nuclear facilities utilizing liquid metals are discussed.

REE and Hf distribution among mineral phases in the CV-CK clan : a way to explain present-day Hf isotopic variations in chondrites

Chondrites are among the most primitive objects in the Solar System and constitute the main building blocks of telluric planets. Among the radiochronometers currently used for dating geological events, Sm–Nd and Lu–Hf are both composed of refractory, lithophile element. They are thought to behave similarly as the parent elements (Sm and Lu) are generally less incompatible than the daughter elements (Nd and Hf) during geological processes. As such, their respective average isotopic compositions for the solar system should be well defined by the average of chondrites, called Chondritic Uniform Reservoir (CHUR). However, while the Sm–Nd isotopic system shows an actual spread of less than 4% in the average chondritic record, the Lu–Hf system shows a larger variation range of 28% [Bouvier A., Vervoort J. D. and Patchett P. J. (2008) The Lu–Hf and Sm–Nd isotopic composition of CHUR: Constraints from unequilibrated chondrites and implications for the bulk composition of terrestrial planets. Earth Planet. Sci. Lett.273, 48–57]. To better understand the contrast between Sm–Nd and Lu–Hf systems, the REE and Hf distribution among mineral phases during metamorphism of Karoonda (CK) and Vigarano-type (CV) carbonaceous chondrites has been examined. Mineral modes were determined from elemental mapping on a set of five CK chondrites (from types 3–6) and one CV3 chondrite. Trace-element patterns are obtained for the first time in all the chondrite-forming minerals of a given class (CK chondrites) as well as one CV3 sample. This study reveals that REE are distributed among both phosphates and silicates. Only 30–50% of Sm and Nd are stored in phosphates (at least in chondrites types 3–5); as such, they are not mobilized during early stages of metamorphism. The remaining fraction of Sm and Nd is distributed among the same mineral phases; these elements are therefore not decoupled during metamorphism. Of the whole-rock total of Lu, the fraction held in phosphate decreases significantly as the degree of metamorphism increases (30% for types 3 and 4, less than 5% in type 6). In contrast to Lu, Hf is mainly hosted by silicates with little contribution from phosphates throughout the CK metamorphic sequence. A significant part of Sm and Nd are stored in phosphates in types 3–5, and these elements behave similarly during CK chondrite metamorphism. That explains the robustness of the Sm/Nd ratios in chondrites through metamorphism, and the slight discrepancies observed in the present-day isotopic Nd values in chondrites. On the contrary, Lu and Hf are borne by several different minerals and consequently they are redistributed during metamorphism–induced recrystallization. The Lu/Hf ratios are therefore significantly disturbed during chondrites metamorphism, leading to the high discrepancies observed in present-day Hf isotopic values in chondrites.

TGF-beta1 in Aplysia: role in long-term changes in the excitability of sensory neurons and distribution of TbetaR-II-like immunoreactivity.

Exogenous recombinant human transforming growth factor beta-1 (TGF-beta1) induced long-term facilitation of Aplysia sensory-motor synapses. In addition, 5-HT-induced facilitation was blocked by application of a soluble fragment of the extracellular portion of the TGF-beta1 type II receptor (TbetaR-II), which presumably acted by scavenging an endogenous TGF-beta1-like molecule. Because TbetaR-II is essential for transmembrane signaling by TGF-beta, we sought to determine whether Aplysia tissues contained TbetaR-II and specifically, whether neurons expressed the receptor. Western blot analysis of Aplysia tissue extracts demonstrated the presence of a TbetaR-II-immunoreactive protein in several tissue types. The expression and distribution of TbetaR-II-immunoreactive proteins in the central nervous system was examined by immunohistochemistry to elucidate sites that may be responsive to TGF-beta1 and thus may play a role in synaptic plasticity. Sensory neurons in the ventral-caudal cluster of the pleural ganglion were immunoreactive for TbetaR-II, as well as many neurons in the pedal, abdominal, buccal, and cerebral ganglia. Sensory neurons cultured in isolation and cocultured sensory and motor neurons were also immunoreactive. TGF-beta1 affected the biophysical properties of cultured sensory neurons, inducing an increase of excitability that persisted for at least 48 hr. Furthermore, exposure to TGF-beta1 resulted in a reduction in the firing threshold of sensory neurons. These results provide further support for the hypothesis that TGF-beta1 plays a role in long-term synaptic plasticity in Aplysia.

Good just isn't Good enough. Best System Probabilities and the Foundations of Statistical Mechanics

Statistical physicists assume a probability distribution over micro-states to explain thermodynamic behavior. The question of this paper is whether these probabilities are part of a best system and can thus be interpreted as Humean chances. I consider two strategies, viz. a globalist as suggested by Loewer, and a localist as advocated by Frigg and Hoefer. Both strategies fail because the system they are part of have rivals that are roughly equally good, while ontic probabilities should be part of a clearly winning system. I conclude with the diagnosis that well-defined micro-probabilities under-estimate the robust character of explanations in statistical physics.