From theory to therapy: implications from an in vitro model of ramified microglia

Microglia are the principal immune cells in the central nervous system (CNS), characterized by a highly specific morphology and unusual antigenic phenotype. An increasing number of studies have focused on the role of microglia in the pathogenesis of neurodegenerative diseases. To elucidate the function of microglial cells under several neuropathological conditions, we have studied and established a cell culture model that allows us to cultivate microglial cells in their inactive, resting (ramified) phenotype. In the first part of this work, we describe the interaction of microglia cells with their epithelial (astrocytic) microenvironment. The second part reviews experiments with microglia cell cultures to elucidate underlying signalling pathways and summarizes recent advances of our knowledge in microglial molecular pathways that may ultimately lead to neurodegeneration.     

Two models of multiple sclerosis: Experimental allergic encephalomyelitis (EAE) and theiler's murine encephalomyelitis virus (TMEV) infection. A pathological and immunological comparison

Theiler's murine encephalomyelitis virus (TMEV) infection and experimental allergic encephalomyelitis (EAE) are considered among the best models of human multiple sclerosis (MS). In both models, clinical disease is characterized by paralysis, while pathological changes consist of inflammatory demyelination. In both models there is a genetic influence on susceptibility/resistance to the development of disease. This has been thoroughly studied in TMEV infection, and it has been found to depend on both major histocompatibility complex (MHC) and non-MHC genes. At least four genes have been so far identified. Because of this genetic influence, some strains of mice are more susceptible to both clinical and pathological changes than others, and susceptibility appears to best correlate with the ability of a certain murine strain to develop a delayed-type hypersensitivity (DTH) response to viral antigens. We have also observed that even among mice which are equally susceptible clinically, striking differences may be seen under pathological examination. These consist of different gradients of severity of inflammation, particularly in regards to the macrophage component. There is an inverse relationship between the number of macrophages, and their length of stay in the CNS, and the ability of mice to remyelinate their lesions. The most severe lesions are in SJL/J mice, and remyelination in this strain is extremely poor. The least severe lesions in terms of macrophage invasion are in strains such as NZW and RIIIS/J, and these are able to remyelinate lesions very successfully. Murine chronic relapsing EAE (CR-EAE) shows pathological changes in many ways similar to those in TMEV-infected SJL/J mice, although less severe in terms of degrees of macrophage infiltration and tissue destruction. Mice with CR-EAE have a correspondingly limited ability to remyelinate their lesions. In both models the pathology appears to be mediated through a DTH response. However, while in EAE the DTH response is clearly against neuroantigens, the response in TMEV infection is against the virus itself. The end result in both models would be that of myelin destruction through a lymphotoxincytokine-mediated mechanism. The importance of the DTH response in both models is well illustrated by the effects of tolerance induction in EAE and TMEV infection to neuroantigens and virus, respectively. These are important models of human MS, since the current hypothesis is that a viral infection early in life, on the appropriate genetic background, may trigger a secondary misdirected immune response which could be directed either against myelin antigens and/or possible persistent virus(es). © 1995 Wiley-Liss, Inc.     

Role of microglia in glioma biology.

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors or malignant gliomas. Although the function of these cells in CNS inflammatory processes is being studied, their role in malignant glioma biology remains unclear. On one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors.     

A new role for chondrocytes as non-professional phagocytes. An in vitro study

Chondrocytes are capable of engulfing latex particles, cell detritus, and necrotic and apoptotic remains in vitro. It is conceivable that chondrocytes might be involved in the clearance by phagocytosis of different materials within the cartilage. In fact, so far there is no evidence for the presence of "professional phagocytes" (macrophages and neutrophils) in this tissue. Chondrocyte suspensions obtained from rat knees and hips were cultured to assess phagocytosis of latex particles (1 microm), articular cartilage detritus, and necrotic and apoptotic chondrocyte remains (induced by VP-16 1 mM). We observed that chondrocytes phagocytosed latex particles as evaluated by confocal microscopy and flow cytometry. In addition, we observed that chondrocytes phagocytosed articular cartilage detritus and necrotic and apoptotic VP-16 induced-chondrocytes, as observed by bright field microscopy and transmission electron microscopy.     

The role of cementite in the formation of magnetic hysteresis properties of plastically deformed high-carbon steels: I. Magnetic properties and structural state of cementite

Magnetic properties of cementite after strong plastic deformations and subsequent annealing in a broad range of temperatures are studied. The plastically deformed cementite is shown to exist in a soft (H _c ≈ 80 A/cm) state; the annealed cementite, in a hard (H _c ≈ 240 A/cm) state. The nature of the cementite’s soft and hard states is discussed. The field dependence of the cementite’s magnetostriction is measured. The longitudinal magnetostriction of the polycrystalline cementite’s saturated state is shown to be negative and approximately four times smaller than iron’s magnetostriction in the saturated state.     

Influence of polymer surface chemistry on frictional properties under protein-lubrication conditions: implications for hip-implant design

Wear processes in hip joints are believed to occur chiefly under boundary lubrication conditions. We have shown that the efficiency of boundary lubrication of the ultrahigh-molecular-weight polyethylene (UHWMPE)–alumina tribopair in protein-containing solutions can be improved by modifying the surface hydrophilicity of the UHMWPE. Our experiments show that an oxygen-plasma treatment of polyethylene, producing significantly greater hydrophilicity due to modified surface chemistry, leads to faster and modified protein adsorption. A denser boundary layer of human serum albumin (HSA) proteins on the PE surface appears to enhance boundary lubrication, which leads to a 50% reduction of dynamic friction, as well as to a reduction of stiction, which is believed to be a key factor in wear mechanisms occurring in artificial hip joints. Following tribological testing in pure water, we observed the presence of a polyethylene transfer film on the alumina disc. This film was not formed after tribotesting either in protein or in Ringer's solution.     

A nanometre-scale non-periodic structural variation in high temperature superconducting ceramics and the implications for properties

Non-periodic structural variation has been found in the high T _c cuprates, YBa₂Cu₃O_{7- x} and Hg_0.67Pb_0.33Ba₂Ca₂Cu₃O_8+δ, by image analysis of high resolution transmission electron microscope (HRTEM) images. We use two methods for analysis of the HRTEM images. The first method is a means for measuring the bending of lattice fringes at twin planes. The second method is a low-pass filter technique which enhances information contained by diffuse-scattered electrons and reveals what appears to be an interference effect between domains of differing lattice parameter in the top and bottom of the thin foil. We believe that these methods of image analysis could be usefully applied to the many thousands of HRTEM images that have been collected by other workers in the high temperature superconductor field. This work provides direct structural evidence for phase separation in high T _c cuprates, and gives support to recent stripes models that have been proposed to explain various angle resolved photoelectron spectroscopy and nuclear magnetic resonance data. We believe that the structural variation is a response to an opening of an electronic solubility gap where holes are not uniformly distributed in the material but are confined to metallic stripes. Optimum doping may occur as a consequence of the diffuse boundaries between stripes which arise from spinodal decomposition. Theoretical ideas about the high T _c cuprates which treat the cuprates as homogeneous may need to be modified in order to take account of this type of structural variation.     

散射光法探测微米群粒子场粒子性质的应用研究

提出了用激光进行散射光分析来探知未知群粒子场粒子性质的新的方法.实验中用直径0.22 μm和0.494 μm的粒子分别与过滤的蒸馏水制成不同浓度的悬浮液作为散射粒子场,并采用了波长为0.632 8 μm的激光.通过理论分析,并进行实验研究发现,在微米级群体粒子散射场中,粒子侧向散射光的退偏振情况与粒子的直径密切相关,直径大的粒子其水平方向线偏振度远小于直径小的粒子,而其垂直方向的线偏振度却远大于直径小的粒子.此结论可用作探测未知群粒子场粒子性质特别是用于粒子大小区别判断.     

Magnification mismatches between micrographs: corrective procedures and implications for structural analysis.

Quantitative structural analysis from electron micrographs of biological macromolecules inevitably requires the synthesis of data from many parts of the same micrograph and, ultimately, from multiple micrographs. Higher resolutions require the inclusion of progressively more data, and for the particles analyzed to be consistent to within ever more stringent limits. Disparities in magnification between micrographs or even within the field of one micrograph, arising from lens hysteresis or distortions, limit the resolution of such analyses. A quantitative assessment of this effect shows that its severity depends on the size of the particle under study: for particles that are 100 nm in diameter, for example, a 2% discrepancy in magnification restricts the resolution to approximately 5 nm. In this study, we derive and describe the properties of a family of algorithms designed for cross-calibrating the magnifications of particles from different micrographs, or from widely differing parts of the same micrograph. This approach is based on the assumption that all of the particles are of identical size: thus, it is applicable primarily to cryo-electron micrographs in which native dimensions are precisely preserved. As applied to icosahedral virus capsids, this procedure is accurate to within 0.1-0.2%, provided that at least five randomly oriented particles are included in the calculation. The algorithm is stable in the presence of noise levels typical of those encountered in practice, and is readily adaptable to non-isometric particles. It may also be used to discriminate subpopulations of subtly different sizes.     

Fundamental aspects and technological implications of the solubility concept for the prediction of running properties

The first Goodzeit rule, which relates resistance to cold welding and seizure with mutual solubility of metal sliding couples, has been investigated. The sliding properties of Au-Ag and Pd-Ag alloys against SAE 1045 carbon steel were observed in ultrahigh vacuum and in argon. The abrupt change in friction and wear coinciding with the composition of the alloys at which the solubility of iron into the alloy vanishes found by De Gee was not confirmed. Instead a continuous decrease in friction coefficient and wear was observed with increasing silver content. Pure silver showed a very limited tendency to metal transfer, although in some cases the transferred layer was removed spontaneously after 200–300 cycles. Electrical conduction measurements made during sliding revealed a correlation between the momentary friction force and the electrical conductivity which indicated that variations in the friction force are synchronous with variations in the contact area.A model is proposed in which the conditions of friction and metal transfer are described in terms of one system and two material properties, i.e. the interfacial shear strength τ_i, the shear strength τ¹ and the strain hardening exponent n of the junction materials. The friction behaviour is described by a modified adhesion theory: instead of a contaminating layer it is the specific atomic interaction of the contacting metals acting over small regions of atomic contact which controls τ_i. The junction growth mechanism is correlated with strain hardening.It is suggested that the first Goodzeit rule must be interpreted as a result of atomic interaction in the interface between the contacting metals. In this way prediction of the running behaviour of both metals and alloys would become possible.     

Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease.     

Gamma-herpesvirus neoplasia: a growing role for COX-2

Both human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) induce neoplasia. Burkitt's and Hodgkin's lymphomas harbor EBV sequences, while KSHV has been associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric castleman's disease (MCD). Each of these gamma-herpesvirus-associated malignancies displays typical characteristics of neoplasia, such as angiogenesis and cell survival. One enzyme commonly overexpressed in breast, prostate, and colon cancers is cyclooxygenase-2 (COX-2). Recently, COX-2 overexpression has been reported in herpesvirus infections in vitro. This review will outline potential mechanisms by which COX-2 may participate in herpesvirus-induced neoplasia.     

Regeneration,regenerated gratings and composite glass properties: the implications for high temperature micro and nano milling and optical sensing

A review of regenerated gratings and their application is presented. The relationship between new material perspectives based on the fundamental properties of amorphous structures and composite glass and the implications for practical component development is outlined. These have significant consequences on the high temperature performance possible for photonic components, such as short and long pitch fibre gratings, and call for a broader re-evaluation of fundamental fibre and waveguide design and fabrication to further optimise optical sensing and instrument technologies specifically for harsh environments such as those frequently found in the energy sector, both traditional and new. The work is even more relevant in light of global pursuits into extraterrestrial environments where extreme conditions are routinely present.     

Comparison of mechanical and optical properties of a newly marketed universal composite resin with contemporary universal composite resins: An in vitro study

The purpose of this study was to evaluate the surface roughness, microhardness, color change, and translucency of a newly marketed universal nanohybrid composite resin (CR) (G-aenial A'CHORD) comparing with four contemporary universal CRs including two nanofilled (Filtek and Estelite Asteria) and two nanohybrid CRs (Charisma Dimond and Neo Spectra ST HV in vitro). Sixty-five specimens (8.0 mm × 2.0 mm) were fabricated (n = 13, per group). After finishing and polishing, specimens were subjected to surface roughness and microhardness tests. Color and translucency of the specimens were evaluated at baseline and after darkening with coffee solution at day 1 and day 7. A representative specimen from each group was investigated under scanning electron microscopy (SEM). Data was analyzed statistically (p < .05). There were significant differences among the groups in terms of surface roughness, microhardness, color, and translucency. The surface roughness was recorded as: Charisma Diamond > Neo Spectra ST HV, Filtek > Estelite Asteria, G-aenial A'CHORD, whereas Vickers Hardness number was as: Filtek, Charisma Diamond > Neo Spectra ST HV > G-aenial A'CHORD, Estelite Asteria. Color change was as: Charisma Diamond > Neo Spectra ST HV, Filtek, G-aenial A'CHORD > Estelite Asteria and the translucency was as: Neo Spectra ST HV > G-aenial A'CHORD, Filtek > Estelite Asteria, Charisma Diamond. SEM examinations revealed smooth surfaces for G-aenial A'CHORD, Neo Spectra ST HV and Estelite Asteria. Mechanical and optical properties of universal composite resins with different compositions show variations.     

The role of cementite in the formation of magnetic hysteresis properties of plastically deformed high-carbon steels: II. Magnetic properties of patented wire made of steel 70

It is shown that, during discussion of the mechanism reliable for formation of the coercive force in high-carbon steel, in addition to the interaction between the domain walls and weakly magnetic cementite inclusions, the contribution from the cementite’s magnetic hardness should be considered. With the use of the temperature dependence of the coercive force in deformed and annealed specimens, the contribution of each of the considered mechanisms to the specimens’ coercive force is estimated.     

The role of cementite in the formation of magnetic hysteresis properties of plastically deformed high-carbon steels: III. Magnetic properties of patented wire made of steel 25

Temperature dependences of the coercive force of mechanically alloyed cementite and wires made of patented steel 25 that were subjected to plastic deformation and subsequent annealing are presented. As is shown, cementite can be in both low-and high-coercivity states, for which the coercive force measured at room temperature is 80 and 240 A/cm, respectively; the coercive force measured at liquid-nitrogen temperature (?196°C) is 190 and 530 A/cm, respectively. Based on an analysis of the temperature dependences of the coercive force of deformed wires made of patented steel 25, the role of cementite in the formation of the coercive force of low-carbon steels was determined. It is shown that, in spite of a relatively small amount of pearlite, the contribution due to the magnetic hardness of cementite to the coercive force should be taken into account. In this case, the contribution due to the interaction of ferrite domain walls with weakly magnetic cementite inclusions is substantially lower.     

Evidence for ciliary pigment localization in colored ciliates and implications for their photosensory transduction chain: a confocal microscopy study

In this study we report for the first time the localization of a photoreceptor pigment in the cilia of the colored heterotrich ciliates Blepharisma japonicum red and blue form, Fabrea salina, and Stentor coeruleus, as result of a confocal microscopy investigation. Optical sectioning confocal microscopy has been used for studying the spatial distribution of the pigment in the cell body, surprisingly showing that, besides its expected presence in the cortical region immediately below the cell membrane, it is located in the cilia too. In order to ascertain possible differences in the pigment fluorescence properties along the cell body, we have measured emission spectra from different parts of it (anterior, posterior, and cilia). Our results clearly indicate that in all cases the spectra are the same, within experimental errors. Finally, we have evaluated the pigment relative fluorescence efficiency of these ciliates. In an ordered scale from lower to greater efficiency, we have S. coeruleus, B. japonicum blue, B. japonicum red, and F. salina. The possible implications of our findings for the process of photosensory transduction are discussed.     

Disassembly leveling and lot sizing for multiple product types: a basic model and its extension

We consider two interrelated problems that occurred in disassembly systems: disassembly leveling and lot sizing. Disassembly leveling, one of disassembly process planning decisions, is to determine disassembly structures that specify parts and/or subassemblies to be obtained from disassembling used/end-of-life products, and disassembly lot sizing is the problem of determining the amounts of disassembly operations required to satisfy the demands of their parts and/or subassemblies. Unlike the existing studies, this study considers the two problems at the same time for the objective of minimizing the sum of disassembly setup and operation costs. In particular, we consider a generalized version in which disassembly levels may be different even for products of the same type. Two types of the problem are considered in this study. The first one is the basic problem without parts commonality, i.e., products do not share their parts or subassemblies, for which a polynomial time optimal algorithm is suggested after developing a mathematical programming model. The second one is an extended problem with parts commonality. After developing another mathematical programming model for the extension, we prove that it is NP hard. Then, a heuristic algorithm is suggested together with its computational results.     

New evidence for a role of Bisphenol A in cell integrity. Implications in the human population

Bisphenol A (BPA) is a xenoestrogen known for its implications for the endocrine systems and several other organs, including the kidneys. Recent renal studies have shown that BPA can induce alterations of the cytoskeleton and cell adhesion mechanisms such as a podocytopathy with proteinuria and hypertension, alterations involved in the progression of renal diseases. These data and the fact that BPA is known to be present in the urine of almost the entire population strongly suggest the critical need to reevaluate BPA exposures considered safe.