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Events Underlying (event + underlying)
Kinds of Events Underlying Selected AbstractsProteomic Identification of the Involvement of the Mitochondrial Rieske Protein in EpilepsyEPILEPSIA, Issue 3 2005Heike Junker Summary:,Purpose: Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague,Dawley rat is associated with a critical developmental interval of 25 ± 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relation to normal and pathologic brain function. Methods: By using proteomics on cerebral tissue from our new rat kindling model, we undertook a global analysis of protein expression in kindled animals. Some of the identified proteins were further investigated by using immunohistochemistry. Results: We report the identification of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry, the Rieske protein is well expressed in the hippocampus, except in the CA1 subfield, an area of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. Conclusions: These results indicate that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy. [source] Erythropoiesis and red cell function in vertebrate embryosEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005R. Baumann Abstract All vertebrate embryos produce a specific erythroid cell population , primitive erythrocytes , early in development. These cells are characterized by expression of the specific embryonic haemoglobins. Many aspects of primitive erythropoiesis and the physiological function of primitive red cells are still enigmatic. Nevertheless, recent years have seen intensive efforts to characterize in greater detail the molecular events underlying the initiation of erythropoiesis in vertebrate embryos. Several key genes have been identified that are necessary for primitive and the subsequent definitive erythropoiesis, which differs in several aspect from primitive erythropoiesis. This review gives in its first part a short overview dealing with comparative aspects of primitive and early definitive erythropoiesis in higher and lower vertebrates and in the second part we discuss the physiological function of primitive red cells based mainly on results from mammalian and avian embryos. [source] Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Sascha Rutz Abstract The Notch pathway is involved in cell differentiation processes in various organs and at several developmental stages. The importance of Notch for early T lymphocyte development is well established. Recently, Notch has been implicated in directing naive T helper cell differentiation towards the Th1, Th2 or regulatory T cell lineages. However, the molecular events underlying these processes are poorly understood. We show that the Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jagged1 induce a dose-dependent inhibition of early activation markers CD69 and CD25, as well as inhibition of proliferation after anti-CD3 stimulation of purified CD4+ T cells. Similarly, the rapid activation of transcription factors NF-AT, AP-1 and NF-,B is suppressed. In contrast, triggering of Notch by Delta-like4 enhances T cell activation and proliferation. The observed effects are dependent on simultaneous cross-linking of TCR and Notch but independent of ,-secretase-mediated cleavage of Notch. These data suggest direct interference between Notch and early TCR signal transduction events, independent of the classical Notch pathway via release of the Notch intracellular domain. A Notch-mediated alteration of TCR signaling strength may contribute to the recently described modulation of naïve T cell differentiation by Notch ligands. [source] Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006Salvatore Galati Abstract To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92,3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs. [source] Induced and repressed genes after irradiation sensitizing by pentoxyphylline,INTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Waldemar Waldeck Abstract Aim in cancer therapy is to increase the therapeutic ratio eliminating the disease while minimizing toxicity to normal tissues. Radiation therapy is a main component in targeting cancer. Radiosensitizing agents like pentoxyphylline (PTX) have been evaluated to improve radiotherapy. Commonly, cells respond to radiation by the activation of specific early and late response genes as well as by inhibition of genes, which are expressed under normal conditions. A display of the genetic distinctions at the level of transcription is given here to characterize the molecular events underlying the radiosensitizing mechanisms. The method of suppression subtractive hybridization allows the visualization of both induced and repressed genes in irradiated cells compared with cells sensitized immediately after irradiation. The genes were isolated by cDNA-cloning, differential analysis and sequence similarity search. Genes involved in protein synthesis, metabolism, proteolysis and transcriptional regulation were detected. It is important that genes like KIAA280, which were only known as unidentified EST sequences before without function, but inaccessible by array technology were recovered as functional genes. Database searches for PTX-induced genes detected a human mRNA completely unknown. In case of suppressed genes, we detected several mRNAs; one thereof shows homology to a hypothetical protein possibly involved in signal transduction. A further mRNA encodes the protein BM036 supposed to associate with the E2F transcription factor. A hypothetical protein H41 was detected, which may repress the Her-2/neu receptor influencing breast cancer, gliomas and prostate tumors. Radiation combined with PTX may lead to a better prognosis by down regulation of the Her-2/neu, which will be proven by clinical studies in the near future. © 2006 Wiley-Liss, Inc. [source] Frequent amplification and overexpression of CCND1 in male breast cancerINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Maarit Bärlund Abstract Genetic events underlying the pathogenesis of breast cancer have been studied extensively and several clinically significant markers have been identified. For example, amplification and overexpression of the ERBB2 oncogene is associated with poor prognosis in breast cancer and ERBB2 serves as a target for antibody-based therapy. Current knowledge on the pathogenesis of male breast cancer (MBC) is limited. The purpose of our study was to investigate the potential relevance of a series of genes known to be amplified in female breast cancer (FBC) in a the development and pathogenesis of MBC. To this end, we applied fluorescence in situ hybridization and immunohistochemistry to the analysis of 128 breast tumors from males. Amplification of ERBB2, MYC, PPM1D and ZNF217 was detected rarely (1,2% of tumors) indicating a considerably lower amplification frequency than in FBC. CCND1 amplification was observed in 12% of cases, being in good concordance with findings from FBC. In addition, CCND1 overexpression was detected in 63% of tumors and was associated with ER positivity (p < 0.0001). Our results indicate distinct differences in the genetic basis of MBC and FBC and suggest that marked differences exist in the pathogenesis of these diseases. The lack of ERBB2 involvement was especially unexpected and implies that ERBB2 -targeted therapies are unlikely to be beneficial in MBC. Furthermore, the high frequency of hormone receptor positivity and the association between ER positivity and CCND1 overexpression supports the notion that hormonal regulation is likely to be essential for the development of MBC. © 2004 Wiley-Liss, Inc. [source] Microcephalia with mandibular and dental dysplasia in adult Zmpste24-deficient miceJOURNAL OF ANATOMY, Issue 5 2008F. De Carlos Abstract ZMPSTE24 (also called FACE-1) is a zinc-metalloprotease involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. Mutations in the ZMPSTE24 gene or in that encoding its substrate prelamin A (LMNA) result in a series of human inherited diseases known collectively as laminopathies and showing regional or systemic manifestations (i.e. the Hutchinson,Gilford progeria syndrome). Typically, patients suffering some laminopathies show craniofacial or mandible anomalies, aberrant dentition or facial features characteristic of aged persons. To analyse whether Zmpste24,/, mice reproduce the cranial phenotype observed in humans due to mutations in ZMPSTE24 or LMNA, we conducted a craniometric study based on micro-computer tomography (µCT) images. Furthermore, using simple radiology, µCT, µCT-densitometry and scanning electron microscopy, we analysed the mandible and the teeth from Zmpste24,/, mice. Finally, the structure of the lower incisor was investigated using an H&E technique. The results demonstrate that Zmpste24,/, mice are microcephalic and show mandibular and dental dysplasia affecting only the mandible teeth. In all cases, the lower incisor of mice lacking Zmpste24 was smaller than in control animals, showed cylindrical morphology and a transverse fissure at the incisal edge, and the pulpal cavity was severely reduced. Structurally, the dental layers were normally arranged but cellular layers were disorganized. The inferior molars showed a reduced cusp size. Taken together, these data strongly suggest that Zmpste24,/, mice represent a good model to analyse the craniofacial and teeth malformations characteristic of lamin-related pathologies, and might contribute to a better understanding of the molecular events underlying these diseases. [source] The zebrafish (Danio rerio) caudal complex , a model to study vertebral body fusionJOURNAL OF APPLIED ICHTHYOLOGY, Issue 2 2010A. Bensimon-Brito Summary Impairment of segmentation during embryonic development leads to congenital fusion of vertebrae. Nevertheless, vertebral fusion can also occur during post-embryonic life. Fusion can cause reduction in mobility and may be pathological, but it can also be part of normal development and mechanically required, such as in the teleost caudal skeleton, or in the tetrapod sacrum. Using a series of closely spaced ontogenetic stages of zebrafish, stained for mineralized (Alizarin red) and cartilaginous (Alcian blue) structures, we have characterized all fusions occurring during the formation of the caudal skeleton. The urostyle results from the vertebral fusion of the compound centrum preural1-ural1 [PU1++U1] and ural2 [U2+]. Based on developmental and morphological characters: (i) number of vestigial haemal arches, (ii) occasional presence of a haemal arch rudiment, (iii) occasional individuals with separate centra rudiments or distinct mineralization time points, and (iv) evidence for internal separation, we propose that the urostyle forms as a fusion product of five, and not three vertebral centra, as previously described. The last fusion to occur in development, between the compound centrum [PU1++U1] and U2+, is a relatively slow process that typically occurs in Cypriniformes and Salmoniformes and is therefore considered reliable to monitor the fusion process. The vertebrae adjacent to the urostyle, preurals 2 and 3, are highly susceptible to fusion, and thus inadequate as a negative control to fusion, in contrast to trunk vertebrae, where fusion is never observed. With this we have established the basis for a new model to study vertebral fusion and to unravel cellular and molecular events underlying this process. [source] Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspectsJOURNAL OF NEUROCHEMISTRY, Issue 4 2005Tiziana Rubino Abstract We investigated the role of the Ras/extracellular-regulated kinase (ERK) pathway in the development of tolerance to ,9 -tetrahydrocannabinol (THC)-induced reduction in spontaneous locomotor activity by a genetic (Ras-specific guanine nucleotide exchange factor (Ras-GRF1) knock-out mice) and pharmacological approach. Pre-treatment of wild-type mice with SL327 (50 mg/kg i.p.), a specific inhibitor of mitogen-activated protein kinase kinase (MEK), the upstream kinase of ERK, fully prevented the development of tolerance to THC-induced hypolocomotion. We investigated the impact of the inhibition of ERK activation on the biological processes involved in cannabinoid tolerance (receptor down-regulation and desensitization), by autoradiographic cannabinoid CB1 receptor and cannabinoid-stimulated [35S]GTP,S binding studies in subchronically treated mice (THC, 10 mg/kg s.c., twice a day for 5 days). In the caudate putamen and cerebellum of Ras-GRF1 knock-out mice and SL327 pre-treated wild-type mice, CB1 receptor down-regulation and desensitization did not occur, suggesting that ERK activation might account for CB1 receptor plasticity involved in the development of tolerance to THC hypolocomotor effect. In contrast, the hippocampus and prefrontal cortex showed CB1 receptor adaptations regardless of the genetic or pharmacological inhibition of the ERK pathway, suggesting regional variability in the cellular events underlying the altered CB1 receptor function. These findings suggest that at least in the caudate putamen and cerebellum, the Ras/ERK pathway is essential for triggering the alteration in CB1 receptor function responsible for tolerance to THC-induced hypomotility. [source] Can antiglycolipid antibodies present in HIV-infected individuals induce immune demyelination?NEUROPATHOLOGY, Issue 4 2000Steven Petratos Of the eight clinically defined neuropathies associated with HIV infection, there is compelling evidence that acute and chronic inflammatory demyelinating polyneuropathy (IDPN) have an autoimmune pathogenesis. Many non-HIV infected individuals who suffer from sensorymotor nerve dysfunction have autoimmune indicators. The immunopathogenesis of demyelination must involve neuritogenic components in myelin. The various antigens suspected to play a role in HIV-seronegative IDPN include (i) P2 protein; (ii) sulfatide (GalS); (iii) various gangliosides (especially GM1); (iv) galactocerebroside (GalC); and (v) glycoproteins or glycolipids with the carbohydrate epitope glucuronyl-3-sulfate. These glycoproteins or glycolipids may be individually targeted, or an immune attack may be raised against a combination of any of these epitopes. The glycolipids, however, especially GalS, have recently evoked much interest as mediators of immune events underlying both non-HIV and HIV-associated demyelinating neuropathies. The present review outlines the recent research findings of antiglycolipid antibodies present in HIV-infected patients with and without peripheral nerve dysfunction, in an attempt to arrive at some consensus as to whether these antibodies may play a role in the immunopathogenesis of HIV-associated inflammatory demyelinating polyneuropathy. [source] Dynamics of growth and dissemination of Salmonella in vivoCELLULAR MICROBIOLOGY, Issue 10 2010Kathryn G. Watson Summary The last decade has witnessed increasing research on dissemination of bacterial pathogens in their hosts and on the processes that underlie bacterial spread and growth during organ colonization. Here, we discuss work on the mouse model of human typhoid fever caused by Salmonella enterica serovar Typhimurium. This has revealed the use of several routes of systemic dissemination that result in colonization and growth within the spleen and liver, the major sites of bacterial proliferation. We also highlight techniques that enable in vivo analysis of the infecting population at the spatiotemporal and single cell levels. These approaches have provided more detailed insights into the events underlying the dynamics of Salmonella replication, spread and clearance within host organs and tissues. [source] | |||||||||||||