Studies on immune activation in rheumatoid arthritis and reactive arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis, progressive joint destruction, and disability. Reactive arthritis (ReA) is a sterile joint inflammation following a distant mucosal infection. The clinical course of these diseases is variable and cannot be predicted with reasonable accuracy by clinical and laboratory markers. The predictive value of circulating soluble interleukin-2 receptor (sIL-2R), a marker of lymphocyte activation, measured by Immulite® automated immunoassay analyzer, was evaluated in two cohorts of RA patients. In 175 patients with active early RA randomized to treatment with either on disease-modifying antirheumatic drug (DMARD) or a combination of 3 DMARDs and prednisolone, low baseline sIL-2R level predicted remission after 6 months in patients treated with a single DMARD. In 24 patients with active RA refractory to DMARDs, low baseline sIL-2R level predicted rapid clinical response to treatment with infliximab, an anti-tumour necrosis factor antibody. Furthermore, in a cohort of 26 patients with acute ReA, high baseline sIL-2R level predicted remission after 6 months. Levels of circulating soluble E-selectin (sE-selectin), a marker of endothelial activation, were measured annually by enzyme-linked immunosorbent assay (ELISA) in a cohort of 85 patients with early RA. During a five-year follow-up, sE-selectin levels were associated with activity and outcome of RA. The levels of neutrophil and monocyte CD11b/CD18 expression measured by flow cytometry, and circulating levels of sE-selectin measured by ELISA, and procalcitonin by immunoluminometric assay, were compared in 28 patients with acute ReA and 16 patients with early RA. The levels of the markers were comparable in ReA, RA, and healthy control subjects. In conlusion, sIL-2R may provide a new predictive marker in early RA treated with a single DMARD and refractory RA treated with infliximab. In addition, sIL-2R level predicts remission in acute ReA.

Regulation of tumor suppressor protein p53 in cellular stress and tumorigenesis

Functional loss of tumor suppressor protein p53 is a common feature in diverse human cancers. The ability of this protein to sense cellular damage and halt the progression of the cell cycle or direct the cells to apoptosis is essential in preventing tumorigenesis. Tumors having wild-type p53 also respond better to current chemotherapies. The loss of p53 function may arise from TP53 mutations or dysregulation of factors controlling its levels and activity. Probably the most significant inhibitor of p53 function is Mdm2, a protein mediating its degradation and inactivation. Clearly, the maintenance of a strictly controlled p53-Mdm2 route is of great importance in preventing neoplastic transformation. Moreover, impairing Mdm2 function could be a nongenotoxic way to increase p53 levels and activity. Understanding the precise molecular mechanisms behind p53-Mdm2 relationship is thus essential from a therapeutic point of view. The aim of this thesis study was to discover factors affecting the negative regulation of p53 by Mdm2, causing activation of p53 in stressed cells. As a model of cellular damage, we used UVC radiation, inducing a complex cellular stress pathway. Exposure to UVC, as well as to several chemotherapeutic drugs, causes robust transcriptional stress in the cells and leads to activation of p53. By using this model of cellular stress, our goal was to understand how and by which proteins p53 is regulated. Furthermore, we wanted to address whether these pathways affecting p53 function could be altered in human cancers. In the study, two different p53 pathway proteins, nucleophosmin (NPM) and promyelocytic leukemia protein (PML), were found to participate in the p53 stress response following UV stress. Subcellular translocations of these proteins were discovered rapidly after exposure to UV. The alterations in the cellular localizations were connected to transient interactions with p53 and Mdm2, implicating their significance in the regulation of p53 stress response. NPM was shown to control Mdm2-p53 interface and mediate p53 stabilization by blocking the ability of Mdm2 to promote p53 degradation. Furthermore, NPM mediated p53 stabilization upon viral insult. We further detected a connection between cellular pathways of NPM and PML, as PML was found to associate with NPM in UV-radiated cells. The observed temporal UV-induced interactions strongly imply existence of a multiprotein complex participating in the p53 response. In addition, PML controlled the UV response of NPM, its localization and complex formation with chromatin associated factors. The relevance of the UV-promoted interactions was demonstrated in studies in a human leukemia cell line, being under abnormal transcriptional repression due to expression of oncogenic PML-RARa fusion protein. Reversing the leukemic phenotype with a therapeutically significant drug was associated with similar complex formation between p53 and its partners as following UV. In conclusion, this thesis study identifies novel p53 pathway interactions associated with the recovery from UV-promoted as well as oncogenic transcriptional repression.

Interdiffusion and activation energy in Ti3Au phase with A15 crystal structure

The knowledge of diffusion parameters, such as integrated diffusion coefficient and the activation energy for diffusion is important to understand the growth rate of the product phase and the atomic mechanism of diffusion. These parameters are determined in Ti3Au phase with A15 crystal structure. The calculated diffusion parameters will help in validating the theoretical analysis on defect structure of the phase.

Muscle activation patterns in the Nordic hamstring exercise: Impact of prior strain injury

This study aimed to determine: 1) the spatial patterns of hamstring activation during the Nordic hamstring exercise (NHE); 2) whether previously injured hamstrings display activation deficits during the NHE, and; 3) whether previously injured hamstrings exhibit altered cross-sectional area. Ten healthy, recreationally active males with a history of unilateral hamstring strain injury underwent functional magnetic resonance imaging (fMRI) of their thighs before and after 6 sets of 10 repetitions of the NHE. Transverse (T2) relaxation times of all hamstring muscles (biceps femoris long head, (BFlh); biceps femoris short head (BFsh); semitendinosus (ST); semimembranosus (SM)), were measured at rest and immediately after the NHE and cross-sectional area (CSA) was measured at rest. For the uninjured limb, the ST’s percentage increase in T2 with exercise was 16.8, 15.8 and 20.2% greater than the increases exhibited by the BFlh, BFsh and SM, respectively (p<0.002 for all). Previously injured hamstring muscles (n=10) displayed significantly smaller increases in T2 post-exercise than the homonymous muscles in the uninjured contralateral limb (mean difference -7.2%, p=0.001). No muscles displayed significant between limb differences in CSA. During the NHE, the ST is preferentially activated and previously injured hamstring muscles display chronic activation deficits compared to uninjured contralateral muscles.

Origin of the activation barrier in the process of hydrogen abstraction: the perturbation treatment

The perturbation treatment previously given is extended to explain the process of hydrogen abstraction from the various hydrogen donor molecules by the triplet nπ* state of ketones or the ground state of the alkyl or alkoxy radical. The results suggest that, as the ionization energy of the donor bonds is decreased, the reaction is accelerated and it is not influenced by the bond strength of the donor bonds. The activation barrier in such reactions arises from a weakening of the charge resonance term as the ionization energy of the donor bond increases.

Consumption of anthocyanin-rich Queen Garnet plum juice reduces platelet activation related thrombogenesis in healthy volunteers

The anti-thrombotic properties of an anthocyanin-rich Queen Garnet plum juice (QGPJ) and anthocyanin-free prune juice (PJ) were studied in this randomised, double-blind, crossover trial. Twenty-one healthy subjects (M = 10, F = 11) consumed QGPJ, PJ or placebo, 200 mL/day for 28-days followed by a 2-week wash-out period. Only QGPJ supplementation inhibited platelet aggregation induced by ADP (<5%, P = 0.02), collagen (<2.7%, P < 0.001) and arachidonic acid (<4%, P < 0.001); reduced platelet activation-dependent surface-marker P-selectin expression of activated de-granulated platelets (<17.2%, P = 0.04); prolonged activated-partial thromboplastin clotting time (>2.1 s, P = 0.03); reduced plasma-fibrinogen (<7.5%, P = 0.02) and malondialdehyde levels, a plasma biomarker of oxidative stress ( P = 0.016). PJ supplementation increased plasma hippuric acid content ( P = 0.018). QGPJ or PJ supplementation did not affect blood cell counts, lipid profile, or inflammation markers. Our findings suggest that QGPJ but not PJ has the potential to significantly attenuate thrombosis by reducing platelet activation/hyper-coagulability and oxidative stress.

Nature of the activation of succinate dehydrogenase byvarious effectors and in hypobaria and hypoxia

Hepatic mitochondrial succinate dehydrogenase (succinate:(acceptor)oxidoreductase, EC 1.3.99.1) was activated by preincubation of mitochondria with four diverse classes of compounds, the dicarboxylic acids, nitrophenols, quinols (and ubiquinols) and pyrophosphates. Of the various compounds tested malonate, oxaloacetate and pyrophosphate, well-known competitive inhibitors of the enzyme, and also hydroquinone and ubiquinols were effective even at low concentrations and showed maximal stimulation in 2 min.

Thermal activation parameters for low temperature deformation of alpha-hafnium

Abstract is not available.

Transcriptional events during early phase of germination of rice embryos

GERMINATION transfers a metabolically inert embryo into an active state of growth and development. The presence of conserved mRNAs has been demonstrated in different species of eggs and seeds1–4. In rice embryos, germination was shown to be independent of the synthesis of RNA up to 18–24 h after the start of imbibition5, although RNA synthesis was detected as early as 9 h after the start of imbibition. In this report, the sequence of the transcriptional events taking place during the early phase of the germination of rice embryos are presented.

Role of Eda and Troy pathways in ectodermal organ development

Several organs of the embryo develop as appendages of the ectoderm, the outermost layer of the embryo. These organs include hair follicles, teeth and mammary glands, which all develop as a result of reciprocal tissue interactions between the surface epithelium and the underlying mesenchyme. Several signalling molecules regulate ectodermal organogenesis the most important ones being Wnts, fi broblast growth factors (Fgfs), transforming growth factor -βs (Tgf-βs) including bone morphogenetic proteins (Bmps), hedgehogs (Hhs), and tumour necrosis factors (Tnfs). This study focuses on ectodysplasin (EDA), a signalling molecule of the TNF superfamily. The effects of EDA are mediated by its receptor EDAR, an intracellular adapter protein EDARADD, and downstream activation of the transcription factor nuclear factor kappa-B (NF-кB). Mice deficient in Eda (Tabby mice), its receptor Edar (downless mice) or Edaradd (crinkled mice) show identical phenotypes characterised by defective ectodermal organ development. These mouse mutants serve as models for the human syndrome named hypohidrotic ectodermal dysplasia (HED) that is caused by mutations either in Eda, Edar or Edaradd. The purpose of this study was to characterize the ectodermal organ phenotype of transgenic mice overexpressing of Eda (K14-Eda mice), to study the role of Eda in ectodermal organogenesis using both in vivo and in vitro approaches, and to analyze the potential redundancy between the Eda pathway and other Tnf pathways. The results suggest that Eda plays a role during several stages of ectodermal organ development from initiation to differentiation. Eda signalling was shown to regulate the initiation of skin appendage development by promoting appendageal cell fate at the expense of epidermal cell fate. These effects of Eda were shown to be mediated, at least in part, through the transcriptional regulation of genes that antagonized Bmp signalling and stimulated Shh signalling. It was also shown that Eda/Edar signalling functions redundantly with Troy, which encodes a related TNF receptor, during hair development. This work has revealed several novel aspects of the function of the Eda pathway in hair and tooth development, and also suggests a previously unrecognized role for Eda in mammary gland development.