The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves’ Disease

Osteoporosis-related fractures are one of the complications of Graves’ disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves’ disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves’ disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves’ disease.     

Seroepidemiological study of Toxoplasma gondii infection in the rural area Okcheon-gun, Korea

There have been some reports about the prevalence of anti-Toxoplasma gondii antibody among Koreans, and most of all data were taken from patients visiting hospitals. However, the epidemiological data of the community-based study in Korea are rare. This study was performed to evaluate the seroprevalence of toxoplasmosis among the inhabitants of the rural area Okcheon-gun, Korea. A total of 1,109 serum samples (499 males, 610 females) were examined for the IgG antibodies by ELISA. To set up the cut-off point for ELISA, we used a commercial latex agglutination (LA) kit. The sensitivity and specificity of ELISA against LA test were 89.5%, and 98.6% respectively. Among 1,109 sera, 6.9% showed seropositivity by ELISA. The positive rates of males and females were 6.0% and 7.2%, respectively. However, there were no significant differences between sexes. Comparing the age groups, the highest seropositive rate showed in the seventies or higher, and their rates had a tendency to increase with age (0.05 < p < 0.3). These results revealed that the seroprevalence of toxoplasmosis in rural inhabitants is similar to previous reports in Korea; however we need further investigation to clarify the prevalence of toxoplasmosis in the general population.     

Negative evidence on the transgenerational inheritance of defense priming in Arabidopsis thaliana

Defense priming allows plants to enhance their immune responses to subsequent pathogen challenges. Recent reports suggested that acquired resistances in parental generation can be inherited into descendants. Although epigenetic mechanisms are plausible tools enabling the transmission of information or phenotypic traits induced by environmental cues across generations, the mechanism for the transgenerational inheritance of defense priming in plants has yet to be elucidated. With the initial aim to elucidate an epigenetic mechanism for the defense priming in plants, we reassessed the transgenerational inheritance of plant defense, however, could not observe any evidence supporting it. By using the same dipping method with previous reports, Arabidopsis was exposed repeatedly to Pseudomonas syringae pv tomato DC3000 (Pst DC3000) during vegetative or reproductive stages. Irrespective of the developmental stages of parental plants that received pathogen infection, the descendants did not exhibit primed resistance phenotypes, defense marker gene (PR1) expression, or elevated histone acetylation within PR1 chromatin. In assays using the pressure-infiltration method for infection, we obtained the same results as above. Thus, our results suggest that the previous observations on the transgenerational inheritance of defense priming in plants should be more extensively and carefully reassessed.     

Covalent NEDD8 Conjugation Increases RCAN1 Protein Stability and Potentiates Its Inhibitory Action on Calcineurin

Similar to ubiquitin, regulatory roles for NEDD8 (neural precursor cell-expressed developmentally down-regulated 8) are being clarified during cell growth, signal transduction, immune response, and development. However, NEDD8 targets and their functional alterations are not well known. Regulator of calcineurin 1 (RCAN1/DSCR1P1) is located near the Down syndrome critical region on the distal part of chromosome 21, and its gene product is an endogenous inhibitor of calcineurin signaling. RCAN1 is modified by ubiquitin and consequently undergoes proteasomal degradation. Here we report that NEDD8 is conjugated to RCAN1 (RCAN1-1S) via three lysine residues, K96, K104, and K107. Neddylation enhances RCAN1 protein stability without affecting its cellular location. In addition, we found that neddylation significantly inhibits proteasomal degradation of RCAN1, which may underlie the ability of NEDD8 to enhance RCAN1 stability. Furthermore, neddylation increases RCAN1 binding to calcineurin, which potentiates its inhibitory activity toward downstream NFAT signaling. The present study provides a new regulatory mechanism of RCAN1 function and highlights an important role for diverse RCAN1-involved cellular physiology.     

SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.     

Crystal structure of a rigid four-spectrin-repeat fragment of the human desmoplakin plakin domain

The plakin protein family serves to connect cell-cell and cell-matrix adhesion molecules to the intermediate filament cytoskeleton. Desmoplakin (DP) is an integral part of desmosomes, where it links desmosomal cadherins to the intermediate filaments. The 1056-amino-acid N-terminal region of DP contains a plakin domain common to members of the plakin family. Plakin domains contain multiple copies of spectrin repeats (SRs). We determined the crystal structure of a fragment of DP, residues 175-630, consisting of four SRs and an inserted SH3 domain. The four repeats form an elongated, rigid structure. The SH3 domain is present in a loop between two helices of an SR and interacts extensively with the preceding SR in a manner that appears to limit inter-repeat flexibility. The intimate intramolecular association of the SH3 domain with the preceding SR is also observed in plectin, another plakin protein, but not in α-spectrin, suggesting that the SH3 domain of plakins contributes to the stability and rigidity of this subfamily of SR-containing proteins.