Immunoproteasome Overexpression Underlies the Pathogenesis of Thyroid Oncocytes and Primary Hypothyroidism: Studies in Humans and Mice

BACKGROUND:Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. METHODOLOGY/PRINCIPAL FINDINGS:Using transgenic mice chronically expressing IFNgamma in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. CONCLUSIONS/SIGNIFICANCE:In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism

Movement of the external ear in human embryo

Introduction: External ears, one of the major face components, show an interesting movement during craniofacial morphogenesis in human embryo. The present study was performed to see if movement of the external ears in a human embryo could be explained by differential growth. Methods: In all, 171 samples between Carnegie stage (CS) 17 and CS 23 were selected from MR image datasets of human embryos obtained from the Kyoto Collection of Human Embryos. The three-dimensional absolute positio

Enhanced Nogo-P3 amplitudes of mothers compared with non-mother women during an emotional Go/Nogo task

Background: It is known that emotion regulatory responses of humans are changed by the experiences they have, but in particular, they are changed by becoming a mother. A recent study has found how a woman's emotion regulatory response to a child's crying changes after becoming a mother. However, mothers' emotion regulatory responses other than those to children and the association between emotion regulatory response and parental stress are still unknown. Methods: Eighteen healthy Japanese females (nine mothers and nine non-mothers) participated in the experiment. They performed an emotional Go/Nogo task, with facial expressions of others (angry, happy, and neutral faces) used as emotional stimuli. The percentage of correct responses, response time, and event-related potentials (ERPs) during the task was measured. Results: This comparison revealed that the mother group had a larger P3 (Nogo-P3) amplitude than the non-mother group when Nogo trials were held. This indicates that in mothers, there was greater activation of the behavioral inhibition-related brain areas than in non-mother women when they inhibited inappropriate behavior following recognition of facial expressions of others. In addition, in the mother group, there was a negative correlation between parental stress levels and Nogo-P3 amplitudes evoked by angry faces. This suggests that there is a relation between the level of parental stress of mothers and their emotion regulatory responses to angry faces. Conclusions: Our results demonstrate that mothers' emotion regulatory processes may differ from those of non-mothers in response, not only to a child's crying but also to expressions of emotions by others, and also suggest that the inhibitory recognition activity of mothers can be affected by parental stres

Comparative Proteomic Analysis of Methanothermobacter themautotrophicus ΔH in Pure Culture and in Co-Culture with a Butyrate-Oxidizing Bacterium

To understand the physiological basis of methanogenic archaea living on interspecies H2 transfer, the protein expression of a hydrogenotrophic methanogen, Methanothermobacter thermautotrophicus strain ΔH, was investigated in both pure culture and syntrophic coculture with an anaerobic butyrate oxidizer Syntrophothermus lipocalidus strain TGB-C1 as an H2 supplier. Comparative proteomic analysis showed that global protein expression of methanogen cells in the model coculture was substantially different from that of pure cultured cells. In brief, in syntrophic coculture, although methanogenesis-driven energy generation appeared to be maintained by shifting the pathway to the alternative methyl coenzyme M reductase isozyme I and cofactor F420-dependent process, the machinery proteins involved in carbon fixation, amino acid synthesis, and RNA/DNA metabolisms tended to be down-regulated, indicating restrained cell growth rather than vigorous proliferation. In addition, our proteome analysis revealed that α subunits of proteasome were differentially acetylated between the two culture conditions. Since the relevant modification has been suspected to regulate proteolytic activity of the proteasome, the global protein turnover rate could be controlled under syntrophic growth conditions. To our knowledge, the present study is the first report on N-acetylation of proteasome subunits in methanogenic archaea. These results clearly indicated that physiological adaptation of hydrogenotrophic methanogens to syntrophic growth is more complicated than that of hitherto proposed

Management strategy for acute pancreatitis in the JPN Guidelines

The diagnosis of acute pancreatitis is based on the following findings: (1) acute attacks of abdominal pain and tenderness in the epigastric region, (2) elevated blood levels of pancreatic enzymes, and (3) abnormal diagnostic imaging findings in the pancreas associated with acute pancreatitis. In Japan, in accordance with criteria established by the Japanese Ministry of Health, Labour, and Welfare, the severity of acute pancreatitis is assessed based on the clinical signs, hematological findings, and imaging findings, including abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Severity must be re-evaluated, especially in the period 24 to 48 h after the onset of acute pancreatitis, because even cases diagnosed as mild or moderate in the early stage may rapidly progress to severe. Management is selected according to the severity of acute pancreatitis, but it is imperative that an adequate infusion volume, vital-sign monitoring, and pain relief be instituted immediately after diagnosis in every patient. Patients with severe cases are treated with broad-spectrum antimicrobial agents, a continuous high-dose protease inhibitor, and continuous intraarterial infusion of protease inhibitors and antimicrobial agents; continuous hemodiafiltration may also be used to manage patients with severe cases. Whenever possible, transjejunal enteral nutrition should be administered, even in patients with severe cases, because it seems to decrease morbidity. Necrosectomy is performed when necrotizing pancreatitis is complicated by infection. In this case, continuous closed lavage or open drainage (planned necrosectomy) should be the selected procedure. Pancreatic abscesses are treated by surgical or percutaneous drainage. Emergency endoscopic procedures are given priority over other methods of management in patients with acute gallstone-associated pancreatitis, patients suspected of having bile duct obstruction, and patients with acute gallstone pancreatitis complicated by cholangitis. These strategies for the management of acute pancreatitis are shown in the algorithm in this article