The lipid droplet coat protein perilipin 5 also localizes to muscle mitochondria

Perilipin 5 (PLIN5/OXPAT) is a lipid droplet (LD) coat protein mainly present in tissues with a high fat-oxidative capacity, suggesting a role for PLIN5 in facilitating fatty acid oxidation. Here, we investigated the role of PLIN5 in fat oxidation in skeletal muscle. In human skeletal muscle, we observed that PLIN5 (but not PLIN2) protein content correlated tightly with OXPHOS content and in rat muscle PLIN5 content correlated with mitochondrial respiration rates on a lipid-derived substrate. This prompted us to examine PLIN5 protein expression in skeletal muscle mitochondria by means of immunogold electron microscopy and Western blots in isolated mitochondria. These data show that PLIN5, in contrast to PLIN2, not only localizes to LD but also to mitochondria, possibly facilitating fatty acid oxidation. Unilateral overexpression of PLIN5 in rat anterior tibialis muscle augmented myocellular fat storage without increasing mitochondrial density as indicated by the lack of change in protein content of five components of the OXPHOS system. Mitochondria isolated from PLIN5 overexpressing muscles did not possess increased fatty acid respiration. Interestingly though, 14C-palmitate oxidation assays in muscle homogenates from PLIN5 overexpressing muscles revealed a 44.8% (P = 0.05) increase in complete fatty acid oxidation. Thus, in mitochondrial isolations devoid of LD, PLIN5 does not augment fat oxidation, while in homogenates containing PLIN5-coated LD, fat oxidation is higher upon PLIN5 overexpression. The presence of PLIN5 in mitochondria helps to understand why PLIN5, in contrast to PLIN2, is of specific importance in fat oxidative tissues. Our data suggests involvement of PLIN5 in directing fatty acids from the LD to mitochondrial fatty acid oxidation

The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma

<p>Abstract</p> <p>Background</p> <p>Nasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites.</p> <p>Methods</p> <p>We immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report.</p> <p>Results</p> <p>Overall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%.</p> <p>Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them.</p> <p>Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027).</p> <p>Conclusion</p> <p>Positive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

A hybrid method of laparoscopic-assisted open liver resection through a short upper midline laparotomy can be applied for all types of hepatectomies

Background Although hepatectomy procedures should be designed to provide both curability and safety, minimal invasiveness also should be pursued. Methods We analyzed the data related to our method for laparoscopy-assisted open resections (hybrid method) through a short upper midline incision for various types of hepatectomies. Of 215 hepatectomies performed at Nagasaki University Hospital between November 2009 and June 2012, 102 hepatectomies were performed using hybrid methods. Results A hybrid method was applicable for right trisectionectomy in 1, right hemihepatectomy in 32, left hemihepatectomy in 29, right posterior sectionectomy in 7, right anterior sectionectomy in 1, left lateral sectionectomy in 2, and segmentectomy in 7 patients, and for a minor liver resection in 35 patients (12 combined resections). The median duration of surgery was 366.5 min (range 149-709) min, and the median duration of the laparoscopic procedure was 32 min (range 18-77) min. The median blood loss was 645 g (range 50-5,370) g. Twelve patients (12 %) developed postoperative complications, including bile leakage in three patients, wound infections in two patients, ileus in two patients, and portal venous thrombus, persistent hyperbilirubinemia, incisional hernia, local liver infarction each in one patient. There were no perioperative deaths. Conclusions Our method of hybrid hepatectomy through a short upper midline incision is considered to be applicable for all types of hepatectomy and is a reasonable approach with no abdominal muscle disruption, which provides safe management of the hepatic vein and parenchymal resection even for patients with bilobular disease

Idebenone and Resveratrol Extend Lifespan and Improve Motor Function of HtrA2 Knockout Mice

Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD

FTY720 Suppresses Liver Tumor Metastasis by Reducing the Population of Circulating Endothelial Progenitor Cells

Background: Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem. Recent studies have shown that hepatic ischemia-reperfusion (I/R) injury and endothelial progenitor cells (EPCs) contribute to tumor growth and metastasis. We aim to investigate the mechanism of FTY720, which was originally applied as an immunomodulator, on suppression of liver tumor metastasis after liver resection and partial hepatic I/R injury. Methodology/Principal Findings: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Two weeks after orthotopic liver tumor implantation, the rats underwent liver resection for tumor-bearing lobe and partial hepatic I/R injury. FTY720 (2 mg/kg) was administered through the inferior caval vein before and after I/R injury. Blood samples were taken at days 0, 1, 3, 7, 14, 21 and 28 for detection of circulating EPCs (CD133+CD34+). Our results showed that intrahepatic and lung metastases were significantly inhibited together with less tumor angiogenesis by FTY720 treatment. The number of circulating EPCs was also significantly decreased by FTY720 treatment from day 7 to day 28. Hepatic gene expressions of CXCL10, VEGF, CXCR3, CXCR4 induced by hepatic I/R injury were down-regulated in the treatment group. Conclusions/Significance: FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by attenuating hepatic I/R injury and reducing circulating EPCs. © 2012 Li et al.published_or_final_versio

ASCI 2010 contrast media guideline for cardiac imaging: a report of the Asian Society of Cardiovascular Imaging cardiac computed tomography and cardiac magnetic resonance imaging guideline working group

The use of contrast media for cardiac imaging becomes increasing as the widespread of cardiac CT and cardiac MR. A radiologist needs to carefully consider the indication and the injection protocol of contrast media to be used as well as the possibility of adverse effect. There are several guidelines for contrast media in western countries. However, these are focusing the adverse effect of contrast media. The Asian Society of Cardiovascular Imaging, the only society dedicated to cardiovascular imaging in Asia, formed a Working Group and created a guideline, which summarizes the integrated knowledge of contrast media for cardiac imaging. In cardiac imaging, coronary artery evaluation is feasible by non-contrast MR angiography, which can be an alternative examination in high risk patients for the use of iodine contrast media. Furthermore, the body habitus of Asian patients is usually smaller than that of their western counterparts. This necessitates modifications in the injection protocol and in the formula for calculation of estimated glomerular filtration rate. This guideline provided fundamental information for the use of contrast media for Asian patients in cardiac imaging

The Critical Role of N- and C-Terminal Contact in Protein Stability and Folding of a Family 10 Xylanase under Extreme Conditions

Stabilization strategies adopted by proteins under extreme conditions are very complex and involve various kinds of interactions. Recent studies have shown that a large proportion of proteins have their N- and C-terminal elements in close contact and suggested they play a role in protein folding and stability. However, the biological significance of this contact remains elusive.In the present study, we investigate the role of N- and C-terminal residue interaction using a family 10 xylanase (BSX) with a TIM-barrel structure that shows stability under high temperature, alkali pH, and protease and SDS treatment. Based on crystal structure, an aromatic cluster was identified that involves Phe4, Trp6 and Tyr343 holding the N- and C-terminus together; this is a unique and important feature of this protein that might be crucial for folding and stability under poly-extreme conditions. folding and activity. Alanine substitution with Phe4, Trp6 and Tyr343 drastically decreased stability under all parameters studied. Importantly, substitution of Phe4 with Trp increased stability in SDS treatment. Mass spectrometry results of limited proteolysis further demonstrated that the Arg344 residue is highly susceptible to trypsin digestion in sensitive mutants such as ΔF4, W6A and Y343A, suggesting again that disruption of the Phe4-Trp6-Tyr343 (F-W-Y) cluster destabilizes the N- and C-terminal interaction. Our results underscore the importance of N- and C-terminal contact through aromatic interactions in protein folding and stability under extreme conditions, and these results may be useful to improve the stability of other proteins under suboptimal conditions

Wnt5a Regulates Ventral Midbrain Morphogenesis and the Development of A9–A10 Dopaminergic Cells In Vivo

Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9–10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5–E13.5. Analysis of Wnt5a−/− mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a−/− mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors