Gene Systems Network Inferred from Expression Profiles in Hepatocellular Carcinogenesis by Graphical Gaussian Model

Hepatocellular carcinoma (HCC) in a liver with advanced-stage chronic hepatitis C (CHC) is induced by hepatitis C virus, which chronically infects about 170 million people worldwide. To elucidate the associations between gene groups in hepatocellular carcinogenesis, we analyzed the profiles of the genes characteristically expressed in the CHC and HCC cell stages by a statistical method for inferring the network between gene systems based on the graphical Gaussian model. A systematic evaluation of the inferred network in terms of the biological knowledge revealed that the inferred network was strongly involved in the known gene-gene interactions with high significance (P<10−4), and that the clusters characterized by different cancer-related responses were associated with those of the gene groups related to metabolic pathways and morphological events. Although some relationships in the network remain to be interpreted, the analyses revealed a snapshot of the orchestrated expression of cancer-related groups and some pathways related with metabolisms and morphological events in hepatocellular carcinogenesis, and thus provide possible clues on the disease mechanism and insights that address the gap between molecular and clinical assessments

Mass spectrometry imaging of the capsaicin localization in the capsicum fruits

We succeeded in performing mass spectrometry imaging (MSI) of the localization of capsaicin in cross-sections of the capsicum fruits at a resolution of 250 µm using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Post source decay of protonated capsaicin ion revealed structural information of the corresponding acid amide of vanillylamide and C9 chain fatty acid. MALDI-TOF-MSI confirmed that localization of capsaicin in the placenta is higher than that in the pericarp. In addition, it revealed no localization of capsaicin in seed and the higher localization of capsaicin at placenta surface compared with that in the internal region. A quantitative difference was detected between localizations of capsaicin at placenta, pericarp and seed in the capsicum fruits. This imaging approach is a promising technique for rapid quality evaluation general food as well as health food and identification of medicinal capsaicin in plant tissues

Ubiquitin chains in the Dsk2 UBL domain mediate Dsk2 stability and protein degradation in yeast

Ubiquitin-like (UBL)-ubiquitin-associated (UBA) proteins, including Dsk2 and Rad23, act as delivery factors that target polyubiquitinated substrates to the proteasome. We report here that the Dsk2 UBL domain is ubiquitinated in yeast cells and that Dsk2 ubiquitination of the UBL domain is involved in Dsk2 stability, depending on the Dsk2 UBA domain. Also, Dsk2 lacking ubiquitin chains impaired ubiquitin-dependent protein degradation and decreased the interaction of Dsk2 with polyubiquitinated proteins in cells. Moreover, Dsk2 ubiquitination affected ability to restore the temperature-sensitive growth defect of dsk2 Delta. These results indicate that ubiquitination in the UBL domain of Dsk2 has in vivo functions in the ubiquitin-proteasome pathway in yeast

Localization Analysis of Natural Toxin of Solanum tuberosum L. via Mass Spectrometric Imaging

The use of mass spectrometry imaging (MSI) revealed the localization of alpha-solanine and alpha-chaconine as natural toxins for Potato (Solanum tuberosum L.). The content of Potato glycoalkaloids, alpha-solanine and alpha-chaconine, were quantitatively determined by high performance liquid chromatography (HPLC). Matrix assisted laser desorption/ionization-based tandem mass spectrometry (MS) could determine alpha-solanine and alpha-chaconine from raw potato extraction and section. After budbreak, alpha-solanine and alpha-chaconine were produced and localized at periderm and germ compared with that before budbreak. At germ region, these glycoalkaloids did not exist whole germ region but eccentrically localize at germ surface and central region. The amount of alpha-chaconine was twofold higher than alpha-solanine at periderm. At germ region, there was no difference between these toxins

Regulation of Proapoptotic Mammalian ste20–Like Kinase MST2 by the IGF1-Akt Pathway

Hippo, a Drosophila serine/threonine kinase, promotes apoptosis and restricts cell growth and proliferation. Its mammalian homolog MST2 has been shown to play similar role and be regulated by Raf-1 via a kinase-independent mechanism and by RASSF family proteins through forming complex with MST2. However, regulation of MST2 by cell survival signal remains largely unknown.Using immunoblotting, in vitro kinase and in vivo labeling assays, we show that IGF1 inhibits MST2 cleavage and activation induced by DNA damage through the phosphatidylinosotol 3-kinase (PI3K)/Akt pathway. Akt phosphorylates a highly conserved threonine-117 residue of MST2 in vitro and in vivo, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation-Thr180 and kinase activity. As a result, MST2 proapoptotic and growth arrest function was significantly reduced. Further, inverse correlation between pMST2-T117/pAkt and pMST2-T180 was observed in human breast tumors.Our findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2

Simulations on High-z Long Gamma-Ray Burst Rate

Since the launch of Swift satellite, the detections of high-z (z>4) long gamma-ray bursts (LGRBs) have been rapidly growing, even approaching the very early Universe (the record holder currently is z=8.3). The observed high-z LGRB rate shows significant excess over that estimated from the star formation history. We investigate what may be responsible for this high productivity of GRBs at high-z through Monte Carlo simulations, with effective Swif/BAT trigger and redshift detection probabilities based on current Swift/BAT sample and CGRO/BATSE LGRB sample. We compare our simulations to the Swift observations via log N-log P, peak luminosity (L) and redshift distributions. In the case that LGRB rate is purely proportional to the star formation rate (SFR), our simulations poorly reproduce the LGRB rate at z>4, although the simulated log N-log P distribution is in good agreement with the observed one. Assuming that the excess of high-z GRB rate is due to the cosmic metallicity evolution or unknown LGRB rate increase parameterized as (1+z)^delta, we find that although the two scenarios alone can improve the consistency between our simulations and observations, incorporation of them gives much better consistency. We get 0.2<epsilon<0.6 and delta<0.6, where epsilon is the metallicity threshold for the production of LGRBs. The best consistency is obtained with a parameter set (epsilon, delta)=(~0.4, ~0.4), and BAT might trigger a few LGRBs at z~14. With increasing detections of GRBs at z>4 (~15% of GRBs in current Swift LGRB sample based on our simulations), a window for very early Universe is opening by Swift and up-coming SVOM missions.Comment: 9 pages, including 8 figures and 1 table, one more figure added. Accepted for publication in MNRA

Ceruloplasmin Protects Against Rotenone-Induced Oxidative Stress and Neurotoxicity

To clarify the neuroprotective property of ceruloplasmin and the pathogenesis of aceruloplasminemia, we generated ceruloplasmin-deficient (CP−/−) mice on the C57BL/10 genetic background and further treated them with a mitochondrial complex I inhibitor, rotenone. There was no iron accumulation in the brains of CP−/− mice at least up to 60 weeks of age. Without rotenone treatment, CP−/− mice showed slight motor dysfunction compared with CP+/+ mice, but there were no detectable differences in the levels of oxidative stress markers between these two groups. A low dose of rotenone did not affect the mitochondrial complex I activity in our mice, however, it caused a significant change in motor behavior, neuropathology, or the levels of oxidative stress markers in CP−/− mice, but not in CP+/+ mice. Our data support that ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity, probably through its antioxidant properties independently of its function of iron metabolism

Superficial siderosis associated with aceruloplasminemia. Case report

A 63-year-old woman with a past history of right subdural hematoma (SDH) at the age of 61 years was referred to our hospital under a suspicion of aceruloplasminemia (ACP). A neurological examination revealed very mild cognitive impairment and cerebellar ataxia. Blood chemistry data showed deficient ceruloplasmin (Cp), decreased copper, and increased ferritin. A nonsense mutation (c.2630G > A, p.Trp858Ter) was detected in the Cp gene. Brain magnetic resonance imaging (MRI) showed marked hypointensity at the surface of the cerebrum, cerebellum, and brainstem bilaterally, in addition to the bilateral basal ganglia, thalamus, and dentate nucleus, suggesting the coexistence of ACP and superficial siderosis (SS). The characteristics of SS in ACP have not been examined neuroradiologically or neuropathologically in great detail, while SDH and its curative surgery are known to cause SS. The distribution of the hypointensity areas on MRI was expanded bilaterally to the subtentorial areas of this patient, which was much more widespread than observed in typical SS after SDH. We speculate that the underlying ACP may expand the SS induced by SDH. Cp would accelerate iron export from the brain via the blood-cerebrospinal fluid (CSF) barrier, or CSF-brain barrier when excessive iron is loaded into the subarachnoid space.ArticleJOURNAL OF THE NEUROLOGICAL SCIENCES. 339(41641):231-234 (2014)journal articl

Selection Effects on the Observed Redshift Dependence of GRB Jet Opening Angles

Apparent redshift dependence of the jet opening angles ($\theta_{\rm j}$) of gamma-ray bursts (GRBs) is observed from current GRB sample. We investigate whether this dependence can be explained with instrumental selection effects and observational biases by a bootstrapping method. Assuming that (1) the GRB rate follows the star formation history and the cosmic metallicity history and (2) the intrinsic distributions of the jet-corrected luminosity ($L_{\rm \gamma}$) and $\theta_{\rm j}$ are a Gaussian or a power-law function, we generate a mock {\em Swift}/BAT sample by considering various instrumental selection effects, including the flux threshold and the trigger probability of BAT, the probabilities of a GRB jet pointing to the instrument solid angle and the probability of redshift measurement. Our results well reproduce the observed $\theta_{\rm j}-z$ dependence. We find that in case of $L_{\gamma}\propto \theta_{\rm j}^2$ good consistency between the mock and observed samples can be obtained, indicating that both $L_{\rm \gamma}$ and $\theta_{\rm j}$ are degenerate for a flux-limited sample. The parameter set $(L_{\rm \gamma}, \theta_{\rm j})=(4.9\times 10^{49} \rm {erg\ s}^{-1},\ 0.054 {rad})$ gives the best consistency for the current {\em Swift} GRB sample. Considering the beaming effect, the derived intrinsic local GRB rate accordingly is $2.85\times 10^2$ Gpc$^{-3}$ yr$^{-1}$, inferring that $\sim 0.59$ of Type Ib/c SNe may be accompanied by a GRB.Comment: 25pages, 7 figures. ApJ in pres