Methamphetamine induces Shati/Nat8L expression in the mouse nucleus accumbens via CREB- and dopamine D1 receptor-dependent mechanism

Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated Nacetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/ Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction

Performance limits of the three MEMS inertial energy generator transduction types

Accepted versio

TP63 and TP73 in cancer, an unresolved “family” puzzle of complexity, redundancy and hierarchy

AbstractTP53 belongs to a small gene family that includes, in mammals, two additional paralogs, TP63 and TP73. The p63 and p73 proteins are structurally and functionally similar to p53 and their activity as transcription factors is regulated by a wide repertoire of shared and unique post-translational modifications and interactions with regulatory cofactors. p63 and p73 have important functions in embryonic development and differentiation but are also involved in tumor suppression. The biology of p63 and p73 is complex since both TP63 and TP73 genes are transcribed into a variety of different isoforms that give rise to proteins with antagonistic properties, the TA-isoforms that act as tumor-suppressors and DN-isoforms that behave as proto-oncogenes. The p53 family as a whole behaves as a signaling “network” that integrates developmental, metabolic and stress signals to control cell metabolism, differentiation, longevity, proliferation and death. Despite the progress of our knowledge, the unresolved puzzle of complexity, redundancy and hierarchy in the p53 family continues to represent a formidable challenge

Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis

We have compiled the p73-mediated cell cycle arrest and apoptosis pathways. p73 is a member of the p53 family, consisting of p53, p63 and p73. p73 exists in several isoforms, presenting different domain structures. p73 functions not only as a tumor suppressor in apoptosis but also as differentiator in embryo development. p53 mutations are responsible for half of the human cancers; p73 can partially substitute mutant p53 as tumor suppressor. The pathways we assembled create a p73-centered network consisting of 53 proteins and 176 interactions. We clustered our network into five functional categories: Upregulation, Activation, Suppression, Transcriptional Activity and Degradation. Our literature searches led to discovering proteins (c-Jun and pRb) with apparent opposing functional effects; these indicate either currently missing proteins and interactions or experimental misidentification or functional annotation. For convenience, here we present the p73 network using the molecular interaction map (MIM) notation. The p73 MIM is unique amongst MIMs, since it further implements detailed domain features. We highlight shared pathways between p53 and p73. We expect that the compiled and organized network would be useful to p53 family-based studies

Identification and Classification of Conserved RNA Secondary Structures in the Human Genome

The discoveries of microRNAs and riboswitches, among others, have shown functional RNAs to be biologically more important and genomically more prevalent than previously anticipated. We have developed a general comparative genomics method based on phylogenetic stochastic context-free grammars for identifying functional RNAs encoded in the human genome and used it to survey an eight-way genome-wide alignment of the human, chimpanzee, mouse, rat, dog, chicken, zebra-fish, and puffer-fish genomes for deeply conserved functional RNAs. At a loose threshold for acceptance, this search resulted in a set of 48,479 candidate RNA structures. This screen finds a large number of known functional RNAs, including 195 miRNAs, 62 histone 3′UTR stem loops, and various types of known genetic recoding elements. Among the highest-scoring new predictions are 169 new miRNA candidates, as well as new candidate selenocysteine insertion sites, RNA editing hairpins, RNAs involved in transcript auto regulation, and many folds that form singletons or small functional RNA families of completely unknown function. While the rate of false positives in the overall set is difficult to estimate and is likely to be substantial, the results nevertheless provide evidence for many new human functional RNAs and present specific predictions to facilitate their further characterization

New Landscapes and Horizons in Hepatocellular Carcinoma Therapy

Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient

UV Photochemistry of Benzene and Cyclohexadienyl Radical in Solid Parahydrogen

Matrix-isolation spectroscopy in solid parahydrogen is a powerful technique for the study of photochemical reactions in detail. It is especially suited for the detection of chemical intermediates and unstable molecular products of photochemical reactions that are otherwise difficult to observe using other conventional spectroscopic techniques. Here, we have revisited UV photochemistry of benzene induced by 193 and 253.7 nm excitations by matrix-isolation infrared spectroscopy using solid parahydrogen as a host matrix. In addition to the formation of benzvalene, fulvene, and Dewar benzene as photoproducts of the UV photolysis of benzene, we have confirmed the production of cyclohexadienyl radical in solid parahydrogen as an intermediate species for a ring-opening reaction to 1,3,5-hexatriene. Moreover, we have identified 1,3-hexadien-5-yne and <i>o</i>-benzyne as minor products of the photochemical reaction. The reaction mechanisms of these species based on the analysis of FTIR spectra and quantum chemical calculations are discussed

Luciferase assay using various fragments of <i>Shati/Nat8L</i> promoter regions in PC12 cells.

<p>(A) PC12 cells transfected with PGl3-Basic Vector containing five kinds of promoter region for the luciferase assay. Detection of luciferase 22 h after 2 h-methamphetamine (METH) stimulation using a Dual Luciferase Assay kit. ^##<i>p</i> < 0.05 and ^###<i>p</i> < 0.001 vs luciferase activities on PC12 cells comparing with −980 bp and −680 bp vector (Newman–Keuls post hoc test). <i>n</i> = 4. (<b>B</b>) METH induces activities of transcriptional factors in PC12 cells treated with METH.*<i>p</i> < 0.05 and **<i>p</i> < 0.01 vs PBS (Student’s <i>t</i>-test). <i>n</i> = 4. Error bars represent the SEM.</p

Effects of Methamphetamine (METH) on <i>Shati/Nat8L</i> mRNA in the Nucleus Accumbens (NAc) of mice and cultured cells.

<p><b>(A)</b><i>Shati/Nat8L</i> mRNA levels in NAc of mice repeatedly administered saline or METH (2 mg/kg/day) for 6 days. NAc samples taken 2 h after the last treatment. <i>n</i> = 4. *<i>p</i> < 0.05 vs saline group (Student’s <i>t</i>-test). Increasing levels of <i>Shati/Nat8L</i> mRNA induced by METH (1 μM) in (B) PC12 <b>(B)</b> and (C) Neuro2a cells. These cells were exposed to METH for 2 h. After the procedure, samples were taken for measurement of <i>Shati/Nat8L</i> mRNA **<i>p</i> < 0.001 vs PBS group (Student’s <i>t</i>-test). <i>n</i> = 4. Error bars represent the SEM.</p