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Pirh2 is a p53 inducible gene that encodes a RING-H2 domain and is proposed to be a main regulator of p53 protein, thus fine tuning the DNA damage response. Pirh2 interacts physically with p53 and promotes its MDM2-independent ubiquitination and subsequent degradation as well as participates in an auto-regulatory feedback loop that controls p53 function. Pirh2 also self-ubiquitinates. Interestingly, Pirh2 is overexpressed in a wide range of human tumors. In this study, we investigated the domains and residues essential for Pirh2 self-ubiquitination. Deletions were made in each of the three major domains of Pirh2: the N-terminal domain (NTD), Ring domain (RING), and C-terminal domain (CTD). The effects of these deletions on Pirh2 self-ubiquitination were then assessed using in vitro ubiquitination assays. Our results demonstrate that the RING domain is essential, but not sufficient, for Pirh2 self-ubiquitination and that residues 240–250 of the C-terminal domain are also essential. Our results demonstrate that Pirh2 mediated p53 polyubiquitination occurs mainly through the K48 residue of ubiquitin in vitro. Our data further our understanding of the mechanism of Pirh2 self-ubiquitination and may help identify valuable therapeutic targets that play roles in reducing the effects of the overexpression of Pirh2, thus maximizing p53''s response to DNA damage. 相似文献
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Johanna T. W. Wigman Jim van Os Evert Thiery Catherine Derom Dina Collip Nele Jacobs Marieke Wichers 《PloS one》2013,8(3)
Background
Mental disorders may be reducible to sets of symptoms, connected through systems of causal relations. A clinical staging model predicts that in earlier stages of illness, symptom expression is both non-specific and diffuse. With illness progression, more specific syndromes emerge. This paper addressed the hypothesis that connection strength and connection variability between mental states differ in the hypothesized direction across different stages of psychopathology.Methods
In a general population sample of female siblings (mostly twins), the Experience Sampling Method was used to collect repeated measures of three momentary mental states (positive affect, negative affect and paranoia). Staging was operationalized across four levels of increasing severity of psychopathology, based on the total score of the Symptom Check List. Multilevel random regression was used to calculate inter- and intra-mental state connection strength and connection variability over time by modelling each momentary mental state at t as a function of the three momentary states at t-1, and by examining moderation by SCL-severity.Results
Mental states impacted dynamically on each other over time, in interaction with SCL-severity groups. Thus, SCL-90 severity groups were characterized by progressively greater inter- and intra-mental state connection strength, and greater inter- and intra-mental state connection variability.Conclusion
Diagnosis in psychiatry can be described as stages of growing dynamic causal impact of mental states over time. This system achieves a mode of psychiatric diagnosis that combines nomothetic (group-based classification across stages) and idiographic (individual-specific psychopathological profiles) components of psychopathology at the level of momentary mental states impacting on each other over time. 相似文献35.
Jeremy S. Schaefer Dina Montufar-Solis Niyati Nakra Nadarajah Vigneswaran John R. Klein 《PloS one》2013,8(2)
Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquinsan/san mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquinsan/san mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquingt/gt mice) had small intestinal inflammation that mimicked that of Roquinsan/san mice. MLN cells in Roquinsan/san mice consisted of activated proliferating T cells, and had increased numbers of CD44hi CD62Llo KLRG1+ short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquinsan/san mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquinsan/san mice consisted of a high proportion of Gr-1+ T cells that included IL-17A+ cells and CD8+ IFN-γ+ cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquinsan/san mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn''s disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process. 相似文献
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Albarakati Alaa Jameel A. Baty Roua S. Aljoudi Ahmad M. Habotta Ola A. Elmahallawy Ehab K. Kassab Rami B. Abdel Moneim Ahmed E. 《Molecular biology reports》2020,47(4):2591-2603
Molecular Biology Reports - Lead (Pb) is one of the most common heavy metal pollutants affecting living organisms. It induces nephrotoxicity with significant alterations in renal structure and... 相似文献
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Nadia M. S. Arafa Mona Abdel-Rahman Manal F. El-khadragy Rami B. Kassab 《Neurochemical research》2013,38(1):174-185
The neuroprotective effect of Nigella sativa (NS) on amino acid neurotransmitters alteration in pentylenetetrazole (PTZ) and ciprofloxacin (CFX) treated rats in different brain regions was examined. The oral administration of NS induced an elevation in aspartate and glutamate contents, whereas the levels of GABA and glycine were decreased. Furthermore, the treated groups with PTZ and CFX caused a decrease in aspartate, glutamate and total antioxidant capacity levels, while the concentrations of GABA and glycine were increased after 14 days. Moreover, the pre- and post-treatment with NS in PTZ and CFX treated rats return the levels of these parameters near control values. So, it could be concluded that the treatment with CFX induced imbalance between the excitatory and the inhibitory amino acids which may lead to the initiation of epileptic seizures and the treatment with NS was found to ameliorate these neurological defects which reflect its potent antiepileptic activity. 相似文献
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Barbara Tomassetti Annalina Lombardi Enzo Cerasani Antonio Di Sabatino Loretta Pace Dina Ammazzalorso Marco Verdecchia 《Aerobiologia》2013,29(1):55-70
Airborne particles (pollens and fungal spores) are recognized as important causes of allergies and many other pathologies whose main symptoms are usually associated with respiratory problems. In addition, these particles seem to be responsible for clinical symptoms of oculorhinitis and bronchial asthma. Many authors showed how pollen and spore concentrations are critically linked to meteorological conditions, while other studies investigated the possibility to estimate these concentrations through meteorological parameters. So, many different approaches have been proposed, and one of the most sophisticated is based on the use of a complex artificial neural network architecture. Once the neural device is calibrated using simultaneous time series of observed meteorological parameters and airborne biological particles, it is straightforward to use the Neural Network to predict spore concentrations using operational Limited Area Meteorological Model. In a previous work, it has been shown that the MM5 meteorological model developed by National Center for Atmospheric Research and Pennsylvania State University can be coupled with the above-cited neural predictor to provide a good prediction of Alternaria and Pleospora spore in the location of L’Aquila (Central Italy). Following the same approach, this work aims to provide the mapping of spore concentration over a wide area covered by high-resolution meteorological prediction in Central Italy. The complex patterns of fungal spore concentrations in selected areas will be described, and the high temporal variability of such fields will be discussed as well. The possibility to infer useful information from the predicted pattern of spore concentrations is discussed, as an example it appears that for people suffering from allergy to fungal spores is more comfortable to spend summertime close to the east coast of Italian Peninsula respect to the west coast. A further step of this work may easily lead to an operational use of the model for supporting the clinical management of allergies and for establishing a preventive strategy in agriculture to avoid unsafe and useless pollution of atmosphere, crops and fields. 相似文献