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41.
William R. Scott Cigdem Gelegen Keval Chandarana Efthimia Karra Ahmed Yousseif Chloé Amouyal Agharul I. Choudhury Fabrizio Andreelli Dominic J. Withers Rachel L. Batterham 《PloS one》2013,8(3)
Background
Neuronatin (NNAT) is an endoplasmic reticulum proteolipid implicated in intracellular signalling. Nnat is highly-expressed in the hypothalamus, where it is acutely regulated by nutrients and leptin. Nnat pre-mRNA is differentially spliced to create Nnat-α and -β isoforms. Genetic variation of NNAT is associated with severe obesity. Currently, little is known about the long-term regulation of Nnat.Methods
Expression of Nnat isoforms were examined in the hypothalamus of mice in response to acute fast/feed, chronic caloric restriction, diet-induced obesity and modified gastric bypass surgery. Nnat expression was assessed in the central nervous system and gastrointestinal tissues. RTqPCR was used to determine isoform-specific expression of Nnat mRNA.Results
Hypothalamic expression of both Nnat isoforms was comparably decreased by overnight and 24-h fasting. Nnat expression was unaltered in diet-induced obesity, or subsequent switch to a calorie restricted diet. Nnat isoforms showed differential expression in the hypothalamus but not brainstem after bypass surgery. Hypothalamic Nnat-β expression was significantly reduced after bypass compared with sham surgery (P = 0.003), and was positively correlated with post-operative weight-loss (R2 = 0.38, P = 0.01). In contrast, Nnat-α expression was not suppressed after bypass surgery (P = 0.19), and expression did not correlate with reduction in weight after surgery (R2 = 0.06, P = 0.34). Hypothalamic expression of Nnat-β correlated weakly with circulating leptin, but neither isoform correlated with fasting gut hormone levels post- surgery. Nnat expression was detected in brainstem, brown-adipose tissue, stomach and small intestine.Conclusions
Nnat expression in hypothalamus is regulated by short-term nutrient availability, but unaltered by diet-induced obesity or calorie restriction. While Nnat isoforms in the hypothalamus are co-ordinately regulated by acute nutrient supply, after modified gastric bypass surgery Nnat isoforms show differential expression. These results raise the possibility that in the radically altered nutrient and hormonal milieu created by bypass surgery, resultant differential splicing of Nnat pre-mRNA may contribute to weight-loss. 相似文献42.
Giovanna Poce Robert H. Bates Salvatore Alfonso Martina Cocozza Giulio Cesare Porretta Lluís Ballell Joaquin Rullas Fátima Ortega Alessandro De Logu Emanuela Agus Valentina La Rosa Maria Rosalia Pasca Edda De Rossi Baojie Wae Scott G. Franzblau Fabrizio Manetti Maurizio Botta Mariangela Biava 《PloS one》2013,8(2)
1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in
vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED99 of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery. 相似文献
43.
Background
Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native α-helical structures and their self-assembly into nonnative intermolecular β-sheets has been proposed to trigger amyloid fibril formation in Alzheimer’s and Parkinson’s diseases.Methods
Here, we use a battery of biophysical techniques to elucidate the conformational conversion of native α-helices into amyloid fibrils using an all-α FF domain as a model system.Results
We show that under mild denaturing conditions at low pH this FF domain self-assembles into amyloid fibrils. Theoretical and experimental dissection of the secondary structure elements in this domain indicates that the helix 1 at the N-terminus has both the highest α-helical and amyloid propensities, controlling the transition between soluble and aggregated states of the protein.Conclusions
The data illustrates the overlap between the propensity to form native α-helices and amyloid structures in protein segments.Significance
The results presented contribute to explain why proteins cannot avoid the presence of aggregation-prone regions and indeed use stable α-helices as a strategy to neutralize such potentially deleterious stretches. 相似文献44.
Roberta Grande Domenico Corsi Raffaello Mancini Donatello Gemma Fabrizio Ciancola Isabella Sperduti Lorena Rossi Agnese Fabbri Maria G. Diodoro Enzo Ruggeri Germano Zampa Sara Bianchetti Teresa Gamucci 《PloS one》2013,8(12)
Background
Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC.Methods
RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively.Results
834 patients with T3N0 CC were recruited. Median age was 69 (29–93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1–76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3–24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints.In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005).Conclusions
Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC. 相似文献45.
Xingxing Cai Jing Fan Zhuxi Jiang Barbara Basso Francesco Sala Alberto Spada Fabrizio Grassi Bao-Rong Lu 《PloS one》2013,8(11)
The characterization of genetic divergence and relationships of a set of germplasm is essential for its efficient applications in crop breeding and understanding of the origin/evolution of crop varieties from a given geographical region. As the largest rice producing country in Europe, Italy holds rice germplasm with abundant genetic diversity. Although Italian rice varieties and the traditional ones in particular have played important roles in rice production and breeding, knowledge concerning the origin and evolution of Italian traditional varieties is still limited. To solve the puzzle of Italian rice origin, we characterized genetic divergence and relationships of 348 rice varieties from Italy and Asia based on the polymorphisms of microsatellite fingerprints. We also included common wild rice O. rufipogon as a reference in the characterization. Results indicated relatively rich genetic diversity (H
e = 0.63-0.65) in Italian rice varieties. Further analyses revealed a close genetic relationship of the Italian traditional varieties with those from northern China, which provides strong genetic evidence for tracing the possible origin of early established rice varieties in Italy. These findings have significant implications for the rice breeding programs, in which appropriate germplasm can be selected from a given region and utilized for transferring unique genetic traits based on its genetic diversity and evolutionary relationships. 相似文献
46.
Luca Madaro Fabrizio Antonangeli Annarita Favia Bianca Esposito Filippo Biamonte Marina Bouché Elio Ziparo Gigliola Sica Antonio Filippini Alessio D'Alessio 《Journal of cellular biochemistry》2013,114(8):1843-1851
Caveolin‐1 (CAV1) is the principal structural component of caveolae which functions as scaffolding protein for the integration of a variety of signaling pathways. In this study, we investigated the involvement of CAV1 in endothelial cell (EC) functions and show that siRNA‐induced CAV1 silencing in the human EC line EA.hy926 induces distinctive morphological changes, such as a marked increase in cell size and formation of stress fibers. Design‐based stereology was employed in this work to make unbiased quantification of morphometric properties such as volume, length, and surface of CAV1 silenced versus control cells. In addition, we showed that downregulation of CAV1 affects cell cycle progression at G1/S phase transition most likely by perturbation of AKT signaling. With the aim to assess the contribution of CAV1 to typical biological processes of EC, we report here that CAV1 targeting affects cell migration and matrix metalloproteinases (MMPs) activity, and reduces angiogenesis in response to VEGF, in vitro. Taken together our data suggest that the proper expression of CAV1 is important not only for maintaining the appropriate morphology and size of ECs but it might represent a prospective molecular target for studying key biological mechanisms such as senescence and tumorigenesis. J. Cell. Biochem. 114: 1843–1851, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
47.
Roman Borovec Fabrizio Menardo Massimo Meregalli 《Zoological Journal of the Linnean Society》2013,167(2):243-258
The genus Holcophloeus gen. nov. is here proposed to include Trachyphloeus cruciatus Seidlitz, 1868, and two new species native to North Africa, based on a phylogenetic analysis and an evaluation of the diagnostic characters. The taxonomic position of Holcophloeus in relation to the tribes Trachyphloeini Lacordaire, 1863, and Holcorhinini Desbrochers, 1898, is discussed, and the new genus is attributed to the Holcorhinini. Holcophloeus laurae sp. nov. from south‐eastern Morocco and Holcophloeus weilli sp. nov. from northern Libya are described and illustrated and a key to the species of the new genus is given. The lectotype of Trachyphloeus cruciatus Seidlitz, 1868, is designated. The genus Massimiellus Borovec, 2009, is transferred from Trachyphloeini to Holcorhinini. © 2013 The Linnean Society of London 相似文献
48.
Alessandro Romano Agostino Sorgonà Antonio Lupini Fabrizio Araniti Piergiorgio Stevanato Giovanni Cacco Maria Rosa Abenavoli 《Acta Physiologiae Plantarum》2013,35(3):853-865
The identification of morpho-physiological traits related to drought tolerance and high yield potential is a challenge when selecting sugar beet genotypes with greater tolerance to water stress. In this paper, root morphological parameters, antioxidant systems, leaf relative water content (RWC) and H+-ATPase activity as key morpho-physiological traits involved in drought tolerance/susceptibility of sugar beet were studied. Genotypes showing a different drought tolerance index (DTI) but a similar yield potential, under moderate (?0.6 Mpa) and severe (?1.2 MPa) water stress, were selected and their morpho-physiological traits were investigated. The results showed a wide genetic variation in morpho-physiological parameters which demonstrated the different adaptive strategies under moderate and severe drought conditions in sugar beet. In particular, an efficient antioxidant system and redox signalling made some sugar beet genotypes more tolerant to drought stress. The alternative strategy of other genotypes was the reduction of root tissue density, which produced a less dense root system improving the axial hydraulic conductivity. These results could be considered as interesting challenge for a better understanding of the drought tolerance mechanisms in sugar beet. 相似文献
49.
Annalisa Vilasi Silvia Vilasi Rocco Romano Fausto Acernese Fabrizio Barone Maria Luisa Balestrieri Rosa Maritato Gaetano Irace Ivana Sirangelo 《Journal of cellular physiology》2013,228(6):1359-1367
A range of debilitating human diseases is known to be associated with the formation of stable highly organized protein aggregates known as amyloid fibrils. The early prefibrillar aggregates behave as cytotoxic agents and their toxicity appears to result from an intrinsic ability to impair fundamental cellular processes by interacting with cellular membranes, causing oxidative stress and increase in free Ca2+ that lead to apoptotic or necrotic cell death. However, specific signaling pathways that underlie amyloid pathogenicity remain still unclear. This work aimed to clarify cell impairment induced by amyloid aggregated. To this end, we used a combined proteomic and one‐dimensional 1H‐NMR approach on NIH‐3T3 cells exposed to prefibrillar aggregates from the amyloidogenic apomyoglobin mutant W7FW14F. The results indicated that cell exposure to prefibrillar aggregates induces changes of the expression level of proteins and metabolites involved in stress response. The majority of the proteins and metabolites detected are reported to be related to oxidative stress, perturbation of calcium homeostasis, apoptotic and survival pathways, and membrane damage. In conclusion, the combined proteomic and 1H‐NMR metabonomic approach, described in this study, contributes to unveil novel proteins and metabolites that could take part to the general framework of the toxicity induced by amyloid aggregates. These findings offer new insights in therapeutic and diagnostic opportunities. J. Cell. Physiol. 228: 1359–1367, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
50.
Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr668 of ß-CTF because phosphorylation of Thr668 is increased in AD cases. We created a knock-in mouse bearing a Thr668Ala mutation (APPTA mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr668 is a viable therapeutic strategy for human dementias. 相似文献