The role of the TRAF-interacting protein in proliferation and differentiation.

Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. Addition of ubiquitin moieties to proteins is carried out by the sequential action of three enzymes: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; and E3, ubiquitin ligase. The TRAF-interacting protein (TRAIP, TRIP, RNF206) functions as Really Interesting New Gene (RING)-type E3 ubiquitin ligase, but its physiological substrates are not yet known. TRAIP was reported to interact with TRAF [tumor necrosis factor (TNF) receptor-associated factors] and the two tumor suppressors CYLD and Syk (spleen tyrosine kinase). Ectopically expressed TRAIP was shown to inhibit nuclear factor-kappa B (NF-κB) signalling. However, recent results suggested a role for TRAIP in biological processes other than NF-κB regulation. Knock-down of TRAIP in human epidermal keratinocytes repressed cellular proliferation and induced a block in the G1/S phase of the cell cycle without affecting NF-κB signalling. TRAIP is necessary for embryonal development as mutations affecting the Drosophila homologue of TRAIP are maternal effect-lethal mutants, and TRAIP knock-out mice die in utero because of aberrant regulation of cell proliferation and apoptosis. These findings underline the tight link between TRAIP and cell proliferation. In this review, we summarize the data on TRAIP and put them into a larger perspective regarding the role of TRAIP in the control of tissue homeostasis.

Preferential assembly of epithelial sodium channel (ENaC) subunits in Xenopus oocytes: role of furin-mediated endogenous proteolysis.

The epithelial sodium channel (ENaC) is preferentially assembled into heteromeric alphabetagamma complexes. The alpha and gamma (not beta) subunits undergo proteolytic cleavage by endogenous furin-like activity correlating with increased ENaC function. We identified full-length subunits and their fragments at the cell surface, as well as in the intracellular pool, for all homo- and heteromeric combinations (alpha, beta, gamma, alphabeta, alphagamma, betagamma, and alphabetagamma). We assayed corresponding channel function as amiloride-sensitive sodium transport (I(Na)). We varied furin-mediated proteolysis by mutating the P1 site in alpha and/or gamma subunit furin consensus cleavage sites (alpha(mut) and gamma(mut)). Our findings were as follows. (i) The beta subunit alone is not transported to the cell surface nor cleaved upon assembly with the alpha and/or gamma subunits. (ii) The alpha subunit alone (or in combination with beta and/or gamma) is efficiently transported to the cell surface; a surface-expressed 65-kDa alpha ENaC fragment is undetected in alpha(mut)betagamma, and I(Na) is decreased by 60%. (iii) The gamma subunit alone does not appear at the cell surface; gamma co-expressed with alpha reaches the surface but is not detectably cleaved; and gamma in alphabetagamma complexes appears mainly as a 76-kDa species in the surface pool. Although basal I(Na) of alphabetagamma(mut) was similar to alphabetagamma, gamma(mut) was not detectably cleaved at the cell surface. Thus, furin-mediated cleavage is not essential for participation of alpha and gamma in alphabetagamma heteromers. Basal I(Na) is reduced by preventing furin-mediated cleavage of the alpha, but not gamma, subunits. Residual current in the absence of furin-mediated proteolysis may be due to non-furin endogenous proteases.

Role of microRNAs in the pathogenesis of Ewing's sarcoma

SummaryEwing's sarcoma family tumors (ESFT) are the second most frequent cancer of bone in adolescents and young adults. ESFT are characterized by a chromosomal translocation that involves the 5' segment of the EWSR1 gene and the 3' segment of an ets transcription factor family member gene. In 85% of cases the chromosomal translocation generates the fusion protein EWSR1-FLI-1. Recent work from our laboratory identified mesenchymal stem cells (MSC) as the putative cell of origin of ESFT and characterized a CD133+ subpopulation of ESFT cells with tumor initating and self-renewal capacity, known as cancer stem cells (CSC). MicroRNAs (miRNAs) are small non-coding RNA that regulate protein expression at the post-transcriptional level by either repressing translation or destabilizing mRNA. MiRNAs participate in several biological processes including cell proliferation and differentiation. We used miRNA expression profile comparison between MSC and ESFT cell lines and CD133+ ESFT cells and CD133" ESFT cells to investigate the role of miRNAs in ESFT pathogenesis. MiRNA expression profile comparison of MSC and ESFT cell lines identified 35 differentially expressed miRNAs. Among these was down-regulation of let-7a which results, in part, by the direct repression of let-7a-l promoter by EWSR1-FLI-1. Overexpression of let-7a in ESFT cells blocked ESFT tumorigenesis through an High-motility group AT-hook2 (HMGA2)-mediated mechanism.MiRNA profiling of CD133+ ESFT and CD 133" ESFT cells revealed a broad repression of miRNAs in CD133+ ESFT mediated by down-regulation of TARBP2, a central regulator of the miRNA maturation pathway. Down-regulation of TARBP2 in ESFT cell lines results in a miRNA expression profile reminescent of that observed in CD133+ ESFT and associated with increased tumorigenicity. Enhancement of TARBP2 activity using the antibiotic enoxacin or overexpression of miRNA-143 or miRNA-145, two targets of TARBP2, impaired ESFT CSC self-renewal and block ESFT tumorigenicity. Moreover in vivo administration of synthetic let- 7a, miRNA-143 or miRNA-145 blocks ESFT tumor growth.Thus, dysregulation of miRNA expression is a key feature in ESFT pathogenesis and restoration of their expressions might be used as a new therapeutic tool.RésuméLe sarcome d'Ewing est la deuxième tumeur osseuse la plus fréquente chez l'enfant et le jeune adolescent. Le sarcome d'Ewing est caractérisé par une translocation chromosomique qui produit une protéine de fusion EWSR1-FLI-1. Des récents travaux ont identifié les cellules mésenchymateuses souches (MSC) comme étant les cellules à l'origine du sarcome d'Ewing ainsi qu'une sous-population de cellules exprimant le marqueur CD 133, dans le sarcome d'Ewing connu comme les cellules cancéreuses souches (CSC). Ces cellules ont la capacité d'initier la croissance tumorale et possèdent des propriétés d'auto-renouvellement. Les microRNAs (miRNAs) sont de petits ARN qui ne codent pas pour des protéines et qui contrôlent l'expression des protéines en bloquant la traduction ou en dégradant l'ARNm. Les miRNAs participent à différents processus biologiques comme la prolifération et la différenciation cellulaires.Le but de ce travail est d'étudier le rôle des miRNAs dans le sarcome d'Ewing. Un profil d'expression de miRNAs entre les MSC et des lignées cellulaires de sarcome d'Ewing a mis en évidence 35 miRNAs différemment exprimés. Parmi ceux-ci, la répression de let-7a est liée à la répression directe du promoteur de let-7a-l par EWSR-FLI-1. La sur-expression de let-7a dans des lignées cellulaires de sarcome d'Ewing inhibe leur croissance tumorale. Cette inhibition de croissance tumorale est régulée par la protéine high-motility group AT-hook2 (HMGA2).Un profil d'expression de miRNAs entre les cellules du sarcome d'Ewing CD133+ et CD133" montre une sous-expression d'un grand nombre de miRNAs dans les cellules CD133+ par rapport aux cellules CD133". Cette différence d'expression de miRNAs est due à la répression du gène TARBP2 qui participe à la maturation des miRNAs. La suppression de TARBP2 dans des cellules d'Ewing induit un profil d'expression de miRNAs similaire aux cellules CD133+ du sarcome d'Ewing et augmente la tumorigenèse des lignées cellulaires. De plus l'utilisation d'enoxacin, une molécule qui augmente l'activité de TARBP2 ou la sur- expression des miRNA143 ou miRNA-145 dans les CSC du sarcome d'Ewing bloque l'auto- renouvellement des cellules et la croissance tumorale. Finalement, l'administration de let-7a, miRNA-143 ou miRNA-145, dans des souris bloque la croissance du sarcome d'Ewing. Ces résultats indiquent que la dysrégulation des miRNAs participe à la pathogenèse du sarcome d'Ewing et que les miRNAs peuvent être utilisés comme des agents thérapeutiques.

Role of surgery in the management of brain arteriovenous malformations: prospective cohort study.

BACKGROUND AND PURPOSE: Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. METHODS: Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of ≥2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). RESULTS: A total of 7.7% of patients with Spetzler-Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler-Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. CONCLUSIONS: Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler-Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler-Ponce C bAVMs.

Multinational Firms’ Heterogeneity in Tax Responsiveness: the Role of Transfer Pricing

In this paper we show that the ability of multinational firms to manipulate transfer prices affects the tax sensitivity of foreign direct investment (FDI). We offer a model of international capital allocation where firms are heterogeneous in their ability to manipulate transfer prices. Perhaps paradoxically, we show that the ability to shift profits can make parent companies' investment more sensitive to host-country tax rates, as long as investors expect fisscal authorities to use price and profit detection methods. We then offer a comprehensive empirical study to test our predictions in the case of Japanese FDI. We exploit the finding that the unobservable ability to manipulate transfer prices is correlated with whole ownership of a±liates and R&D expenditure. Based on country, parent firm and sector characteristics, we estimate an investment equation on a sample of 3614 Japanese affiliates in 49 emerging countries. We obtain a greater semi-elasticity of investment to the statutory tax rate in a±liates that are wholly-owned and that have R&D intensive parents. We interpret these results as indirect evidence that abusive transfer pricing is one of the determinants of FDI activity.

The role of attention in multisensory integration processes

Report for the scientific sojourn at the University of Queensland, Australia, between June to October 2007. The integration of sensory information coming from different modalities is a subjectively effortless and automatic process. However, recent findings converge on the idea that there might be some limitations on how much multisensory information can our brains integrate at a given moment. The overall objective of this research visit was to expand and reinforce our current line of research addressing the role that attention plays on the mechanisms responsible for multisensory integration. There is also a critical review of the literature as well as a list of research questions of potential interest in the area of the neuropsychology of multisensory attention.

Alveolar echinococcosis of the liver: Diffusion-weighted MRI findings and potential role in lesion characterisation

PURPOSE: To report the diffusion-weighted MRI findings in alveolar echinococcosis (AE) of the liver and evaluate the potential role of apparent diffusion coefficients (ADCs) in the characterisation of lesions. MATERIALS AND METHODS: We retrospectively included 22 patients with 63 AE liver lesions (≥1cm), examined with 3-T liver MRI, including a free-breathing diffusion-weighted single-shot echo-planar imaging sequence (b-values=50, 300 and 600s/mm(2)). Two radiologists jointly assessed the following lesion features: size, location, presence of cystic and/or solid components (according to Kodama's classification system), relative contrast enhancement, and calcifications (on CT). The ADCtotal, ADCmin and ADCmax were measured in each lesion and the surrounding liver parenchyma. RESULTS: Three type 1, 19 type 2, 17 type 3, three type 4 and 21 type 5 lesions were identified. The mean (±SD) ADCtotal, ADCmin and ADCmax for all lesions were 1.73±0.50, 0.76±0.38 and 2.63±0.76×10(-3)mm(2)/s, respectively. The mean ADCtotal for type 1, type 2, type 3, type 4 and type 5 lesions were 1.97±1.01, 1.76±0.53, 1.73±0.41, 1.15±0.42 and 1.76±0.44×10(-3)mm(2)/s, respectively. No significant differences were found between the five lesion types, except for type 4 (p=0.0363). There was a significant correlation between the presence of a solid component and low ADCmin (r=0.39, p=0.0016), whereas an inverse correlation was found between the relative contrast enhancement and ADCtotal (r=-0.34, p=0.0072). CONCLUSION: The ADCs of AE lesions are relatively low compared to other cystic liver lesions, which may help in the differential diagnosis. Although ADCs are of little use to distinguish between the five lesion types, their low value reflects the underlying solid component.

Sex difference and the role of leptin in the association between high-sensitivity C-reactive protein and adiposity in two different populations.

Elevated high-sensitivity C-reactive protein (hs-CRP) concentration is associated with an increased risk of cardiovascular disease but this association seems to be largely mediated via conventional cardiovascular risk factors. In particular, the association between hs-CRP and obesity has been extensively demonstrated and correlations are stronger in women than men. We used fractional polynomials-a method that allows flexible modeling of non linear relations-to investigate the dose/response mathematical relationship between hs-CRP and several indicators of adiposity in Caucasians (Switzerland) and Africans (Seychelles) surveyed in two population-based studies. This relationship was non-linear exhibiting a steeper slope for low levels of hs-CRP and a higher level in women. The observed sex difference in the relationship between hs-CRP and adiposity almost disappeared upon adjustment for leptin, suggesting that these sex differences might be partially mediated, by leptin. All these relationship were similar in Caucasians and Africans. This is the first report on a non-linear relation, stratified by gender, between hs-CRP and adiposity.

Role of thyroid hormones and their receptors in peripheral nerve regeneration.

After peripheral nerve injury in adult mammals, reestablishment of functional connections depends on several parameters including neurotrophic factors, the extracellular matrix, and hormones. However, little is known about the contribution of hormones to peripheral nerve regeneration. Thyroid hormones, which are required for the development and maturation of the central nervous system, are also important for the development of peripheral nerves. The action of triiodothyronine (T3) on responsive cells is mediated through nuclear thyroid hormone receptors (TRs) which modulate the expression of specific genes in target cells. Thus, to study the effect of T3, it is first necessary to know whether the target tissues possess TRs. The fact that sciatic nerve cells possess functional TRs suggests that these cells can respond to T3 and, as a consequence, that thyroid hormone may be involved in peripheral nerve regeneration. The silicone nerve guide model provides an excellent system to study the action of local administration of T3. Evidence from such studies demonstrate that animals treated locally with T3 at the level of transection have more complete regeneration of sciatic nerve and better functional recovery. Among the possible regulatory mechanisms by which T3 enhances peripheral nerve regeneration is rapid action on both axotomized neurons and Schwann cells which, in turn, produce a lasting and stimulatory effect on peripheral nerve regeneration. It is probable that T3 up- or down-regulates gene expression of one or more growth factors, extracellular matrix, or cell adhesion molecules, all of which stimulate peripheral nerve regeneration. This could explain the greater effect of T3 on nerve regeneration compared with the effect of any one growth factor or adhesion molecule.

The Role of Institutions in Cross-Section Income and Panel Data Growth Models: A Deeper Investigation on the Weakness and Proliferation of Instruments

This paper investigates the role of institutions in determining per capita income levels and growth. It contributes to the empirical literature by using different variables as proxies for institutions and by developing a deeper analysis of the issues arising from the use of weak and too many instruments in per capita income and growth regressions. The cross-section estimation suggests that institutions seem to matter, regardless if they are the only explanatory variable or are combined with geographical and integration variables, although most models suffer from the issue of weak instruments. The results from the growth models provides some interesting results: there is mixed evidence on the role of institutions and such evidence is more likely to be associated with law and order and investment profile; government spending is an important policy variable; collapsing the number of instruments results in fewer significant coefficients for institutions.