Film cooling adiabatic effectiveness measurements of pressure side trailing edge cooling configurations

Nowadays total inlet temperature of gas turbine is far above the permissible metal temperature; as a consequence, advanced cooling techniques must be applied to protect from thermal stresses, oxidation and corrosion the components located in the high pressure stages, such as the blade trailing edge. A suitable design of the cooling system for the trailing edge has to cope with geometric constraints and aerodynamic demands; state-of-the-art of cooling concepts often use film cooling on blade pressure side: the air taken from last compressor stages is ejected through discrete holes or slots to provide a cold layer between hot mainstream and the blade surface. With the goal of ensuring a satisfactory lifetime of blades, the design of efficient trailing edge film cooling schemes and, moreover, the possibility to check carefully their behavior, are hence necessary to guarantee an appropriate metal temperature distribution. For this purpose an experimental survey was carried out to investigate the film covering performance of different pressure side trailing edge cooling systems for turbine blades. The experimental test section consists of a scaled-up trailing edge model installed in an open loop suction type test rig. Measurements of adiabatic effectiveness distributions were carried out on three trailing edge cooling system configurations. The baseline geometry is composed by inclined slots separated by elongated pedestals; the second geometry shares the same cutback configuration, with an additional row of circular film cooling holes located upstream; the third model is equipped with three rows of in-line film cooling holes. Experiments have been performed at nearly ambient conditions imposing several blowing ratio values and using carbon dioxide as coolant in order to reproduce a density ratio close to the engine conditions (DR=1.52). To extend the validity of the survey a comparison between adiabatic effectiveness measurements and a prediction by correlative approach was performed to compare the experimental results with 1D methodologies

Regulation of p73 activity by post-translational modifications

The transcription factor p73 is a member of the p53 family that can be expressed as at least 24 different isoforms with pro- or anti-apoptotic attributes. The TAp73 isoforms are expressed from an upstream promoter and are regarded as bona fide tumor suppressors; they can induce cell cycle arrest/apoptosis and protect against genomic instability. On the other hand, ΔNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TAp73 or p53 to block their transcriptional activities. Therefore, the ratio of TAp73 isoforms to ΔNp73 isoforms is critical for the quality of the response to a genomic insult and needs to be delicately regulated at both transcriptional and post-translational level. In this review, we will summarize the current knowledge on the post-translational regulatory pathways involved to keep p73 protein under control. A comprehensive understanding of p73 post-translational modifications will be extremely useful for the development of new strategies for treating and preventing cancer

p63 and p73, the ancestors of p53

p73 and p63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, p73 and p63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides overlapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for p63 and p73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and p73 knockout mouse phenotypes. Here, we describe the contribution of p63 and p73 to human pathology with emphasis on their roles in tumorigenesis and development

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization.

Members of the p53 tumor suppressor family are expressed as multiple isoforms. Isoforms having an N-terminal transactivation domain are transcriptionally active while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumour suppressor function of TAp73β. This can in principle be due to blocking of the promotor or by direct interaction between both proteins. P63 and p73 can hetero oligomerize through their tetramerization domains and a hetero-oligomer consisting of two p63 and two p73 molecules is thermodyna mically more stable than both homo tetramers. Here we show that hetero tetramer complexes exist also in differentiating keratinocytes. Through structure determination of the hetero tetramer we reveal why this hetero tetramer is the thermodynamically prefer red species. Based on this structure we have created mutants that either enable the formation of only heterotetramers or only homotetramers, allowing to investigate the function of these heterotetramers. Using these tools we show that inhibition of TAp73β in squamous cell carcinomas is due to promotor squelching and not direct interaction

Conformational stability and activity of p73 require a second helix in the tetramerization domain.

p73 and p63, the two ancestral members of the p53 family, are involved in neurogenesis, epithelial stem cell maintenance and quality control of female germ cells. The highly conserved oligomerization domain (OD) of tumor suppressor p53 is essential for its biological functions, and its structure was believed to be the prototype for all three proteins. However, we report that the ODs of p73 and p63 differ from the OD of p53 by containing an additional alpha-helix that is not present in the structure of the p53 OD. Deletion of this helix causes a dissociation of the OD into dimers; it also causes conformational instability and reduces the transcriptional activity of p73. Moreover, we show that ODs of p73 and p63 strongly interact and that a large number of different heterotetramers are supported by the additional helix. Detailed analysis shows that the heterotetramer consisting of two homodimers is thermodynamically more stable than the two homotetramers. No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization.

Members of the p53 tumor suppressor family are expressed as multiple isoforms. Isoforms having an N-terminal transactivation domain are transcriptionally active while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumour suppressor function of TAp73β. This can in principle be due to blocking of the promotor or by direct interaction between both proteins. P63 and p73 can hetero oligomerize through their tetramerization domains and a hetero-oligomer consisting of two p63 and two p73 molecules is thermodyna mically more stable than both homo tetramers. Here we show that hetero tetramer complexes exist also in differentiating keratinocytes. Through structure determination of the hetero tetramer we reveal why this hetero tetramer is the thermodynamically prefer red species. Based on this structure we have created mutants that either enable the formation of only heterotetramers or only homotetramers, allowing to investigate the function of these heterotetramers. Using these tools we show that inhibition of TAp73β in squamous cell carcinomas is due to promotor squelching and not direct interaction