Evolution of NCoR-1 and NCoR-2 corepressor alternative mRNA splicing in placental mammals.

ObjectiveThe NCoR-1 and NCoR-2 corepressors are products of an early gene duplication near the beginning of vertebrate evolution and play both overlapping and divergent roles in development and physiology. Alternative-splicing of NCoR-1 and NCoR-2 further customizes their functions. To better understand the evolutionary basis of this phenomenon we extended our prior study of NCoR-1 and NCoR-2 alternative-splicing to an expanded series of species.ResultsAlternative-splicing of NCoR-2 was observed in all vertebrates examined whereas alternative-splicing of NCoR-1 was largely limited to placental mammals. Notably the most prominent of the NCoR-1 alternative-splicing events specific to the placental lineage, in exon 37 that plays a key role in murine metabolism, mimics in many features an analogous alternative-splicing event that appeared in NCoR-2 much earlier at the beginning of the vertebrate radiation. Detection of additional alternative-splicing events, at exons 28 in NCoR-1 or NCoR-2, was limited to the Rodentia or Primates examined, indicating both corepressor paralogs continued to acquire additional splice variations more recently and independently of one another. Our results suggest that the NCoR-1/NCoR-2 paralogs have been subject to a mix of shared and distinct selective pressures, resulting in the pattern of divergent and convergent alternative-splicing observed in extant species

Corepressor diversification by alternative mRNA splicing is species specific.

BackgroundSMRT and NCoR are corepressor paralogs that help mediate transcriptional repression by a variety of transcription factors, including the nuclear hormone receptors. The functions of both corepressors are extensively diversified in mice by alternative mRNA splicing, generating a series of protein variants that differ in different tissues and that exert different, even diametrically opposite, biochemical and biological effects from one another.ResultsWe report here that the alternative splicing previously reported for SMRT appears to be a relatively recent evolutionary phenomenon, with only one of these previously identified sites utilized in a teleost fish and a limited additional number of the additional known sites utilized in a bird, reptile, and marsupial. In contrast, extensive SMRT alternative splicing at these sites was detected among the placental mammals. The alternative splicing of NCoR previously identified in mice (and shown to regulate lipid and carbohydrate metabolism) is likely to have arisen separately and after that of SMRT, and includes an example of convergent evolution.ConclusionsWe propose that the functions of both SMRT and NCoR have been diversified by alternative splicing during evolution to allow customization for different purposes in different tissues and different species

Application of Graph-Based Chemical Nomenclature to Theoretical and Preparative Chemistry

Development of graph-based systematic names containing mathematical descriptions of molecular graphs is described. Such names can be regarded as compact connection tables. Exploration of the use of graph-based systematic names for information storage and retrieval purposes, in substructure lsearching, and as an aid in pattern recognition, structure-activity relationships, drug design, etc., is discussed

Application of Graph-Based Chemical Nomenclature to Theoretical and Preparative Chemistry

Development of graph-based systematic names containing mathematical descriptions of molecular graphs is described. Such names can be regarded as compact connection tables. Exploration of the use of graph-based systematic names for information storage and retrieval purposes, in substructure lsearching, and as an aid in pattern recognition, structure-activity relationships, drug design, etc., is discussed

POST-TRANSCRIPTIONAL REGULATION OF MAMMALIAN HEAT SHOCK FACTORS

Heat shock transcription factors (HSFs) function to regulate the expression of heatshock proteins (hsps) or molecular chaperones in the cell. Mammalian cells have twowell-characterized HSFs, HSF1 and HSF2. HSF1 functions to regulate the stress-inducedexpression of hsps. The function of HSF2 appears to be in regulating hsp expressionduring development and differentiation.In this work, I describe two distinct HSF1 mRNA isoforms (HSF1-a and HSF1-b)that are generated by alternative splicing of the HSF1 pre-mRNA. The two HSF1 mRNAisoforms result from the inclusion (HSF1-a), or omission (HSF1-b), of a 66 nucleotideexon of the HSF1 gene, which encodes a 22 amino acid sequence. These results showthat the levels of the HSF1-a and HSF1-b mRNA isoforms are regulated in a tissuedependentmanner, with testis expressing predominantly the HSF1-b isoform while heartand brain express primarily the HSF1-a isoform.In addition, I describe two distinct HSF2 mRNA isoforms (HSF2-a and HSF2-b)that are generated by alternative splicing of the HSF2 pre-mRNA. The two HSF2 mRNAisoforms result from the inclusion (HSF2-a), or omission (HSF2-b), of a 54 nucleotideexon of the HSF2 gene, which encodes a 18 amino acid sequence. These results showthat the levels of the HSF2-a and HSF2-b mRNA isoforms are regulated in a tissuedependentmanner, with testis and brain expressing predominantly the HSF2-a isoformwhile heart, liver, and kidney express primarily the HSF2-b isoform. Furthermore, HSF2isoform levels are regulated both in a developmental and cell type dependent manner inthe testis. In a reporter assay, HSF2-a is a 2.6-fold better transcriptional activator thanthe HSF2-b isoform.We have demonstrated also that HSF2, but not HSF1 is a substrate for SUMO-1and SUMO-2 modification in vitro. Consistent with this, we have demonstrated thatHSF2 can interact with a portion of Ubc9, the SUMO-1 conjugating enzyme, in a twohybridassay. We have also shown that GFP-HSF2 colocalizes with SUMO-1 in discretenuclear domain structures in 7% of GFP-HSF2 expressing HeLa cells. Finally, we haveshown that lysine 82 of HSF2 is the primary site of SUMO-1 modification in vitro

Toward a Unitary Commerce Clause: What the Negative Commerce Clause Reveals About the Commerce Power

The Supreme Court’s recent Commerce Clause cases have acknowledged that in order to give full effect to the values of federalism embedded in the Constitution and the related notion that the national government is one of limited powers, some limitation on the commerce power is needed. But without an understanding of why we have the Commerce Clause in the first place, it is difficult to articulate a limitation of the power, much less one that furthers the values of federalism. Unfortunately, the Court’s own precedent in the affirmative Commerce Clause context does not provide doctrinal support for a functionalist approach given that the Court has instead relied on formalistic divides, such as the commercial/noncommercial and activity/inactivity dichotomies. In contrast, the dormant Commerce Clause, or more accurately the negative Commerce Clause, provides a clear statement of the Clause’s purpose, as well as the starting point of a coherent limitation of the commerce power. The doctrine is able to provide this understanding because it has been insulated from the Court’s affirmative Commerce Clause jurisprudence and remains anchored to the Commerce Clause’s purpose. Stated succinctly, the Court has enforced the negative Commerce Clause to achieve the dual interests of interstate commercial harmony and economic union, both of which give doctrinal support to collective action views of federalism. At a minimum, the negative Commerce Clause shows that the Court should and can avoid formalistic categories and instead employ a functionalist inquiry that only permits Congress to regulate commerce among the several states when it furthers the ends of the Commerce Clause

Mr. & Mrs: A Social Cognitive Approach to Understanding how the Marital Context Influences Physical Activity

Recent literature has demonstrated the power of marriage in influencing spousal physical activity behavior, yet the relationship between marriage and activity is not fully understood. The purpose of this qualitative study was to add to current literature by examining the mechanisms within the marital context that may influence physical activity. Employing constructs of Social Cognitive Theory to guide the inquiry, researchers used the qualitative techniques of in-depth interviews, photo elicitation and field notes to gather data in 2012 from twelve spousal pairs (n=24 participants). Results indicated verbal persuasion by husbands encouraged wives, yet verbal persuasion by wives was perceived as nagging by men. Verbal persuasion by husbands increased a few of wives’ sense of self-efficacy (25%), yet the majority of women (83%) felt that persuasion increased motivation, not necessarily confidence. Results also highlighted the power of modeling to increase husbands’ physical activity. Overwhelmingly, men reacted less positively to verbal persuasion than modeling (75%). This study demonstrated the utility of Social Cognitive Theory in advancing our understanding of spousal physical activity and underscored the need for health professionals to consider the marital dyad when designing health interventions

Furthering alternative cultures of valuation in higher education research

The value of higher education is often implicit or assumed in educational research. The underlying and antecedent premises that shape and influence debates about value remain unchallenged which perpetuates the dominant, but limiting, terms of the debate and fosters reductionism. I proceed on the premise that analyses of value are not self–supporting or self-referential but are embedded within prevailing cultures of valuation. I contend that challenging, and providing alternatives to, dominant narratives of higher education requires an appreciation of those cultures. I therefore highlight some of the existing cultures of valuation and their influence. I then propose Sayer’s concept of lay normativity as a culture of valuation and discuss how it translates into the practices of research into higher education, specifically the practice of analysis. I animate the discussion by detecting the presence of lay normativity in the evaluative space of the capability approach