Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract

Synpolydactyly (SPD) is a dominantly inherited congenital limb malformation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a duplicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been shown to be caused by expansions of an imperfect trinucleotide repeat sequence encoding a 15-residue polyalanine tract in HOXD13. We have studied 16 new and 4 previously published SPD families, with between 7 and 14 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of change in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of phenotype with increasing expansion size, affecting both hands (P = 0.012) and feet (P < 0.00005). Affected individuals from a family with a 14-alanine expansion, the largest so far reported, all have a strikingly similar and unusually severe limb phenotype, involving the first digits and distal carpals. Affected males from this family also have hypospadias, not previously described in SPD, but consistent with HOXD13 expression in the developing genital tubercle. The remarkable correlation between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 protein, and has interesting implications for the role of polyalanine tracts in the control of transcription.

Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions

The evolution of novelty in tightly integrated biological systems, such as hormones and their receptors, seems to challenge the theory of natural selection: it has not been clear how a new function for any one part (such as a ligand) can be selected for unless the other members of the system (e.g., a receptor) are already present. Here I show—based on identification and phylogenetic analysis of steroid receptors in basal vertebrates and reconstruction of the sequences and functional attributes of ancestral proteins—that the first steroid receptor was an estrogen receptor, followed by a progesterone receptor. Genome mapping and phylogenetic analyses indicate that the full complement of mammalian steroid receptors evolved from these ancient receptors by two large-scale genome expansions, one before the advent of jawed vertebrates and one after. Specific regulation of physiological processes by androgens and corticoids are relatively recent innovations that emerged after these duplications. These findings support a model of ligand exploitation in which the terminal ligand in a biosynthetic pathway is the first for which a receptor evolves; selection for this hormone also selects for the synthesis of intermediates despite the absence of receptors, and duplicated receptors then evolve affinity for these substances. In this way, novel hormone-receptor pairs are created, and an integrated system of increasing complexity elaborated. This model suggests that ligands for some “orphan” receptors may be found among intermediates in the synthesis of ligands for phylogenetically related receptors.

Nonequilibrium expansions of air with coupled chemical reactions

Caption title.

Polynomial Expansions for Solutions of Higher-Order Bessel Heat Equation in Quantum Calculus

Mathematics Subject Class.: 33C10,33D60,26D15,33D05,33D15,33D90

On the Transformations of Symplectic Expansions and the Respective Bäcklund Transformation for the KDV Equation

2000 Mathematics Subject Classification: Primary: 34B40; secondary: 35Q51, 35Q53

The European Parliament, membership expansions, and organizational change

The European Union (EU) is an extraordinary achievement. From a regional economic organization, it grew into a polity within fifty years. The original EU of six members expanded incrementally to 27 over forty years, and it now comprises a population of almost 500 million people. While the five expansions of the European Economic Community/European Community/European Union (EU) have received considerable scholarly attention, surprisingly little attention has been given to their impacts on "Europe's" only legislative body, currently known as the European Parliament (EP). More specifically, little is known about how waves of new members (from widely diverse parties and national backgrounds) affected—and were affected by—the EP's organizational structure and its internal processes. The purpose of this study therefore is to help fill this gap by describing and explaining how the various EEC/EC/EU expansions or "membership shocks" (1973, 1981, 1986, 1995, and 2004) affected the EP's organizational structure and its internal Rules of Procedure (RoP). The central research question of this dissertation is the following: What were the major structural and procedural effects of the five membership expansions of what eventually became the European Union on the European Parliament? This dissertation answers this question by using concepts and measures drawn from organizational theory. While other studies have applied concepts and hypotheses from organizational theory to legislatures, such an approach has never been used to analyze the EP, which is conceptualized here as a "membership organization." This study, through an analysis of the EP, demonstrates that organization theory can help us fully understand the effects of membership expansions on any membership organization. That is, understanding how this particular organization responded to change can inform not only how others in this class (legislatures) do so, but how this process unfolds in a variety of times and places. The principal findings of this study are as follows: (1) EP staff growth revealed an interesting pattern: Staff did not increase concurrently with EP membership. That is, it turned out that the rate of membership growth exceeded the rate of staff increase, suggesting professionalization of EP staff and their relative empowerment vis-à-vis MEPs; (2) The number of rules and the precision within them increased; (3) the largest number of EP rule changes focused on increasing EP efficiency; and (4) The authority was centralized in the hands of EP leadership, that is, the EP President, the Conference of Presidents and also two major political groups.

Widespread range expansions shape latitudinal variation in insect thermal limits

I thank the authors of previous studies on global variation in insect thermal tolerances who have generously provided open access use of their data sets.

Bond Fund Performance During Recessions and Expansions: Empirical Evidence from a Small Market

This paper provides the first investigation about bond mutual fund performance during recession and expansion periods separately. Based on multi-factor performance evaluation models, results show that bond funds significantly underperform the market during both phases of the business cycle. Nevertheless, unlike equity funds, bond funds exhibit considerably higher alphas during good economic states than during market downturns. These results, however, seem entirely driven by the global financial crisis subperiod. In contrast, during the recession associated to the Euro sovereign debt crisis, bond funds are able to accomplish neutral performance. This improved performance throughout the debt crisis seems to be related to more conservative investment strategies, which reflect an increase in managers’ risk aversion.

Series representations of the remainders in the expansions for certain functions with applications

We present a summary of the series representations of the remainders in the expansions in ascending powers of t of 2/(et+1)2/(et+1) , sech t and coth t and establish simple bounds for these remainders when t>0t>0 . Several applications of these expansions are given which enable us to deduce some inequalities and completely monotonic functions associated with the ratio of two gamma functions. In addition, we derive a (presumably new) quadratic recurrence relation for the Bernoulli numbers Bn.

Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6 % in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 % of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.

Dependence of the crossover exponent with the diffusion rate in the generalized contact process model

We study how the crossover exponent, phi, between the directed percolation (DP) and compact directed percolation (CDP) behaves as a function of the diffusion rate in a model that generalizes the contact process. Our conclusions are based in results pointed by perturbative series expansions and numerical simulations, and are consistent with a value phi = 2 for finite diffusion rates and phi = 1 in the limit of infinite diffusion rate.