Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy.

Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20-30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner-nuclear membrane proteins. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-I-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.     

Persistence of full glacial conditions in the central Pacific until 15,000 years ago

The magnitude of atmospheric cooling during the Last Glacial Maximum and the timing of the transition into the current interglacial period remain poorly constrained in tropical regions, partly because of a lack of suitable climate records. Glacial moraines provide a method of reconstructing past temperatures, but they are relatively rare in the tropics. Here we present a reconstruction of atmospheric temperatures in the central Pacific during the last deglaciation on the basis of cosmogenic 3He ages of moraines and numerical modelling of the ice cap on Mauna Kea volcano, Hawaii--the only highland in the central Pacific on which moraines that formed during the last glacial period are preserved. Our reconstruction indicates that the Last Glacial Maximum occurred between 19,000 and 16,000 years ago in this region and that temperatures at high elevations were about 7 degrees C lower than today during this interval. Glacial retreat began about 16,000 years ago, but temperatures were still about 6.5 degrees C lower than today until 15,000 years ago. When combined with estimates of sea surface temperatures in the central Pacific Ocean, our reconstruction indicates that the lapse rate during the Last Glacial Maximum was higher than at present, which is consistent with the proposal that the atmosphere was drier at that time. Furthermore, the persistence of full glacial conditions until 15,000 years ago is consistent with the relatively late and abrupt transition to warmer temperatures in Greenland, indicating that there may have been an atmospheric teleconnection between the central Pacific and North Atlantic regions during the last deglaciation.     

A recurrent mutation in PALB2 in Finnish cancer families

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.     

A Probability for Classification Based on the Dirichlet Process Mixture Model

In this paper we provide an explicit probability distribution for classification purposes when observations are viewed on the real line and classifications are to be based on numerical orderings. The classification model is derived from a Bayesian nonparametric mixture of Dirichlet process model; with some modifications. The resulting approach then more closely resembles a classical hierarchical grouping rule in that it depends on sums of squares of neighboring values. The proposed probability model for classification relies on a numerical procedure based on a reversible Markov chain Monte Carlo (MCMC) algorithm for determining the probabilities. Some numerical illustrations comparing with alternative ideas for classification are provided.     

Science of winning soccer: Emergent pattern-forming dynamics in association football

Quantitative analysis is increasingly being used in team sports to better understand performance in these stylized, delineated, complex social systems. Here, the authors provide a first step toward understanding the pattern-forming dynamics that emerge from collective offensive and defensive behavior in team sports. The authors propose a novel method of analysis that captures how teams occupy sub-areas of the field as the ball changes location. The authors use this method to analyze a game of association football (soccer) based upon a hypothesis that local player numerical dominance is key to defensive stability and offensive opportunity. The authors find that the teams consistently allocated more players than their opponents in sub-areas of play closer to their own goal. This is consistent with a predominantly defensive strategy intended to prevent yielding even a single goal. The authors also find differences between the two teams’ strategies: while both adopted the same distribution of defensive, midfield, and attacking players (a 4: 3: 3 system of play), one team was significantly more effective in maintaining both defensive and offensive numerical dominance for defensive stability and offensive opportunity. That team indeed won the match with an advantage of one goal (2 to 1) but the analysis shows the advantage in play was more pervasive than the single goal victory would indicate. The proposed focus on the local dynamics of team collective behavior is distinct from the traditional focus on individual player capability. It supports a broader view in which specific player abilities contribute within the context of the dynamics of multiplayer team coordination and coaching strategy. By applying this complex system analysis to association football, the authors can understand how players’ and teams’ strategies result in successful and unsuccessful relationships between teammates and opponents in the area of play.     

Combining Economic Forecasts by Using a Maximum Entropy Econometric Approach

This paper explores the use of a maximum entropy econometric approach to combine forecasts when the small amount of information available does not allow the use of regression procedures since a dimensionality problem arises. This approach has its roots in information theory and builds on the entropy information measures and the classical maximum entropy principle, which was developed to recover information from underdetermined models. More specifically, we use the maximum entropy econometric approach for the measure of Shannon and we also propose its extension to the quadratic uncertainty measure. The experimental results over a pool of forecasts referring to Spanish inflation show some improvements when compared with equally weighted combined forecasting. Copyright © 2011 John Wiley & Sons, Ltd.     

A chain initiation factor common to both modular and aromatic polyketide synthases.

Antibiotic-producing polyketide synthases (PKSs) are enzymes responsible for the biosynthesis in Streptomyces and related filamentous bacteria of a remarkably broad range of bioactive metabolites, including antitumour aromatic compounds such as mithramycin and macrolide antibiotics such as erythromycin. The molecular basis for the selection of the starter unit on aromatic PKSs is unknown. Here we show that a component of aromatic PKS, previously named 'chain-length factor', is a factor required for polyketide chain initiation and that this factor has decarboxylase activity towards malonyl-ACP (acyl carrier protein). We have re-examined the mechanism of initiation on modular PKSs and have identified as a specific initiation factor a domain of previously unknown function named KSQ, which operates like chain-length factor. Both KSQ and chain-length factor are similar to the ketosynthase domains that catalyse polyketide chain extension in modular multifunctional PKSs and in aromatic PKSs, respectively, except that the ketosynthase domain active-site cysteine residue is replaced by a highly conserved glutamine in KSQ and in chain-length factor. The glutamine residue is important both for decarboxylase activity and for polyketide synthesis.