Multiple roles of class I HDACs in proliferation, differentiation, and development

Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future.     

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.     

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.     

Caudal movements in western fence lizards ( Sceloporus occidentalis ) prior to attempted prey capture

Many snakes employ tail movements to attract prey, but this behavior is rare in lizards. Use of caudal movements to distract prey, however, is rare in all squamates. Recently, caudal movements in a Sceloporus occidentalis individual immediately prior to attempted prey capture were documented. We supplement this sole documentation of caudal movements in S. occidentalis with additional field observations. Additionally, video footage of the behavior was recorded on 2 occasions. From these additional observations, we hypothesize that this behavior might serve to distract prey.     

A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10?2?. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.     

Forecasting the Yield Curve in a Data‐Rich Environment Using the Factor‐Augmented Nelson–Siegel Model

This paper compares various ways of extracting macroeconomic information from a data‐rich environment for forecasting the yield curve using the Nelson–Siegel model. Five issues in extracting factors from a large panel of macro variables are addressed; namely, selection of a subset of the available information, incorporation of the forecast objective in constructing factors, specification of a multivariate forecast objective, data grouping before constructing factors, and selection of the number of factors in a data‐driven way. Our empirical results show that each of these features helps to improve forecast accuracy, especially for the shortest and longest maturities. Factor‐augmented methods perform well in relatively volatile periods, including the crisis period in 2008–9, when simpler models do not suffice. The macroeconomic information is exploited best by partial least squares methods, with principal component methods ranking second best. Reductions of mean squared prediction errors of 20–30% are attained, compared to the Nelson–Siegel model without macro factors. Copyright © 2011 John Wiley & Sons, Ltd.