New insights into short-chain prenyltransferases: structural features, evolutionary history and potential for selective inhibition

Isoprenoids form an extensive group of natural products involved in a number of important biological processes. Their biosynthesis proceeds through sequential 1′-4 condensations of isopentenyl diphosphate (C₅) with an allylic acceptor, the first of which is dimethylallyl diphosphate (C₅). The reactions leading to the production of geranyl diphosphate (C₁₀), farnesyl diphosphate (C₁₅) and geranylgeranyl diphosphate (C₂₀), which are the precursors of mono-, sesqui- and diterpenes, respectively, are catalyzed by a group of highly conserved enzymes known as short-chain isoprenyl diphosphate synthases, or prenyltransferases. In recent years, the sequences of many new prenyltransferases have become available, including those of several plant and animal geranyl diphosphate synthases, revealing novel mechanisms of product chain-length selectivity and an intricate evolutionary path from a putative common ancestor. Finally, there is considerable interest in designing inhibitors specific to short-chain prenyltransferases, for the purpose of developing new drugs or pesticides that target the isoprenoid biosynthetic pathway.     

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.     

Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development

The combinatorial expression of Hox genes is an evolutionarily ancient program underlying body axis patterning in all Bilateria. In the head, the neural crest (NC)––a vertebrate innovation that contributes to evolutionarily novel skeletal and neural features––develops as a structure free of Hox-gene expression. The activation of Hoxa2 in the Hox-free facial NC (FNC) leads to severe craniofacial and brain defects. Here, we show that this condition unveils the requirement of three Six genes, Six1, Six2, and Six4, for brain development and morphogenesis of the maxillo-mandibular and nasofrontal skeleton. Inactivation of each of these Six genes in FNC generates diverse brain defects, ranging from plexus agenesis to mild or severe holoprosencephaly, and entails facial hypoplasia or truncation of the craniofacial skeleton. The triple silencing of these genes reveals their complementary role in face and brain morphogenesis. Furthermore, we show that the perturbation of the intrinsic genetic FNC program, by either Hoxa2 expression or Six gene inactivation, affects Bmp signaling through the downregulation of Bmp antagonists in the FNC cells. When upregulated in the FNC, Bmp antagonists suppress the adverse skeletal and cerebral effects of Hoxa2 expression. These results demonstrate that the combinatorial expression of Six1, Six2, and Six4 is required for the molecular programs governing craniofacial and cerebral development. These genes are crucial for the signaling system of FNC origin, which regulates normal growth and patterning of the cephalic neuroepithelium. Our results strongly suggest that several congenital craniofacial and cerebral malformations could be attributed to Six genes’ misregulation.     

Identification of Markovian open system dynamics for qubit systems

We discuss the problem of identification of the dynamical generators for open two-level quantum systems in a Markovian environment.Based on Bloch sphere representation,the identification problem is converted to the estimation of a 3-dimensional real process matrix A and an inhomogeneous term c.The parameter identifiability and sufficient conditions for completely identification of A and c are obtained.Further discussion shows that the obtained sufficient conditions are not always necessary.The approach can be generalized to finite-level open quantum systems in an arbitary Markovian environment.     

Initiation of mitosis in post-mitotic nuclei ofPhysarum polycephalum

Zusammenfassung Durch Fusion von Mikroplasmodien des SchleimpilzesPhysarum polycephalum wird der Mitosecyclus ihrer Kerne synchronisiert. Durch künstlich verzögerte Fusion können Tochterkerne einer soeben erfolgten Mitose zur Teilnahme an der ersten synchronen Mitose nach der Fusion gezwungen werden, bevor die morphologische Rekonstitution und die Duplikation ihrer DNS vollendet sind.

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Supported by NIH Grant No. RG-8495.     

Conditional predictability of daily exchange rates

At what forecast horizon is one time series more predictable than another? This paper applies the Diebold–Kilian conditional predictability measure to assess the out‐of‐sample performance of three alternative models of daily GBP/USD and DEM/USD exchange rate returns. Predictability is defined as a non‐linear statistic of a model's relative expected losses at short and long forecast horizons, allowing flexible choice of both the estimation procedure and loss function. The long horizon is set to 2 weeks and one month ahead and forecasts evaluated according to MSE loss. Bootstrap methodology is used to estimate the data's conditional predictability using GARCH models. This is then compared to predictability under a random walk and a model using the prediction bias in uncovered interest parity (UIP). We find that both exchange rates are less predictable using GARCH than using a random walk, but they are more predictable using UIP than a random walk. Predictability using GARCH is relatively higher for the 2‐weeks‐than for the 1‐month long forecast horizon. Comparing the results using a random walk to that using UIP reveals ‘pockets’ of predictability, that is, particular short horizons for which predictability using the random walk exceeds that using UIP, or vice versa. Overall, GBP/USD returns appear more predictable than DEM/USD returns at short horizons. Copyright © 2002 John Wiley & Sons, Ltd.     

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ～5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.     

Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility

The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20-50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly. We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060). We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.     

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10???) and 9q31.2 (P = 2.2 × 10?33), we identified 30 new menarche loci (all P < 5 × 10??) and found suggestive evidence for a further 10 loci (P < 1.9 × 10??). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.