AXL and acquired resistance to EGFR inhibitors

A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non-small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor-resistant patients.     

Navigation rules for vessels and neurons: cooperative signaling between VEGF and neural guidance cues

Many organs, such as lungs, nerves, blood and lymphatic vessels, consist of complex networks that carry flows of information, gases, and nutrients within the body. The morphogenetic patterning that generates these organs involves the coordinated action of developmental signaling cues that guide migration of specialized cells. Precision guidance of endothelial tip cells by vascular endothelial growth factors (VEGFs) is well established, and several families of neural guidance molecules have been identified to exert guidance function in both the nervous and the vascular systems. This review discusses recent advances in VEGF research, focusing on the emerging role of neural guidance molecules as key regulators of VEGF function during vascular development and on the novel role of VEGFs in neural cell migration and nerve wiring.     

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.     

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.