Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1

Genomic imprinting is an epigenetic modification that results in expression from only one of the two parental copies of a gene. Differences in methylation between the two parental chromosomes are often observed at or near imprinted genes. Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and excessive growth, results from a disruption of imprinted gene expression in chromosome band 11p15.5. One third of individuals with BWS lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene, and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS1, 2. Here we show that paternal inheritance of a deletion of KvDMR1 results in the de-repression in cis of six genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20-25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings support the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS.     

Two coexisting vortex phases in the peak effect regime in a superconductor

The critical current in the vortex phase of a type-II superconductor such as NbSe2 displays a striking anomaly in the vicinity of the superconductor-to-normal-metal transition. Instead of going to zero smoothly, it rebounds to a sharp and pronounced maximum, just before vanishing at the transition. This counter-intuitive phenomenon, known as the peak effect, has remained an unsolved problem for 40 years. Here we use a scanning a.c. Hall microscope to visualize the real-space distribution of the critical current in NbSe2. We show that in the peak-effect regime two distinct vortex-matter phases with intrinsically different pinning strengths coexist on a macroscopic scale. The composition of the two-phase mixture and the transformation of one phase into another are responsible for the history effects and anomalous voltage response commonly seen when external parameters such as temperature, magnetic field or transport current are varied. We argue that the observed phase coexistence is, in fact, the hallmark of a disorder-driven non-thermal phase transition.     

Structure,function and evolution of haspin and haspinrelated proteins,a distinctive group of eukaryotic protein kinases

The haspins constitute a newly defined protein family containing a distinctive C-terminal eukaryotic protein kinase domain and divergent N termini. Haspin homologues are found in animals, plants and fungi, suggesting an origin early in eukaryotic evolution. Most species have a single haspin homologue. However, Saccharomyces cerevisiae has two such genes, while Caenorhabditis elegans has at least three haspin homologues and approximately 16 haspin-related genes. Mammalian haspin genes have features of retrogenes and are strongly expressed in male germ cells and at lower levels in some somatic tissues. They encode nuclear proteins with serine/threonine kinase activity. Murine haspin is reported to inhibit cell cycle progression in cell lines. One of the S. cerevisiae homologues, ALK1, is a member of the CLB2 gene cluster that peaks in expression at M phase and thus may function in mitosis. Therefore, the haspins are an intriguing group of kinases likely to have important roles during or following both meiosis and mitosis.     

Dynamic instabilities and memory effects in vortex matter

The magnetic flux line lattice in type II superconductors serves as a useful system in which to study condensed matter flow, as its dynamic properties are tunable. Recent studies have shown a number of puzzling phenomena associated with vortex motion, including: low-frequency noise and slow voltage oscillations; a history-dependent dynamic response, and memory of the direction, amplitude duration and frequency of the previously applied current; high vortex mobility for alternating current, but no apparent vortex motion for direct currents; and strong suppression of an a.c. response by small d.c. bias. Taken together, these phenomena are incompatible with current understanding of vortex dynamics. Here we report a generic mechanism that accounts for these observations. Our model, which is derived from investigations of the current distribution across single crystals of NbSe2, is based on a competition between the injection of a disordered vortex phase at the sample edges, and the dynamic annealing of this metastable disorder by the transport current. For an alternating current, only narrow regions near the edges are in the disordered phase, while for d.c. bias, most of the sample is in the disordered phase--preventing vortex motion because of more efficient pinning. The resulting spatial dependence of the disordered vortex system serves as an active memory of the previous history.     

Electrochemical, photoelectrochemical, electrocatalytic and catalytic reduction of redox proteins

Redox proteins catalyse the reactions of a wide variety of otherwise intractable substrates, such as dinitrogen, alkanes, arenes, terpenes and steroids. Two major factors impede the utilization of these enzymes--the inefficient electron transfer between the enzyme and electrode, and the properties often, but not inevitably, associated with enzymes, such as instability, complexity, and expense. We have now shown that the former can be overcome and that proteins can be coupled, via electrodes, to a number of energy sources; the latter is the subject of much effort elsewhere. We demonstrated previously that certain redox proteins can be reduced very efficiently electrochemically (Fig. 1a). Light and hydrogen are the two other convenient energy sources that could be used for such reductions, and we now report the reduction of cytochrome c by these means.     

Ipr1 gene mediates innate immunity to tuberculosis

An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis 1). Here we show that this locus mediates innate immunity in sst1 congenic mouse strains and identify a candidate gene, Intracellular pathogen resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages after activation and infection, but it is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data indicate that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis.