Field Theory for a Deuteron Quantum Liquid

Based on general symmetry principles we study an effective Lagrangian for a neutral system of condensed spin-1 deuteron nuclei and electrons, at greater-than-atomic but less-than-nuclear densities. We expect such matter to be present in thin layers within certain low-mass brown dwarfs. It may also be produced in future shock-wave-compression experiments as an effective fuel for laser induced nuclear fusion. We find a background solution of the effective theory describing a net spin zero condensate of deuterons with their spins aligned and anti-aligned in a certain spontaneously emerged preferred direction. The spectrum of low energy collective excitations contains two spin waves with linear dispersions -- like in antiferromagnets -- as well as gapped longitudinal and transverse modes related to the Meissner effect -- like in superconductors. We show that counting of the Nambu-Goldstone modes of spontaneously broken internal and space-time symmetries obeys, in a nontrivial way, the rules of the Goldstone theorem for Lorentz non-invariant systems. We discuss thermodynamic properties of the condensate, and its potential manifestation in the low-mass brown dwarfs.Comment: 19 LaTeX pages; v2: 2 refs added, JHEP versio

Superconducting nanowire photon number resolving detector at telecom wavelength

The optical-to-electrical conversion, which is the basis of optical detectors, can be linear or nonlinear. When high sensitivities are needed single-photon detectors (SPDs) are used, which operate in a strongly nonlinear mode, their response being independent of the photon number. Nevertheless, photon-number resolving (PNR) detectors are needed, particularly in quantum optics, where n-photon states are routinely produced. In quantum communication, the PNR functionality is key to many protocols for establishing, swapping and measuring entanglement, and can be used to detect photon-number-splitting attacks. A linear detector with single-photon sensitivity can also be used for measuring a temporal waveform at extremely low light levels, e.g. in long-distance optical communications, fluorescence spectroscopy, optical time-domain reflectometry. We demonstrate here a PNR detector based on parallel superconducting nanowires and capable of counting up to 4 photons at telecommunication wavelengths, with ultralow dark count rate and high counting frequency

Caspase-2-Mediated Cleavage of Mdm2 Creates a p53-Induced Positive Feedback Loop

Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.Virginia and D.K. Ludwig Fund for Cancer Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France) (Fellowship)National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051

Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase eta (Pol eta), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol eta at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol eta acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol eta orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol eta missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol eta in replicating through D loop and DNA fragile sites

Winter wheat roots grow twice as deep as spring wheat roots, is this important for N uptake and N leaching losses?

Cropping systems comprising winter catch crops followed by spring wheat could reduce N leaching risks compared to traditional winter wheat systems in humid climates. We studied the soil mineral N (Ninorg) and root growth of winter- and spring wheat to 2.5 m depth during three years. Root depth of winter wheat (2.2 m) was twice that of spring wheat, and this was related to much lower amounts of Ninorg in the 1 to 2.5 m layer after winter wheat (81 kg Ninorg ha-1 less). When growing winter catch crops before spring wheat, N content in the 1 to 2.5 m layer after spring wheat was not different from that after winter wheat. The results suggest that by virtue of its deep rooting, winter wheat may not lead to high levels of leaching as it is often assumed in humid climates. Deep soil and root measurements (below 1 m) in this experiment were essential to answer the questions we posed

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

Smooth tensionful higher-codimensional brane worlds with bulk and brane form fields

Completely regular tensionful codimension-n brane world solutions are discussed, where the core of the brane is chosen to be a thin codimension-(n-1) shell in an infinite volume flat bulk, and an Einstein-Hilbert term localized on the brane is included (Dvali-Gabadadze-Porrati models). In order to support such localized sources we enrich the vacuum structure of the brane by the inclusion of localized form fields. We find that phenomenological constraints on the size of the internal core seem to impose an upper bound to the brane tension. Finite transverse-volume smooth solutions are also discussed.Comment: 1+14 pages, 2 figures; section 2.3 improved, typos corrected and references added. Published versio

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism