Recognition of DNA Supercoil Geometry by Mycobacterium tuberculosis Gyrase

Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M. tuberculosis gyrase on positively supercoiled DNA were investigated. Results indicate that the enzyme acts rapidly on overwound DNA and removes positive supercoils much faster than it introduces negative supercoils into relaxed DNA. Canonical gyrase and topoisomerase IV distinguish supercoil handedness differently during the DNA cleavage reaction: while gyrase maintains lower levels of cleavage complexes on overwound DNA, topoisomerase IV maintains similar levels of cleavage complexes on both over- and underwound substrates. M. tuberculosis gyrase maintained lower levels of cleavage complexes on positively supercoiled DNA in the absence and presence of quinolone-based drugs. By retaining this important feature of canonical gyrase, the dual function M. tuberculosis type II enzyme remains a safe enzyme to act in front of replication forks and transcription complexes. Finally, the N-terminal gate region of the enzyme appears to be necessary to distinguish supercoil handedness during DNA cleavage, suggesting that the capture of the transport segment may influence how gyrase maintains cleavage complexes on substrates with different topological states

Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II

The cleavage reaction of topoisomerase II, which creates double-stranded DNA breaks, plays a central role in both the cure and initiation of cancer. Therefore, it is important to understand the cellular processes that repair topoisomerase II-generated DNA damage. Using a genome-wide approach with Saccharomyces cerevisiae, we found that Δmre11, Δxrs2, Δrad50, Δrad51, Δrad52, Δrad54, Δrad55, Δrad57 and Δmms22 strains were hypersensitive to etoposide, a drug that specifically increases levels of topoisomerase II-mediated DNA breaks. These results confirm that the single-strand invasion pathway of homologous recombination is the major pathway that repairs topoisomerase II-induced DNA damage in yeast and also indicate an important role for Mms22p. Although Δmms22 strains are sensitive to several DNA-damaging agents, little is known about the function of Mms22p. Δmms22 cultures accumulate in G(2)/M, and display an abnormal cell cycle response to topoisomerase II-mediated DNA damage. MMS22 appears to function outside of the single-strand invasion pathway, but levels of etoposide-induced homologous recombination in Δmms22 cells are lower than wild-type. MMS22 is epistatic with RTT101 and RTT107, genes that encode its protein binding partners. Finally, consistent with a role in DNA processes, Mms22p localizes to discrete nuclear foci, even in the absence of etoposide or its binding partners

Phase Transitions in liquid Helium 3

The phase transitions of liquid Helium 3 are described by truncations of an exact nonperturbative renormalization group equation. The location of the first order transition lines and the jump in the order parameter are computed quantitatively. At the triple point we find indications for partially universal behaviour. We suggest experiments that could help to determine the effective interactions between fermion pairs.Comment: 4 pages, 6 figures, LaTe

Information management to enable personalized medicine: stakeholder roles in building clinical decision support

<p>Abstract</p> <p>Background</p> <p>Advances in technology and the scientific understanding of disease processes are presenting new opportunities to improve health through individualized approaches to patient management referred to as personalized medicine. Future health care strategies that deploy genomic technologies and molecular therapies will bring opportunities to prevent, predict, and pre-empt disease processes but will be dependent on knowledge management capabilities for health care providers that are not currently available. A key cornerstone to the potential application of this knowledge will be effective use of electronic health records. In particular, appropriate clinical use of genomic test results and molecularly-targeted therapies present important challenges in patient management that can be effectively addressed using electronic clinical decision support technologies.</p> <p>Discussion</p> <p>Approaches to shaping future health information needs for personalized medicine were undertaken by a work group of the American Health Information Community. A needs assessment for clinical decision support in electronic health record systems to support personalized medical practices was conducted to guide health future development activities. Further, a suggested action plan was developed for government, researchers and research institutions, developers of electronic information tools (including clinical guidelines, and quality measures), and standards development organizations to meet the needs for personalized approaches to medical practice. In this article, we focus these activities on stakeholder organizations as an operational framework to help identify and coordinate needs and opportunities for clinical decision support tools to enable personalized medicine.</p> <p>Summary</p> <p>This perspective addresses conceptual approaches that can be undertaken to develop and apply clinical decision support in electronic health record systems to achieve personalized medical care. In addition, to represent meaningful benefits to personalized decision-making, a comparison of current and future applications of clinical decision support to enable individualized medical treatment plans is presented. If clinical decision support tools are to impact outcomes in a clear and positive manner, their development and deployment must therefore consider the needs of the providers, including specific practice needs, information workflow, and practice environment.</p

Modulation of DNA topoisomerase II activity and expression in melanoma cells with acquired drug resistance

The role of DNA topoisomerases (Topo) IIα and IIβ was investigated in various drug-resistant melanoma cells. Melanoma cells resistant to etoposide, exhibited an up to tenfold reduced Topo II activity corresponding to an increasing degree of drug resistance indicating that modulation of Topo II activity contribute to the drug-resistant phenotype. The reduction of Topo II activity was reflected by decreased nuclear amounts of both Topo II isoforms. © 2000 Cancer Research Campaig

Field-Induced gap due to four-spin exchange in a spin ladder

The effect of the four-spin cyclic exchange interaction at each plaquette in the $S=1/2$ two-leg spin ladder is investigated at T=0, especially focusing on the field-induced gap. The strong rung coupling approximation suggests that it yields a plateau at half of the saturation moment ($m=1/2$) in the magnetization curve, which corresponds to a field-induced spin gap with a spontaneous breaking of the translational symmetry. A precise phase diagram at $m=1/2$ is also presented based on the level spectroscopy analysis of the numerical data obtained by Lanczos method. The boundary between the gapless and plateau phases is confirmed to be of the Kosterlitz-Thouless (KT) universality class.Comment: 10 pages, 3 eps figures (embedded), to be published in J. Phys.: Cond. Matte

Molecular Pathogenesis of Secondary Acute Promyelocytic Leukemia

Balanced chromosomal translocations that generate chimeric oncoproteins are considered to be initiating lesions in the pathogenesis of acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to acute promyelocytic leukemia (APL). An increasing proportion of APL cases are therapy-related (t-APL), which develop following exposure to radiotherapy and/or chemotherapeutic agents that target DNA topoisomerase II (topoII), particularly mitoxantrone and epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast cancer or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp “hotspot” region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by mitoxantrone. Chromosome 15 breakpoints falling outside the “hotspot”, and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL

Universalities of Triplet Pairing in Neutron Matter

The fundamental structure of the full set of solutions of the BCS $^3 P_2$ pairing problem in neutron matter is established. The relations between different spin-angle components in these solutions are shown to be practically independent of density, temperature, and the specific form of the pairing interaction. The spectrum of pairing energies is found to be highly degenerate.Comment: 11 page

Exact solution of a spin-ladder model

An integrable spin-ladder model with nearest-neighbor exchanges and biquadratic interactions is proposed. With the Bethe ansatz solutions of the model hamiltonian, it is found that there are three possible phases in the ground state, i.e., a rung-dimerized phase with a spin gap, and two massless phases. The possible fixed points of the system and the quantum critical behavior at the critical point $J=J_+^c$ are discussed.Comment: 6page Revtex, no figur