DNA double strand breaks but not interstrand crosslinks prevent progress through meiosis in fully grown mouse oocytes

There is some interest in how mammalian oocytes respond to different types of DNA damage because of the increasing expectation of fertility preservation in women undergoing chemotherapy. Double strand breaks (DSBs) induced by ionizing radiation and agents such as neocarzinostatin (NCS), and interstrand crosslinks (ICLs) induced by alkylating agents such as mitomycin C (MMC), are toxic DNA lesions that need to be repaired for cell survival. Here we examined the effects of NCS and MMC treatment on oocytes collected from antral follicles in mice, because potentially such oocytes are readily collected from ovaries and do not need to be in vitro grown to achieve meiotic competency. We found that oocytes were sensitive to NCS, such that this ionizing radiation mimetic blocked meiosis I and caused fragmented DNA. In contrast, MMC had no impact on the completion of either meiosis I or II, even at extremely high doses. However, oocytes treated with MMC did show ?-H2AX foci and following their in vitro maturation and parthenogenetic activation the development of the subsequent embryos was severely compromised. Addition of MMC to 1-cell embryos caused a similarly poor level of development, demonstrating oocytes have eventual sensitivity to this ICL-inducing agent but this does not occur during their meiotic division. In oocytes, the association of Fanconi Anemia protein, FANCD2, with sites of ICL lesions was not apparent until entry into the embryonic cell cycle. In conclusion, meiotic maturation of oocytes is sensitive to DSBs but not ICLs. The ability of oocytes to tolerate severe ICL damage and yet complete meiosis, means that this type of DNA lesion goes unrepaired in oocytes but impacts on subsequent embryo quality

Phase II study of TP300 in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma

Background: TP300, a recently developed synthetic camptothecin analogue, is a highly selective topoisomerase I inhibitor. A phase I study showed good safety and tolerability. As camptothecins have proven active in oesophago-gastric adenocarcinomas, in this phase II study we assessed the efficacy and safety of TP300 in patients with gastric or gastro-oesophageal junction (GOJ) adenocarcinomas. Methods: Eligible patients had metastatic or locally advanced gastric or Siewert Types II or III GOJ inoperable adenocarcinoma. Patients were chemotherapy naïve unless this had been administered in the perioperative setting. TP300 was administered as a 1-h intravenous infusion every 3 weeks (a cycle) for up to 6 cycles at a starting dose of 8 mg/m2 with intra-patient escalation to 10 mg/m2 from cycle 2 in the absence of dose-limiting toxicity. Tumour responses (RECIST 1.1) were assessed every 6 weeks. Toxicity was recorded by NCI-CTCAE version 3.0. Using a modified two-stage Simon design (Stage I and II), a total of 43 patients were to be included providing there were 3 of 18 patients with objective response in Stage I of the study. Results: In Stage I of the study 20 patients (14 males, 6 females), median age 67 years (range 40 − 82), performance status ECOG 0/1, with GC [14] or GOJ carcinoma [6] were enrolled. Of the 16 evaluable patients, 11 received the planned dose increase to 10 mg/m2 at cycle 2, 2 decreased to 6 mg/m2, and 3 continued on 8 mg/m2. There were no objective responses after 2 cycles of treatment. Twelve patients had stable disease for 1 − 5 months and 4 had progressive disease. Median progression free survival (PFS) was 4.1 months (CI [1.6 − 4.9]), median time to progression (TTP) was 2.9 months (CI [1.4 − 4.2]). Grade 3/4 toxicities (worst grade all cycles) included 7 patients (35 %) with neutropenia, 4 patients (20 %) with anaemia, 2 patients (10 %) with thrombocytopenia, and 3 patients (15 %) with fatigue. This study was terminated at the end of Stage I due to a lack of the required (3/18) responders. Conclusions: This study of TP300 showed good drug tolerability but it failed to demonstrate sufficient efficacy as measured by radiological response

Halothane binds to druggable sites in the [Ca2+]4-calmodulin (CaM) complex, but does not inhibit [Ca2+]4-CaM activation of kinase

The mechanism(s) of volatile anesthetics (VA) are poorly understood. We used high resolution NMR spectroscopy to determine the structure of the halothane/calmodulin([Ca2+]4-CaM) complex, and found that halothane molecules bind in the druggable sites. We then examined whether VA binding to druggable sites in calmodulin would effect [Ca2+]4-CaM dependent activity of myosin light chain kinase. We used fluorescence assays to determine that VA effect [Ca2+]4-CaM activation of smooth-muscle-myosin-light-chain-kinase (smMLCK), but not the Kd of [Ca2+]4-CaM binding to skeletal-myosin-light-chain-kinase-peptide recognition sequence (skMLCKp). These results suggest that VA do not alter [Ca2+]4-CaM dependent MLCK activity via direct interactions with [Ca2+]4-CaM

A burst chasing x-ray polarimeter

Gamma-ray bursts are one of the most powerful explosions in the universe and have been detected out to distances of almost 13 billion light years. The exact origin of these energetic explosions is still unknown but the resulting huge release of energy is thought to create a highly relativistic jet of material and a power-law distribution of electrons. There are several theories describing the origin of the prompt GRB emission that currently cannot be distinguished. Measurements of the linear polarization would provide unique and important constraints on the mechanisms thought to drive these powerful explosions. We present the design of a sensitive, and extremely versatile gamma-ray burst polarimeter. The instrument is a photoelectric polarimeter based on a time-projection chamber. The photoelectric time-projection technique combines high sensitivity with broad band-pass and is potentially the most powerful method between 2 and 100 keV where the photoelectric effect is the dominant interaction process. We present measurements of polarized and unpolarized X-rays obtained with a prototype detector and describe the two mission concepts; the Gamma-Ray Burst Polarimeter (GRBP) for the U.S. Naval Academy satellite MidSTAR-2, and the Low Energy Polarimeter (LEP) onboard POET, a broadband polarimetry concept for a small explorer mission

An efficient basis set representation for calculating electrons in molecules

The method of McCurdy, Baertschy, and Rescigno, J. Phys. B, 37, R137 (2004) is generalized to obtain a straightforward, surprisingly accurate, and scalable numerical representation for calculating the electronic wave functions of molecules. It uses a basis set of product sinc functions arrayed on a Cartesian grid, and yields 1 kcal/mol precision for valence transition energies with a grid resolution of approximately 0.1 bohr. The Coulomb matrix elements are replaced with matrix elements obtained from the kinetic energy operator. A resolution-of-the-identity approximation renders the primitive one- and two-electron matrix elements diagonal; in other words, the Coulomb operator is local with respect to the grid indices. The calculation of contracted two-electron matrix elements among orbitals requires only O(N log(N)) multiplication operations, not O(N^4), where N is the number of basis functions; N = n^3 on cubic grids. The representation not only is numerically expedient, but also produces energies and properties superior to those calculated variationally. Absolute energies, absorption cross sections, transition energies, and ionization potentials are reported for one- (He^+, H_2^+ ), two- (H_2, He), ten- (CH_4) and 56-electron (C_8H_8) systems.Comment: Submitted to JC

SuperWASP: Wide Angle Search for Planets

SuperWASP is a fully robotic, ultra-wide angle survey for planetary transits. Currently under construction, it will consist of 5 cameras, each monitoring a 9.5 x 9.5 deg field of view. The Torus mount and enclosure will be fully automated and linked to a built-in weather station. We aim to begin observations at the beginning of 2003.Comment: 4 pages, 1 figure, to be published in proceedings of "Scientific Frontiers in Research on Extrasolar Planets

Reviews

The following publications have been reviewed by the mentioned authors;An Italic Calligraphy Handbook by Carolyn Knudsen Adams, reviewed by John LancasterDesign and British Industry by Richard Stewart, reviewed by John H. CarswellDesign Graphics by David Fair and Marilyn Kenny, reviewed by D. R. JonesGCSE Craft, Design and Technology by Richard Kimbell, John Plater and Tristram Shepard, reviewed by D. R. JonesProblem Solving in Science and Technology by David Rowlands, reviewed by Peter C. MillrayTechnical Drawing, An Usborne Guide by Susan Peach, reviewed by Keith VickersTVEI and Secondary Education: a critical appraisal by Denis Gleeson, reviewed by Martin MersonWorking in Design by the Careers and Occupational Information Centre, reviewed by S. J. Lodg