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

Direct simulation of ion beam induced stressing and amorphization of silicon

Using molecular dynamics (MD) simulation, we investigate the mechanical response of silicon to high dose ion-irradiation. We employ a realistic and efficient model to directly simulate ion beam induced amorphization. Structural properties of the amorphized sample are compared with experimental data and results of other simulation studies. We find the behavior of the irradiated material is related to the rate at which it can relax. Depending upon the ability to deform, we observe either the generation of a high compressive stress and subsequent expansion of the material, or generation of tensile stress and densification. We note that statistical material properties, such as radial distribution functions are not sufficient to differentiate between different densities of amorphous samples. For any reasonable deformation rate, we observe an expansion of the target upon amorphization in agreement with experimental observations. This is in contrast to simulations of quenching which usually result in denser structures relative to crystalline Si. We conclude that although there is substantial agreement between experimental measurements and most simulation results, the amorphous structures being investigated may have fundamental differences; the difference in density can be attributed to local defects within the amorphous network. Finally we show that annealing simulations of our amorphized samples can lead to a reduction of high energy local defects without a large scale rearrangement of the amorphous network. This supports the proposal that defects in amorphous silicon are analogous to those in crystalline silicon.Comment: 13 pages, 12 figure

Geometrical Description of Quantum Mechanics - Transformations and Dynamics

In this paper we review a proposed geometrical formulation of quantum mechanics. We argue that this geometrization makes available mathematical methods from classical mechanics to the quantum frame work. We apply this formulation to the study of separability and entanglement for states of composite quantum systems.Comment: 22 pages, to be published in Physica Script

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia : further evidence and meta-analysis

NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. PostprintPeer reviewe

The OXR domain defines a conserved family of eukaryotic oxidation resistance proteins

BACKGROUND: The NCOA7 gene product is an estrogen receptor associated protein that is highly similar to the human OXR1 gene product, which functions in oxidation resistance. OXR genes are conserved among all sequenced eukaryotes from yeast to humans. In this study we examine if NCOA7 has an oxidation resistance function similar to that demonstrated for OXR1. We also examine NCOA7 expression in response to oxidative stress and its subcellular localization in human cells, comparing these properties with those of OXR1. RESULTS: We find that NCOA7, like OXR1 can suppress the oxidative mutator phenotype when expressed in an E. coli strain that exhibits an oxidation specific mutator phenotype. Moreover, NCOA7's oxidation resistance function requires expression of only its carboxyl-terminal domain and is similar in this regard to OXR1. We find that, in human cells, NCOA7 is constitutively expressed and is not induced by oxidative stress and appears to localize to the nucleus following estradiol stimulation. These properties of NCOA7 are in striking contrast to those of OXR1, which is induced by oxidative stress, localizes to mitochondria, and appears to be excluded, or largely absent from nuclei. CONCLUSION: NCOA7 most likely arose from duplication. Like its homologue, OXR1, it is capable of reducing the DNA damaging effects of reactive oxygen species when expressed in bacteria, indicating the protein has an activity that can contribute to oxidation resistance. Unlike OXR1, it appears to localize to nuclei and interacts with the estrogen receptor. This raises the possibility that NCOA7 encodes the nuclear counterpart of the mitochondrial OXR1 protein and in mammalian cells it may reduce the oxidative by-products of estrogen metabolite-mediated DNA damage

Nanoporous Metal - Combining Strength and Porosity

Recent nanomechanical tests on submicron metal columns and wires have revealed a dramatic increase in yield strength with decreasing sample size. This effect seems to be related to the increased strength observed in metals on decreasing grain size or film thickness, and has been explained by a dislocation nucleation/activation controlled plasticity regime in small sample volumes. The question arises whether one can utilize this new size effect to design materials with improved bulk properties. Here, we demonstrate that nanoporous metal foams can be envisioned as a three-dimensional network of ultrahigh-strength nanocolumns/wires, thus bringing together two seemingly conflicting properties: high strength and high porosity. Specifically, we studied the mechanical properties of nanoporous (np) Au using a combination of nanoindentation and column microcompression tests, as well as supplemental molecular dynamics simulations. We find that np-Au can be as strong as bulk Au, despite being a highly porous material, and that the ligaments in np-Au approach the theoretical yield strength of Au. The combination of high yield strength and high porosity can be used to design a new generation of energy absorbing materials for various engineering applications

How to Build Collective Capabilities: The 3C-Model for Grassroots-led Development

Capabilities need to be built from the bottom-up. Social innovations at the grassroots seek to present new solutions to existing social problems. However, since the poor suffer from limitations on their individual capabilities and agency, they engage in acts of collective agency to generate new collective capabilities that each individual alone would not be able to achieve. The question is: how can these acts of collective agency be initiated, supported and sustained in practice? What roles can development actors (such as the state, donors and NGOs) play in supporting these acts of collective agency? Drawing on the literature on social innovation, the capability approach, participation and empowerment, the paper argues that three crucial C-processes are integral conditions for promoting successful, scalable and sustainable social innovations at the grassroots, namely: (1) Conscientization; (2) Conciliation and (3) Collaboration. By linking the individual, collective and institutional levels of analysis, the paper demonstrates the importance of individual behavioural changes, collective agency and local institutional reforms for the success, sustainability and scalability of social innovations at the grassroots. The paper acknowledges conflict, capture and cooptation as potential limitations and recognizes the role of contextual factors in initiating, implementing and sustaining social innovations at the grassroots

Flavin-Induced Oligomerization in Escherichia coli Adaptive Response Protein AidB

The process known as “adaptive response” allows Escherichia coli to respond to small doses of DNA-methylating agents by upregulating the expression of four proteins. While the role of three of these proteins in mitigating DNA damage is well understood, the function of AidB is less clear. Although AidB is a flavoprotein, no catalytic role has been established for the bound cofactor. Here we investigate the possibility that flavin plays a structural role in the assembly of the AidB tetramer. We report the generation and biophysical characterization of deflavinated AidB and of an AidB mutant that has greatly reduced affinity for flavin adenine dinucleotide (FAD). Using fluorescence quenching and analytical ultracentrifugation, we find that apo AidB has a high affinity for FAD, as indicated by an apparent dissociation constant of 402.1 ± 35.1 nM, and that binding of substoichiometric amounts of FAD triggers a transition in the AidB oligomeric state. In particular, deflavinated AidB is dimeric, whereas the addition of FAD yields a tetramer. We further investigate the dimerization and tetramerization interfaces of AidB by determining a 2.8 Å resolution crystal structure in space group P32 that contains three intact tetramers in the asymmetric unit. Taken together, our findings provide strong evidence that FAD plays a structural role in the formation of tetrameric AidB.National Institutes of Health (U.S.) (grant R01-GM0272663)National Institutes of Health (U.S.) (grant P30-ES002109)National Science Foundation (U.S.) (grant MCB-0543833

Boolean Dynamics with Random Couplings

This paper reviews a class of generic dissipative dynamical systems called N-K models. In these models, the dynamics of N elements, defined as Boolean variables, develop step by step, clocked by a discrete time variable. Each of the N Boolean elements at a given time is given a value which depends upon K elements in the previous time step. We review the work of many authors on the behavior of the models, looking particularly at the structure and lengths of their cycles, the sizes of their basins of attraction, and the flow of information through the systems. In the limit of infinite N, there is a phase transition between a chaotic and an ordered phase, with a critical phase in between. We argue that the behavior of this system depends significantly on the topology of the network connections. If the elements are placed upon a lattice with dimension d, the system shows correlations related to the standard percolation or directed percolation phase transition on such a lattice. On the other hand, a very different behavior is seen in the Kauffman net in which all spins are equally likely to be coupled to a given spin. In this situation, coupling loops are mostly suppressed, and the behavior of the system is much more like that of a mean field theory. We also describe possible applications of the models to, for example, genetic networks, cell differentiation, evolution, democracy in social systems and neural networks.Comment: 69 pages, 16 figures, Submitted to Springer Applied Mathematical Sciences Serie