Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapyinduced leukemia

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy

Cyclic nucleotide specificity of the activator and catalytic sites of a cGMP-stimulated cGMP phosphodiesterase from Dictyostelium discoideum

The cellular slime mold Dictyostelium discoideum has an intracellular phosphodiesterase which specifically hydrolyzes cGMP. The enzyme is activated by low cGMP concentrations, and is involved in the reduction of chemoattractant-mediated elevations of cGMP levels. The interaction of 20 cGMP derivatives with the activator site and with the catalytic site of the enzyme has been investigated. Binding of cGMP to the activator site is strongly reduced (more than 80-fold) if cGMP is no longer able to form a hydrogen bond at N2H2 or O2’H. Modifications at N7, C8, O3’ and O5’ induce only a small reduction of binding affinity. A cyclic phosphate structure, as well as a negatively charged oxygen atom at phosphorus, are essential to obtain activation of the enzyme. Substitution of the axial exocyclic oxygen atom by sulphur is tolerated; modification of the equatorial oxygen atom reduces the binding activity of cGMP to the activator site by 90-fold. Binding of cGMP to the catalytic site is strongly reduced if cGMP is modified at N1H, C6O, C8 and O3’, while modifications at N2H2, N3, N7, O2’H, and O5’ have minor effects. Both exocyclic oxygen atoms are important to obtain binding of cGMP to the catalytic site. The results indicate that activation of the enzyme by cGMP and hydrolysis of cGMP occur at different sites of the enzyme. cGMP is recognized at these sites by different types of molecular interaction between cGMP and the protein. cGMP derivatives at concentrations which saturate the activator site do not induce the same degree of activation of the enzyme (activation 2.3-6.6-fold). The binding affinities of the analogues for the activator site and their maximal activation are not correlated. Our results suggest that the enzyme is activated because cGMP bound to the activator site stabilizes a state of the enzyme which has a higher affinity for cGMP at the catalytic site.

Transcriptomic profiling of neonatal mouse granulosa cells reveals new insights into primordial follicle activation

The dormant population of ovarian primordial follicles is determined at birth and serves as the reservoir for future female fertility. Yet our understanding of the molecular, biochemical, and cellular processes underpinning primordial follicle activation remains limited. The survival of primordial follicles relies on the correct complement and morphology of granulosa cells, which provide signaling factors essential for oocyte and follicular survival. To investigate the contribution of granulosa cells in the primordial-to-primary follicle transition, gene expression profiles of granulosa cells undergoing early differentiation were assessed in a murine model. Ovaries from C57Bl/6 mice were enzymatically dissociated at time-points spanning the initial wave of primordial follicle activation. Post-natal day (PND) 1 ovaries yielded primordial granulosa cells, and PND4 ovaries yielded a mixed population of primordial and primary granulosa cells. The comparative transcriptome of granulosa cells at these time-points was generated via Illumina NextSeq 500 system, which identified 131 significantly differentially expressed transcripts. The differential expression of eight of the transcripts was confirmed by RT-qPCR. Following biological network mapping via Ingenuity Pathway Analysis, the functional expression of the protein products of three of the differentially expressed genes, namely FRZB, POD1, and ZFX, was investigated with in-situ immunolocalization in PND4 mouse ovaries was investigated. Finally, evidence was provided that Wnt pathway antagonist, secreted frizzled-related protein 3 (FRZB), interacts with a suppressor of primordial follicle activation WNT3A and may be involved in promoting primordial follicle activation. This study highlights the dynamic changes in gene expression of granulosa cells during primordial follicle activation and provides evidence for a renewed focus into the Wnt signaling pathway's role in primordial follicle activation

The crime drop and the security hypothesis

Major crime drops were experienced in the United States and most other industrialised countries for a decade from the early to mid-1990s. Yet there is little agreement over explanation or lessons for policy. Here it is proposed that change in the quantity and quality of security was a key driver of the crime drop. From evidence relating to vehicle theft in two countries it is concluded that electronic immobilisers and central locking were particularly effective. It is suggested that reduced car theft may have induced drops in other crime including violence. From this platform a broader security hypothesis, linked to routine activity and opportunity theory, is outlined

Spontaneous Magnetization of the O(3) Ferromagnet at Low Temperatures

We investigate the low-temperature behavior of ferromagnets with a spontaneously broken symmetry O(3) $\to$ O(2). The analysis is performed within the perspective of nonrelativistic effective Lagrangians, where the dynamics of the system is formulated in terms of Goldstone bosons. Unlike in a Lorentz-invariant framework (chiral perturbation theory), where loop graphs are suppressed by two powers of momentum, loops involving ferromagnetic spin waves are suppressed by three momentum powers. The leading coefficients of the low-temperature expansion for the partition function are calculated up to order $p^{10}$. In agreement with Dyson's pioneering microscopic analysis of the cubic ferromagnet, we find that, in the spontaneous magnetization, the magnon-magnon interaction starts manifesting itself only at order $T^4$. The striking difference with respect to the low-temperature properties of the O(3) antiferromagnet is discussed from a unified point of view, relying on the effective Lagrangian technique.Comment: 23 pages, 4 figure

Components of Natural Photosynthetic Apparatus in Solar Cells

Oxygenic photosynthesis is a process of light energy conversion into the chemical energy using water and carbon dioxide. The efficiency of energy conversion in the primary processes of photosynthesis is close to 100%. Therefore, for many years, photosynthesis has attracted the attention of researchers as the most efficient and eco-friendly pathway of solar energy conversion for alternative energy systems. The recent advances in the design of optimal solar cells include the creation of converters, in which thylakoid membranes, photosystems and whole cells of cyanobacteria immobilized on nanostructured electrode are used. As the mechanism of solar energy conversion in photosynthesis is sustainable and environmentally safe, it has a great potential as an example of renewable energy device. Application of pigments such as Chl f and Chl d will extend the spectral diapason of light transforming systems allow to absorb the far-red and near infra-red photons of the spectrum (in the range 700-750 nm). This article presents the recent achievements and challenges in the area of solar cells based on photosynthetic systems

Co-encapsulation of an antigen and CpG oligonucleotides into PLGA microparticles by TROMS technology.

It seems well established that CpG oligonucleotides Th1 biased adjuvant activity can be improved when closely associated with a variety of antigens in, for example, microparticles. In this context, we prepared 1-μm near non-charged PLGA 502 or PLGA 756 microparticles that loaded with high efficiency an antigen (50% ovalbumin (OVA), approximately) into their matrix and CpG-chitosan complexes (near to 20%) onto their surface maintaining OVA and CpG integrity intact. In the intradermal immunization studies, whereas OVA microencapsulated into PLGA 756 alone induced a strong humoral immune response assisted by a very clear Th1 bias (IgG2a/IgG1=0.875) that was decreased by CpG co-delivery (IgG2a/IgG1=0.55), the co-encapsulation of CpG with OVA in PLGA 502 particles significantly improved the antibody response and isotype shifting (IgG2a/IgG1=0.73) in comparison with mice immunized with OVA loaded PLGA 502 (IgG2a/IgG1=0). This improvement was not correlated with the cellular immune response where the effect of co-encapsulated CpG was rather negative (2030.2 pg/mL and 335.3 pg/mL IFN-g for OVA PLGA 502 for OVA CpG PLGA 502, respectively). These results underscore the critical role of polymer nature and microparticle characteristics to show the benefits of coencapsulating CpG motifs in close proximity with an antigen

Development of a novel vaccine delivery system based on Gantrez nanoparticles.

The adjuvant capacity of a novel vaccine vector “Gantrez-nanoparticles” (NP) towards coated or encapsulated ovalbumin (OVA) was investigated. OVA nanoparticles were prepared by a solvent displacement method previously described. The protein was incorporated during the manufacturing process (OVA-encapsulated nanoparticles) or after the preparation (OVA-coated nanoparticles). The mean size of the different nanoparticle formulations was lower than 300 nm, and the OVA content ranged approximately from 67 μg/mg nanoparticles (for OVA-coated nanoparticles) to 30 μg/mg nanoparticles (for OVA-encapsulated nanoparticles). All the OVA-NP formulations were capable of amplifying the antibodies titres (IgG1 and IgG2a) in mice after a single subcutaneous inoculation with respect free OVA or OVA adsorbed to Alum. Furthermore, the elicited response was, for some formulations, predominantly Th1 subtype. Thus, the formulation that contained mainly the antigen inside, and with a low concentration of cross-linking agent, displayed the best potential to induce a Th1 response after 35 days post-immunisation. These results are highly suggestive for the use of Gantrez nanoparticles as an efficient antigen delivery system, especially when a long lasting Th1 cytokine response is required

Dynamic wormholes, anti-trapped surfaces, and energy conditions

Adapting and extending a suggestion due to Page, we define a wormhole throat to be a marginally anti-trapped surface, that is, a closed two-dimensional spatial hypersurface such that one of the two future-directed null geodesic congruences orthogonal to it is just beginning to diverge. Typically a dynamic wormhole will possess two such throats, corresponding to the two orthogonal null geodesic congruences, and these two throats will not coincide, (though they do coalesce into a single throat in the static limit). The divergence property of the null geodesics at the marginally anti-trapped surface generalizes the ``flare-out'' condition for an arbitrary wormhole. We derive theorems regarding violations of the null energy condition (NEC) at and near these throats and find that, even for wormholes with arbitrary time-dependence, the violation of the NEC is a generic property of wormhole throats. We also discuss wormhole throats in the presence of fully antisymmetric torsion and find that the energy condition violations cannot be dumped into the torsion degrees of freedom. Finally by means of a concrete example we demonstrate that even temporary suspension of energy-condition violations is incompatible with the flare-out property of dynamic throats.Comment: 32 pages in plain LaTex, no figures. Additional text and references adde

An integrable discretization of the rational su(2) Gaudin model and related systems

The first part of the present paper is devoted to a systematic construction of continuous-time finite-dimensional integrable systems arising from the rational su(2) Gaudin model through certain contraction procedures. In the second part, we derive an explicit integrable Poisson map discretizing a particular Hamiltonian flow of the rational su(2) Gaudin model. Then, the contraction procedures enable us to construct explicit integrable discretizations of the continuous systems derived in the first part of the paper.Comment: 26 pages, 5 figure