DNA damage induced via independent generation of the radical resulting from formal hydrogen atom abstraction from the C1′-position of a nucleotide

AbstractBackground: Deoxyribonucleotide radicals resulting from formal C1′-hydrogen atom abstraction are important reactive intermediates in a variety of DNA-damage processes. The reactivity of these radicals can be affected by the agents that generate them and the environment in which they are produced. As an initial step in determining the factors that control the reactivity of these important radical species, we developed a mild method for their generation at a defined site within a biopolymer.Results: Irradiation of oligonucleotides containing a photolabile nucleotide produced C1'-DNA radicals. In the absence of potential reactants other than O2, approximately 90% of the damage events involve formation of alkaline-labile lesions, with the remainder resulting in direct strand breaks. The ratio of alkaline-labile lesions to direct strand breaks (∼ 9:1) is independent of whether the radical is generated in single-stranded DNA or double-stranded DNA. Strand damage is almost completely quenched under anaerobic conditions in the presence of low thiol concentrations. Competition studies with 02 indicate that the trapping rate of C1′-DNA radicals by β-mercaptoethanol is ∼ 1.1 x 107 M−1s−1Conclusions: The mild generation of the C1'-DNA radical in the absence of exogenous oxidants makes it possible to examine their intrinsic reactivity. In the absence of other reactants, the formation of direct strand breaks from C1′-radicals is, at most, a minor pathway. Competition studies between β-mercaptoethanol and 02 indicate that significantly higher thiol concentrations than those in vivo or some means of increasing the effective thiol concentration near DNA are needed for these reagents to prevent the formation of DNA lesions arising from the C1'-radical under aerobic conditions

Complexity for Modules Over the Classical Lie Superalgebra gl(m|n)

Let $\mathfrak{g}=\mathfrak{g}_{\bar{0}}\oplus \mathfrak{g}_{\bar{1}}$ be a classical Lie superalgebra and $\mathcal{F}$ be the category of finite dimensional $\mathfrak{g}$-supermodules which are completely reducible over the reductive Lie algebra $\mathfrak{g}_{\bar{0}}$. In an earlier paper the authors demonstrated that for any module $M$ in $\mathcal{F}$ the rate of growth of the minimal projective resolution (i.e., the complexity of $M$) is bounded by the dimension of $\mathfrak{g}_{\bar{1}}$. In this paper we compute the complexity of the simple modules and the Kac modules for the Lie superalgebra $\mathfrak{gl}(m|n)$. In both cases we show that the complexity is related to the atypicality of the block containing the module.Comment: 32 page

Multimodal Neuroimaging-Informed Clinical Applications in Neuropsychiatric Disorders

Recent advances in neuroimaging data acquisition and analysis hold the promise to enhance the ability to make diagnostic and prognostic predictions and perform treatment planning in neuropsychiatric disorders. Prior research using a variety of types of neuroimaging techniques has confirmed that neuropsychiatric disorders are associated with dysfunction in anatomical and functional brain circuits. We first discuss current challenges associated with the identification of reliable neuroimaging markers for diagnosis and prognosis in mood disorders and for neurosurgical treatment planning for deep brain stimulation (DBS). We then present data on the use of neuroimaging for the diagnosis and prognosis of mood disorders and for DBS treatment planning. We demonstrate how multivariate analyses of functional activation and connectivity parameters can be used to differentiate patients with bipolar disorder from those with major depressive disorder and non-affective psychosis. We also present data on connectivity parameters that mediate acute treatment response in affective and non-affective psychosis. We then focus on precision mapping of functional connectivity in native space. We describe the benefits of integrating anatomical fiber reconstruction with brain functional parameters and cortical surface measures to derive anatomically-informed connectivity metrics within the morphological context of each individual brain. We discuss how this approach may be particularly promising in psychiatry, given the clinical and etiological heterogeneity of the disorders, and particularly in treatment response prediction and planning. Precision mapping of connectivity is essential for DBS. In DBS, treatment electrodes are inserted into positions near key grey matter nodes within the circuits considered relevant to disease expression. However, targeting white matter tracts that underpin connectivity within these circuits may increase treatment efficacy and tolerability therefore relevant for effective treatment. We demonstrate how this approach can be validated in the treatment of Parkinson’s disease by identifying connectivity patterns that can be used as biomarkers for treatment planning and thus refine the traditional approach of DBS planning that uses only grey matter landmarks. Finally we describe how this approach could be used in planning DBS treatment of psychiatric disorders

Report from the Passive Microwave Data Set Management Workshop

Passive microwave data sets are some of the most important data sets in the Earth Observing System Data and Information System (EOSDIS), providing data as far back as the early 1970s. The widespread use of passive microwave (PM) radiometer data has led to their collection and distribution over the years at several different Earth science data centers. The user community is often confused by this proliferation and the uneven spread of information about the data sets. In response to this situation, a Passive Microwave Data Set Management Workshop was held 17 ]19 May 2011 at the Global Hydrology Resource Center, sponsored by the NASA Earth Science Data and Information System (ESDIS) Project. The workshop attendees reviewed all primary (Level 1 ]3) PM data sets from NASA and non ]NASA sensors held by NASA Distributed Active Archive Centers (DAACs), as well as high ]value data sets from other NASA ]funded organizations. This report provides the key findings and recommendations from the workshop as well as detailed tabluations of the datasets considered

Association of selenium, tocopherols, carotenoids, retinol, and 15-isoprostane F(2t) in serum or urine with prostate cancer risk: the multiethnic cohort.

We examine the association of antioxidants and 15-isoprostane F(2t) with risk of prostate cancer.We conducted a nested case-control study of serum antioxidant biomarkers (selenium, tocopherols, carotenoids, and retinol) and a urinary oxidation biomarker (15-isoprostane F(2t)) with risk of prostate cancer within the Multiethnic Cohort. Demographic, dietary, and other exposure information was collected by self-administered questionnaire in 1993-1996. We compared prediagnostic biomarker levels from 467 prostate cancer cases and 936 cancer free controls that were matched on several variables. Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs).We observed that there was no overall association of serum concentrations of antioxidants and urinary concentrations of 15-isoprostane F(2t) with risk of prostate cancer or risk of advanced prostate cancer. However, we did observe an inverse association for serum selenium only among African-American men (p trend = 0.02); men in the third tertile of selenium concentrations had a 41% lower risk (95% CI: 0.38-0.93) of prostate cancer when compared to men in the first tertile.Overall, our study found no association of serum antioxidants or 15-isoprostane F(2t) with the risk of prostate cancer. The observed inverse association of selenium with prostate cancer in African-Americans needs to be validated in other studies

An archaeal family-B DNA polymerase variant able to replicate past DNA damage: occurrence of replicative and translesion synthesis polymerases within the B family

A mutant of the high fidelity family-B DNA polymerase from the archaeon Thermococcus gorgonarius (Tgo-Pol), able to replicate past DNA lesions, is described. Gain of function requires replacement of the three amino acid loop region in the fingers domain of Tgo-Pol with a longer version, found naturally in eukaryotic Pol zeta (a family-B translesion synthesis polymerase). Inactivation of the 3'–5' proofreading exonuclease activity is also necessary. The resulting Tgo-Pol Z1 variant is proficient at initiating replication from base mismatches and can read through damaged bases, such as abasic sites and thymine photo-dimers. Tgo-Pol Z1 is also proficient at extending from primers that terminate opposite aberrant bases. The fidelity of Tgo-Pol Z1 is reduced, with amarked tendency tomake changes at G:C base pairs. Together, these results suggest that the loop region of the fingers domain may play a critical role in determining whether a family-B enzyme falls into the accurate genome-replicating category or is an errorprone translesion synthesis polymerase. Tgo-Pol Z1 may also be useful for amplification of damaged DNA

Phase Transitions in Warm, Asymmetric Nuclear Matter

A relativistic mean-field model of nuclear matter with arbitrary proton fraction is studied at finite temperature. An analysis is performed of the liquid-gas phase transition in a system with two conserved charges (baryon number and isospin) using the stability conditions on the free energy, the conservation laws, and Gibbs' criteria for phase equilibrium. For a binary system with two phases, the coexistence surface (binodal) is two-dimensional. The Maxwell construction through the phase-separation region is discussed, and it is shown that the stable configuration can be determined uniquely at every density. Moreover, because of the greater dimensionality of the binodal surface, the liquid-gas phase transition is continuous (second order by Ehrenfest's definition), rather than discontinuous (first order), as in familiar one-component systems. Using a mean-field equation of state calibrated to the properties of nuclear matter and finite nuclei, various phase-separation scenarios are considered. The model is then applied to the liquid-gas phase transition that may occur in the warm, dilute matter produced in energetic heavy-ion collisions. In asymmetric matter, instabilities that produce a liquid-gas phase separation arise from fluctuations in the proton concentration (chemical instability), rather than from fluctuations in the baryon density (mechanical instability).Comment: Postscript file, 50 pages including 23 figure

Dark Matter from Minimal Flavor Violation

We consider theories of flavored dark matter, in which the dark matter particle is part of a multiplet transforming nontrivially under the flavor group of the Standard Model in a manner consistent with the principle of Minimal Flavor Violation (MFV). MFV automatically leads to the stability of the lightest state for a large number of flavor multiplets. If neutral, this particle is an excellent dark matter candidate. Furthermore, MFV implies specific patterns of mass splittings among the flavors of dark matter and governs the structure of the couplings between dark matter and ordinary particles, leading to a rich and predictive cosmology and phenomenology. We present an illustrative phenomenological study of an effective theory of a flavor SU(3)_Q triplet, gauge singlet scalar.Comment: 10 pages, 2 figures; v2: references added, minor changes to collider analysis, conclusions unchange