The study of DNA damage repair in Arabidopsis thaliana

DNA is the major storage of genetic information common to all cellular organisms. Endogenous and exogenous factors may damage DNA and affect plant growth and fitness. To dissect the genetic variation of Arabidopsis thaliana to DNA replication stress, 400 Arabidopsis natural accessions were exposed to hydroxyurea (HU), a drug interfering with deoxyribonucleotide synthesis. This revealed a great variation in relative survival of Arabidopsis accessions to HU. However, extremely hypersensitive accessions were rare. To identify the molecular basis of this natural variation, quantitative trait locus (QTL) mapping with the recombinant inbred line population derived from crosses between HU-sensitive and resistant parents was performed. Two significant QTLs with additive effects and one minor QTL with epistatic effect were identified. Using heterogeneous inbred family analysis, one QTL was validated and fine mapped to a 22 kb region containing eight candidate genes which require further analysis. Genes involved in related biological processes or pathways are often expressed coordinately, thus the uncharacterized candidate genes might be co-expressed with the functionally known genes. This co-expression strategy was applied to search for novel DNA damage repair genes in Arabidopsis and revealed increased sensitivity of mutants in CHROMATIN REMODELING 31 to DNA inter-strand cross-linker, mitomycin C. Furthermore, the chr31 mutant showed delayed cell cycle progression and increased frequencies of somatic homologous recombination (HR). This provides a novel connection between chromatin remodeling and DNA damage responses by so far unknown mechanisms. Nucleoside analogues are frequently used in basic and medical research. However, their mode of action and spectra of effects are not well understood. Analysis of the molecular effects of non-methylable cytidine analogue zebularine in Arabidopsis revealed induction of DNA damage response, post-replicative cell cycle arrest, and increased endoreduplication, but without obvious changes in DNA methylation. Molecular and genetic data suggested that zebularine-induced damage specifically occur during DNA replication in the course of DNA strand synthesis. The signaling of this damage was mediated by additive activity of ATAXIA TELANGIECTASIA MUTATED and ATAXIA_TELANGIECTASIA MUTATED AND RAD3-RELATED kinases. The repair required a functional STRUCTURAL MAINTENANCE OF CHROMOSOMES (SMC) 5-SMC6 complex and was accomplished predominantly by synthesis-dependent strand annealing type of HR. Hence, commonly used “epigenetic inhibitor” zebularine causes specific type of DNA damage

Retraction and Generalized Extension of Computing with Words

Fuzzy automata, whose input alphabet is a set of numbers or symbols, are a formal model of computing with values. Motivated by Zadeh's paradigm of computing with words rather than numbers, Ying proposed a kind of fuzzy automata, whose input alphabet consists of all fuzzy subsets of a set of symbols, as a formal model of computing with all words. In this paper, we introduce a somewhat general formal model of computing with (some special) words. The new features of the model are that the input alphabet only comprises some (not necessarily all) fuzzy subsets of a set of symbols and the fuzzy transition function can be specified arbitrarily. By employing the methodology of fuzzy control, we establish a retraction principle from computing with words to computing with values for handling crisp inputs and a generalized extension principle from computing with words to computing with all words for handling fuzzy inputs. These principles show that computing with values and computing with all words can be respectively implemented by computing with words. Some algebraic properties of retractions and generalized extensions are addressed as well.Comment: 13 double column pages; 3 figures; to be published in the IEEE Transactions on Fuzzy System

Coordinate Ascent for Off-Policy RL with Global Convergence Guarantees

We revisit the domain of off-policy policy optimization in RL from the perspective of coordinate ascent. One commonly-used approach is to leverage the off-policy policy gradient to optimize a surrogate objective -- the total discounted in expectation return of the target policy with respect to the state distribution of the behavior policy. However, this approach has been shown to suffer from the distribution mismatch issue, and therefore significant efforts are needed for correcting this mismatch either via state distribution correction or a counterfactual method. In this paper, we rethink off-policy learning via Coordinate Ascent Policy Optimization (CAPO), an off-policy actor-critic algorithm that decouples policy improvement from the state distribution of the behavior policy without using the policy gradient. This design obviates the need for distribution correction or importance sampling in the policy improvement step of off-policy policy gradient. We establish the global convergence of CAPO with general coordinate selection and then further quantify the convergence rates of several instances of CAPO with popular coordinate selection rules, including the cyclic and the randomized variants of CAPO. We then extend CAPO to neural policies for a more practical implementation. Through experiments, we demonstrate that CAPO provides a competitive approach to RL in practice.Comment: 47 pages, 4 figure

Regulation of axon repulsion by MAX-1 SUMOylation and AP-3.

During neural development, growing axons express specific surface receptors in response to various environmental guidance cues. These axon guidance receptors are regulated through intracellular trafficking and degradation to enable navigating axons to reach their targets. In Caenorhabditis elegans, the UNC-5 receptor is necessary for dorsal migration of developing motor axons. We previously found that MAX-1 is required for UNC-5-mediated axon repulsion, but its mechanism of action remained unclear. Here, we demonstrate that UNC-5-mediated axon repulsion in C. elegans motor axons requires both max-1 SUMOylation and the AP-3 complex β subunit gene, apb-3 Genetic interaction studies show that max-1 is SUMOylated by gei-17/PIAS1 and acts upstream of apb-3 Biochemical analysis suggests that constitutive interaction of MAX-1 and UNC-5 receptor is weakened by MAX-1 SUMOylation and by the presence of APB-3, a competitive interactor with UNC-5. Overexpression of APB-3 reroutes the trafficking of UNC-5 receptor into the lysosome for protein degradation. In vivo fluorescence recovery after photobleaching experiments shows that MAX-1 SUMOylation and APB-3 are required for proper trafficking of UNC-5 receptor in the axon. Our results demonstrate that SUMOylation of MAX-1 plays an important role in regulating AP-3-mediated trafficking and degradation of UNC-5 receptors during axon guidance

Poly[(μ6-benzene-1,3,5-tricarboxyl­ato-κ6 O 1:O 1′:O 3:O 3′:O 5:O 5′)tris­(N,N-dimethyl­formamide-κO)tris­(μ3-formato-κ2 O:O′)trimagnesium(II)]

The title complex, [Mg3(CHO2)3(C9H3O6)(C3H7NO)3]n, exhib­its a two-dimensional structure parallel to (001), which is built up from the MgII atoms and bridging carboxyl­ate ligands (3 symmetry). The MgII atom is six-coordinated by one O atom from a dimethyl­formamide mol­ecule, two O atoms from two μ6-benzene-1,3,5-tricarboxyl­ate ligands and three O atoms from three μ3-formate ligands in a distorted octa­hedral geometry

Pressure Dependence of Fragile-to-Strong Transition and a Possible Second Critical Point in Supercooled Confined Water

By confining water in nano-pores of silica glass, we can bypass the crystallization and study the pressure effect on the dynamical behavior in deeply supercooled state using neutron scattering. We observe a clear evidence of a cusp-like fragile-to-strong (F-S) dynamic transition. Here we show that the transition temperature decreases steadily with an increasing pressure, until it intersects the homogenous nucleation temperature line of bulk water at a pressure of 1600 bar. Above this pressure, it is no longer possible to discern the characteristic feature of the F-S transition. Identification of this end point with the possible second critical point is discussed.Comment: 4 pages, 3 figure

Discovering Chromatin Motifs using FAIRE Sequencing and the Human Diploid Genome

Background: Specific chromatin structures are associated with active or inactive gene transcription. The gene regulatory elements are intrinsically dynamic and alternate between inactive and active states through the recruitment of DNA binding proteins, such as chromatin-remodeling proteins. Results: We developed a unique genome-wide method to discover DNA motifs associated with chromatin accessibility using formaldehyde-assisted isolation of regulatory elements with high-throughput sequencing (FAIRE-seq). We aligned the FAIRE-seq reads to the GM12878 diploid genome and subsequently identified differential chromatin-state regions (DCSRs) using heterozygous SNPs. The DCSR pairs represent the locations of imbalances of chromatin accessibility between alleles and are ideal to reveal chromatin motifs that may directly modulate chromatin accessibility. In this study, we used DNA 6-10mer sequences to interrogate all DCSRs, and subsequently discovered conserved chromatin motifs with significant changes in the occurrence frequency. To investigate their likely roles in biology, we studied the annotated protein associated with each of the top ten chromatin motifs genome-wide, in the intergenic regions and in genes, respectively. As a result, we found that most of these annotated motifs are associated with chromatin remodeling, reflecting their significance in biology. Conclusions: Our method is the first one using fully phased diploid genome and FAIRE-seq to discover motifs associated with chromatin accessibility. Our results were collected to construct the first chromatin motif database (CMD), providing the potential DNA motifs recognized by chromatin-remodeling proteins and is freely available at http://syslab.nchu.edu.tw/chromatin

Risk of pneumocystosis after early discontinuation of prophylaxis among HIV-infected patients receiving highly active antiretroviral therapy

<p>Abstract</p> <p>Background</p> <p>Risk of pneumocystosis after discontinuation of primary or secondary prophylaxis among HIV-infected patients before CD4 counts increase to ≧200 cells/μL (early discontinuation) after receiving highly active antiretroviral therapy (HAART) is rarely investigated.</p> <p>Methods</p> <p>Medical records of 660 HIV-infected patients with baseline CD4 counts <200 cells/μL who sought HIV care and received HAART at a university hospital in Taiwan between 1 April, 1997 and 30 September, 2007 were reviewed to assess the incidence rate of pneumocystosis after discontinuation of prophylaxis for pneumocystosis.</p> <p>Results</p> <p>The incidence rate of pneumocystosis after HAART was 2.81 per 100 person-years among 521 patients who did not initiate prophylaxis or had early discontinuation of prophylaxis, which was significantly higher than the incidence rate of 0.45 per 100 person-years among 139 patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL (adjusted risk ratio, 5.32; 95% confidence interval, 1.18, 23.94). Among the 215 patients who had early discontinuation of prophylaxis after achievement of undetectable plasma HIV RNA load, the incidence rate of pneumocystosis was reduced to 0.31 per 100 person-years, which was similar to that of the patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL (adjusted risk ratio, 0.63; 95% confidence interval, 0.03, 14.89).</p> <p>Conclusions</p> <p>Compared with the risk of pneumocystosis among patients who continued prophylaxis until CD4 counts increased to ≧200 cells/μL after HAART, the risk was significantly higher among patients who discontinued prophylaxis when CD4 counts remained <200 cells/μL, while the risk could be reduced among patients who achieved undetectable plasma HIV RNA load after HAART.</p