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  • Biosynthesis pathways of pyrimidine and purine are shown to play an important role in regular cellular activities. The biosynthesis can occur either through de novo or salvage pathways based on the requirement of the cell. The pyrimidine biosynthesis pathway has been linked to several disorders and various autoimmune diseases. Orotate phosphoribosyl transferase (OPRTase) is an important enzyme which catalyzes the conversion of orotate to orotate monophosphate in the fifth step of pyrimidine biosynthesis. Phylogenetic analysis of 228 OPRTase sequences shows the distribution of proteins across different living forms of life. High structural similarities between Thermus thermophilus and other organisms kindled us to concentrate on OPRTase as an anti-pathogenic target. In this study, a homology model of OPRTase was constructed using 2P1Z as a template. About 100ns molecular dynamics simulation was performed to investigate the conformational stability and dynamic patterns of the protein. The amino acid residues (Met1, Asp2, Glu43, Ala44, Glu47, Lys51, Ala157 and Leu158) lining in the binding site were predicted using SiteMap. Further, structure based virtual screening was performed on the predicted binding site using ChemBridge, Asinex, Binding, NCI, TosLab and Zinc databases. Compounds retrieved from the screening collections were manually clustered. The resultant protein–ligand complexes were subjected to molecular dynamics simulations, which further validates the binding modes of the hits. The study may provide better insight for designing potent anti-pathogenic agent.
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  • Why are a few drugs with properties beyond the rule of 5 (bRo5) absorbed across the intestinal mucosa while most other bRo5 compounds are not? Are such exceptional bRo5 compounds exclusively taken up by carrier-mediated transport or are they able to permeate the lipid bilayer (passive lipoidal diffusion)? Our experimental data with liposomes indicate that tetracycline, which violates one rule of the Ro5, and rifampicin, violating three of the rules, significantly permeate a phospholipid bilayer with kinetics similar to labetalol and metoprolol, respectively. Published data from experimental work and molecular dynamics simulations suggest that the formation of intramolecular H-bonds and the possibility to adopt an elongated shape besides the presence of a significant fraction of net neutral species facilitate lipid bilayer permeation. As an alternative to lipid bilayer permeation, carrier proteins can be targeted to improve absorption, with the potential drawbacks of drug–drug interactions and non-linear pharmacokinetics.
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  • Increasing the colonization rate of metapopulations can improve persistence, but can also increase exposure to threats. To make good decisions, managers must understand whether increased colonization is beneficial or detrimental to metapopulation persistence. While a number of studies have examined interactions between metapopulations, colonization, and threats, they have assumed that threat dynamics respond linearly to changes in colonization. Here, we determined when to increase colonization while explicitly accounting for non-linear dependencies between a metapopulation and its threats. We developed patch occupancy metapopulation models for species susceptible to abiotic, generalist, and specialist threats and modeled the total derivative of the equilibrium proportion of patches occupied by each metapopulation with respect to the colonization rate. By using the total derivative, we developed a rule for determining when to increase metapopulation colonization. This rule was applied to a simulated metapopulation where the dynamics of each threat responded to increased colonization following a power function. Before modifying colonization, we show that managers must understand: (1) whether a metapopulation is susceptible to a threat; (2) the type of threat acting on a metapopulation; (3) which component of threat dynamics might depend on colonization, and; (4) the likely response of a threat-dependent variable to changes in colonization. The sensitivity of management decisions to these interactions increases uncertainty in conservation planning decisions.
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  • One strategy to safeguard endangered species against extinction is raising subpopulations in ex situ facilities. Feeding animals ex situ is difficult when their diet is cryptic. We present a combined molecular and behavioral approach to assess the diet of Achatinella, a critically endangered genus of tree snail, to determine how diet of captive snails differs from wild snails. Cultured snails are currently fed biofilms growing on leaf surfaces, as well as a Cladosporium fungus isolated from this same habitat. Amplicon sequencing of DNA extracted from feces of wild and cultured snails confirms that this Cladosporium is abundant in the wild (~1.5% of sequences), but it dominates the ex situ snails' diet (~38%) and the diet of captive snails is still significantly less diverse than wild snails. To test the hypothesis that snails have diet preferences, we conducted feeding trials. These used a surrogate snail species, Auriculella diaphana, which is a confamilial Oahu endemic, though non-federally listed. Contrary to our expectations we found that snails do have feeding preferences. Furthermore, our feeding preference trials show that over all other feeding options snails most preferred the “no-microbe” control, which consisted only of potato dextrose agar (PDA). PDA is rich in simple carbohydrates, in contrast to the oligotrophic environment of wild tree-snails. These results suggest further research should focus on calorie budgets of snails, devising new approaches to supplementing their ex situ diet and determining whether a wild diet is an optimum diet.
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  • Hierarchical centering has been described as a reparameterization method applicable to random effects models. It has been shown to improve mixing of models in the context of Markov chain Monte Carlo (MCMC) methods. A hierarchical centering approach is proposed for reversible jump MCMC (RJMCMC) chains which builds upon the hierarchical centering methods for MCMC chains and uses them to reparameterize models in an RJMCMC algorithm. Although these methods may be applicable to models with other error distributions, the case is described for a log-linear Poisson model where the expected value λ includes fixed effect covariates and a random effect for which normality is assumed with a zero-mean and unknown standard deviation. For the proposed RJMCMC algorithm including hierarchical centering, the models are reparameterized by modeling the mean of the random effect coefficients as a function of the intercept of the λ model and one or more of the available fixed effect covariates depending on the model. The method is appropriate when fixed-effect covariates are constant within random effect groups. This has an effect on the dynamics of the RJMCMC algorithm and improves model mixing. The methods are applied to a case study of point transects of indigo buntings where, without hierarchical centering, the RJMCMC algorithm had poor mixing and the estimated posterior distribution depended on the starting model. With hierarchical centering on the other hand, the chain moved freely over model and parameter space. These results are confirmed with a simulation study. Hence, the proposed methods should be considered as a regular strategy for implementing models with random effects in RJMCMC algorithms; they facilitate convergence of these algorithms and help avoid false inference on model parameters.
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  • The analysis of the decision boundaries plays an important role in understanding the characteristics of a classifier in the framework of model-based clustering and discriminant analysis. The wider is the family of decision boundaries generated by a classifier the larger is its flexibility for classification purposes. In this paper, we present rigorous results concerning the decision boundaries of mixtures of (linear) regressions under Gaussian assumptions. In particular, three types of mixtures of regressions are considered: with fixed covariates, with concomitant variables, and with random covariates. The obtained decision boundaries have a geometrical interpretation in terms hyperquadrics and define a taxonomy of the considered models. Beyond Gaussian assumptions, decision boundaries can be investigated numerically; as an example, we illustrate the case of the t distribution.
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  • SQUAMOSA promoter binding protein-like (SPL) transcription factors (TFs) are plant-specific and play vital regulatory roles in plant growth and development. Even though they are one of the unique groups of TFs in plants, their characteristics, evolutionary relationships and expression patterns are largely unknown in maize, an important food crop worldwide. In this study, we identified 31 SPL genes (ZmSPLs) in the maize B73 genome. A phylogenetic analysis showed that these genes were divided into six groups (Groups 1–6) and members within the same group shared conserved exon/intron distributions and motif compositions, implying their functional redundancy. The 31 ZmSPL genes were distributed unevenly on 9 of the 10 chromosomes, with 10 segmental duplication events, suggesting that the expansion of the ZmSPL genes occurred due to segmental duplication. Analysis of the Ka/Ks ratios showed that the duplicated ZmSPL genes had primarily undergone strong purifying selection. In addition, 19 of the 31 ZmSPLs, belonging to Groups 1, 2 and 3, were targets of microRNA miR156, indicating of the miR156-mediated posttranscriptional regulation of these ZmSPL genes. Expression analysis of the ZmSPLs in various tissues at different development stages revealed distinct spatiotemporal patterns. Moreover, quantitative real-time PCR analysis identified several ZmSPL genes that were potentially involved in response to abiotic stresses. Our results present a comprehensive overview of the maize SPL gene family and provide an important foundation for further uncovering the biological functions of ZmSPLs in the growth and development of maize.
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  • Genes from the plant specific Lateral Organ Boundaries Domain (LBD) family encode transcriptional regulators that have a variety of functions in various physiological and developmental processes. In the present study, 31 LBD genes were identified in the mulberry genome. The genome features of all MnLBD genes and phylogenetic studies with Arabidopsis LBD protein sequences, accompanied by the expression analysis of each of the Morus LBD genes provide insights into the functional prediction of mulberry LBDs. The genome-wide surveys of the current mulberry genome have resulted in the identification of catalogs of MnLBD genes that may function in the development of leaf, root, and secondary metabolism in Morus sp.
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  • There is a substantial harvest for Antarctic krill in the Southern Ocean, but little regular scientific monitoring of the resource. Recently, however, the Commission for the Conservation of Marine Living Resources (CCAMLR) has initialised a process to make use of acoustic data from commercial fisheries to increase the amount of relevant information available for making management decisions. We here provide an example where 34 days of acoustic data, collected during commercial krill fishing operations on the vessel ‘Saga Sea’ were processed to produce probability of presence, conditional density and relative abundance estimates on monthly, weekly and daily basis. Data were analyzed using a maximum likelihood time-series and geostatistical approaches, selected to account for the lack of sampling design, and likely correlation in space and time. The applied method showed low sensitivity of monthly estimates to different repeated measure criteria and location sub-settings. Most weekly estimates, but the last one, were also consistent with the full data (monthly) estimate. Highly variable and lower estimates were obtained, however, from daily data sets. Although our results suggest the method had provided an adequate treatment for time and space correlation, we were not able to evaluate potential bias due to preferential sampling of high density krill aggregations and/or limited area coverage within short time periods. The results suggest that this method, combined with some additional design based coverage by the fishing vessels, can be useful to obtain quantitative evaluations of krill density and distribution for management purposes.
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  • The specific interactions between RNA-binding proteins and their target RNAs are an essential level to control gene expression. By combining ultra-violet cross-linking and immunoprecipitation (CLIP) and massive SoliD sequencing we identified the RNAs bound by the RNA-binding protein CELF1, in human HeLa cells. The CELF1 binding sites deduced from the sequence data allow characterizing specific features of CELF1-RNA association. We present therefore the first map of CELF1 binding sites in human cells.
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