Conserved intron positions in ancient protein modules

Background  

The timing of the origin of introns is of crucial importance for an understanding of early genome architecture. The Exon theory of genes proposed a role for introns in the formation of multi-exon proteins by exon shuffling and predicts the presence of conserved splice sites in ancient genes. In this study, large-scale analysis of potential conserved splice sites was performed using an intron-exon database (ExInt) derived from GenBank.     

DPIV measurements of flow disturbances in stented artery models: adverse affects of compliance mismatch

Vascular stents influence the post-procedural hemodynamic environment in ways that may encourage restenosis. Understanding how stents influence flow patterns may lead to more hemodynamically compatible stent designs that alleviate thrombus formation and promote endothelialization. This study employed time-resolved Digital Particle Image Velocimetry (DPIV) to compare the hemodynamic performance of two stents in a compliant vessel. The first stent was a rigid insert, representing an extreme compliance mismatch. The second stent was a commercially available nitinol stent with some flexural characteristics. DPIV showed that compliance mismatch promotes the formation of a ring vortex in the vicinity of the stent. Larger compliance mismatch increased both the size and residence time of the ring vortex, and introduced in-flow stagnation points. These results provide detailed quantitative evidence of the hemodynamic effect of stent mechanical properties. Better understanding of these characteristics will provide valuable information for modifying stent design in order to promote long-term patency.     

Ribosomal Protein Genes RPS10 and RPS26 Are Commonly Mutated in Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%–50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.     

Non-target organism effects tests on Vip3A and their application to the ecological risk assessment for cultivation of MIR162 maize

Transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) provide economic, environmental and health benefits by maintaining or increasing crop yields with fewer applications of insecticide. To sustain these benefits, it is important to delay the evolution of insect resistance to the proteins, and to ensure that the proteins do not harm non-target organisms, particularly those that may control secondary pests that would otherwise flourish because of reduced insecticide applications. Vip3A is a Bt vegetative insecticidal protein that is active against lepidopterous pests. It has a different mode of action from other proteins for control of Lepidoptera in current Bt crops, and when combined with these proteins, it should help to delay the evolution of pest resistance to Bt crops. This paper presents data on the effects of Vip3A on non-target organisms, and an ecological risk assessment of MIR162 maize, which expresses Vip3Aa20. Laboratory studies indicate few adverse effects of Vip3A to non-target organisms: 11 of 12 species tested showed no adverse effects when exposed to high concentrations of Vip3A relative to estimated exposures resulting from cultivation of MIR162 maize. Daphnia magna exposed to Vip3Aa20 were unaffected in terms of survival or fecundity, but grew slightly more slowly than unexposed controls. The data indicate that cultivation of MIR162 maize poses negligible risk to non-target organisms, and that crops producing Vip3A are unlikely to adversely affect biological control organisms such that benefits from reduced insecticide applications are lost.     

Context-dependent encoding of fear and extinction memories in a large-scale network model of the basal amygdala

The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories.     

Time accelerated Monte Carlo simulations of biological networks using the binomial tau-leap method

SUMMARY: Developing a quantitative understanding of intracellular networks requires simulations and computational analyses. However, traditional differential equation modeling tools are often inadequate due to the stochasticity of intracellular reaction networks that can potentially influence the phenotypic characteristics. Unfortunately, stochastic simulations are computationally too intense for most biological systems. Herein, we have utilized the recently developed binomial tau-leap method to carry out stochastic simulations of the epidermal growth factor receptor induced mitogen activated protein kinase cascade. Results indicate that the binomial tau-leap method is computationally 100-1000 times more efficient than the exact stochastic simulation algorithm of Gillespie. Furthermore, the binomial tau-leap method avoids negative populations and accurately captures the species populations along with their fluctuations despite the large difference in their size. AVAILABILITY: http://www.dion.che.udel.edu/multiscale/Introduction.html. Fortran 90 code available for academic use by email. SUPPLEMENTARY INFORMATION: Details about the binomial tau-leap algorithm, software and a manual are available at the above website.     

Full-length p73alpha represses drug-induced apoptosis in small cell lung carcinoma cells

The p73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the NH2 terminus, two different promoters generate the full-length and the DeltaN isoforms, with or without the transactivating domain. At the COOH terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that DeltaNp73 isoforms exert a dominant-negative effect on p73 by blocking their transactivation activity and hence the ability to induce apoptosis. Considerable efforts are made to identify the functional diversity of the COOH-terminal p73 variants. In this study, we found that p73alpha inhibited drug-induced apoptosis in small cell lung carcinoma cells, whereas p73beta promoted it. p73alpha prevented Bax activation, mitochondrial dysfunction, and caspase activation. In addition, p73alpha was also able to reduce apoptosis induced by the BH3-only protein PUMA (p53 up-regulated modulator of apoptosis). Furthermore, we discovered that p73alpha is able to inhibit the pro-apoptotic effect of p73beta, demonstrating the existence of equilibrium between these two p73 isoforms. In conclusion, the reported overexpression of p73alpha in certain tumor types, and our findings that p73alpha exerts anti-apoptotic functions, indicate a potential oncogenic activity for p73.     

A nearly symmetric trinuclear chromium(III) oxo carboxylate assembly: preparation, molecular and crystal structure, and magnetic properties of [Cr3O(O2CPh)6(MeOH)3](NO3) · 2MeOH

Complex [Cr₃O(O₂CPh)₆(MeOH)₃](NO₃) · 2MeOH (1 · 2MeOH) has been synthesized from the one-pot reaction between Cr(NO₃)₃ · 9H₂O and NaO₂CPh in MeOH. The structure of the complex has been solved by single-crystal X-ray crystallography. It crystallizes in the monoclinic space group P2₁/n with a=14.716(6) Å, b=22.569(8) Å, c=15.755(6) Å, β=95.02(1)°, V=5212.5(4) ų and Z=4. Although the cation does not possess any crystallographically imposed symmetry element, its {Cr₃(μ₃-O)} core is nearly symmetric. Each Cr^III…Cr^III vector is further bridged by two η¹:η¹:μ₂ benzoates, with a terminal MeOH molecule completing octahedral coordination at each metal ion. The crystal structure consists of layers that are parallel to (0 1 0) crystallographic plane and are formed through π-π stacking interactions and hydrogen bonds. Variable-temperature magnetic susceptibility and solid-state ¹H NMR studies indicate that the total spin value of the ground state is 1/2. EPR experiments reveal the existence of a distribution of trimers with axial anisotropy in the g tensor.