Towards optimal distance functions for stochastic substitution models

Distance based reconstruction methods of phylogenetic trees consist of two independent parts: first, inter-species distances are inferred assuming some stochastic model of sequence evolution; then the inferred distances are used to construct a tree. In this paper we concentrate on the task of inter-species distance estimation. Specifically, we characterize the family of valid distance functions for the assumed substitution model and show that deliberate selection of distance function significantly improves the accuracy of distance estimates and, consequently, also improves the accuracy of the reconstructed tree.Our contribution consists of three parts: first, we present a general framework for constructing families of additive distance functions for stochastic evolutionary models. Then, we present a method for selecting (near) optimal distance functions, and we conclude by presenting simulation results which support our theoretical analysis.     

Aldosterone up‐regulates 12‐ and 15‐lipoxygenase expression and LDL oxidation in human vascular smooth muscle cells

Several lines of evidence suggest that aldosterone excess may have detrimental effects in the cardiovascular system, independent of its interaction with the renal epithelial cells. Here we examined the possibility that aldosterone modulates 12‐ and/or 15‐lipoxygenase (LO) expression/activity in human vascular smooth muscle cells (VSMC), in vitro, thereby potentially contributing to both vascular reactivity and atherogenesis. Following 24 h treatment of VSMC with aldosterone (1 nmol/L), there was a ～2‐fold increase in the generation rate of 12 hydroxyeicosatetraenoic acid (12‐HETE), 70% increase in platelet type 12‐LO mRNA expression (P < 0.001) along with a ～3‐fold increase in 12‐LO protein expression, which were blocked by the mineralocorticoid receptor (MR) antagonists spironolactone (100 nmol/L) and eplerelone (100 nmol/ml). Additionally, aldosterone (1 nmol/L; 24 h) increased the production of 15‐HETE (50%; P < 0.001) and the expression of 15‐LO type 2 mRNA (50%; P < 0.05) (in VSMC). Aldosterone also increased the 12‐ and 15‐LO type 2 mRNA expression in a line of human aortic smooth muscle cells (T/G HA‐VSMC) (60% and 50%, respectively). Aldosterone‐induced 12‐ and 15‐LO type 2 mRNA expressions were blocked by the EGF‐receptor antagonist AG 1478 and by the MAPK‐kinase inhibitor UO126. Aldosterone‐treated VSMC also showed increased LDL oxidation, (～2‐fold; P < 0.001), which was blocked by spironolactone. In conclusion, aldosterone increased 12‐ and 15‐LO expression in human VSMC, in association with increased 12‐ and 15‐HETE generation and enhanced LDL oxidation and may directly augment VSMC contractility, hypertrophy, and migration through 12‐HETE and promote LDL oxidation via the pro‐oxidative properties of these enzymes. J. Cell. Biochem. 108: 1203–1210, 2009. © 2009 Wiley‐Liss, Inc.     

Molecular dissection of Tomato leaf curl virus resistance in tomato line TY172 derived from Solanum peruvianum

Tomato yellow leaf curl virus (TYLCV) is devastating to tomato (Solanum lycopersicum) crops and resistant cultivars are highly effective in controlling the disease. The breeding line TY172, originating from Solanum peruvianum, is highly resistant to TYLCV. To map quantitative trait loci (QTLs) controlling TYLCV resistance in TY172, appropriate segregating populations were analyzed using 69 polymorphic DNA markers spanning the entire tomato genome. Results show that TYLCV resistance in TY172 is controlled by a previously unknown major QTL, originating from the resistant line, and four additional minor QTLs. The major QTL, we term Ty-5, maps to chromosome 4 and accounts for 39.7–46.6% of the variation in symptom severity among segregating plants (LOD score 33–35). The minor QTLs, originated either from the resistant or susceptible parents, were mapped to chromosomes 1, 7, 9 and 11, and contributed 12% to the variation in symptom severity in addition to Ty-5.     

The archaeabacterial flagellar filament: a bacterial propeller with a pilus-like structure

Common prokaryotic motility modes are swimming by means of rotating internal or external flagellar filaments or gliding by means of retracting pili. The archaeabacterial flagellar filament differs significantly from the eubacterial flagellum: (1) Its diameter is 10-14 nm, compared to 18-24 nm for eubacterial flagellar filaments. (2) It has 3.3 subunits/turn of a 1.9 nm pitch left-handed helix compared to 5.5 subunits/turn of a 2.6 nm pitch right-handed helix for plain eubacterial flagellar filaments. (3) The archaeabacterial filament is glycosylated, which is uncommon in eubacterial flagella and is believed to be one of the key elements for stabilizing proteins under extreme conditions. (4) The amino acid composition of archaeabacterial flagellin, although highly conserved within the group, seems unrelated to the highly conserved eubacterial flagellins. On the other hand, the archaeabacterial flagellar filament shares some fundamental properties with type IV pili: (1) The hydrophobic N termini are largely homologous with the oligomerization domain of pilin. (2) The flagellin monomers follow a different mode of transport and assembly. They are synthesized as pre-flagellin and have a cleavable signal peptide, like pre-pilin and unlike eubacterial flagellin. (3) The archaeabacterial flagellin, like pilin, is glycosylated. (4) The filament lacks a central channel, consistent with polymerization occurring at the cell-proximal end. (5) The diameter of type IV pili, 6-9 nm, is closer to that of the archaeabacterial filament, 10-14 nm. A large body of data on the biochemistry and molecular biology of archaeabacterial flagella has accumulated in recent years. However, their structure and symmetry is only beginning to unfold. Here, we review the structure of the archaeabacterial flagellar filament in reference to the structures of type IV pili and eubacterial flagellar filaments, with which it shares structural and functional similarities, correspondingly.     

Clustering of identical oligomers in coding and noncoding DNA sequences.

We develop a quantitative method for analyzing repetitions of identical short oligomers in coding and noncoding DNA sequences. We analyze sequences presently available in the GenBank separately for primate, mammal, vertebrate, rodent, invertebrate and plant taxonomic partitions. We find that some oligomers "cluster" more than they would if randomly distributed, while other oligomers "repel" each other. To quantify this degree of clustering, we define clustering measures. We find that (i) clustering significantly differs in coding and noncoding DNA; (ii) in most cases, monomers, dimers and tetramers cluster in noncoding DNA but appear to repel each other in coding DNA. (iii) The degree of clustering for different sources (primates, invertebrates, and plants) is more conserved among these sources in the case of coding DNA than in the case of noncoding DNA. (iv) In contrast to other oligomers, we find that trimers always prefer to cluster. (v) Clustering of each particular oligomer is conserved within the same organism.     

A synergistic effect of albumin and fibrinogen on immunoglobulin-induced red blood cell aggregation

Therapeutic administration of immunoglobulins (Ig) has the potential to precipitate thrombotic events. This phenomenon may be explained by red blood cell (RBC) aggregation, which can be potentiated by Ig. The contribution of plasma albumin and fibrinogen to Ig-induced RBC aggregation is unclear. We examined RBC aggregation in three settings: 1) patients receiving therapeutic infusions of Ig; 2) patients receiving plasma supplemented in vitro with Ig; and 3) patients receiving RBC suspensions in standard buffer with varying concentrations of albumin, Ig, and fibrinogen. Ig infusion augmented aggregation of RBCs from patients with normal or high plasma levels of albumin but decreased aggregation in those with lower plasma albumin concentrations. In vitro, RBC aggregation was significantly increased only when all three components, fibrinogen, albumin, and Ig, were present at or above normal concentrations in the suspension but was unaffected when any one of the components was absent from the suspension. Our results suggest a three-way interaction among fibrinogen, Ig, and albumin that synergistically induces RBC aggregation in plasma. Understanding these interactions may help predict clinically important phenomena related to RBC aggregation, such as thrombotic complications of Ig infusion.     

Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation

Gastric filling activates vagal afferents involved in peripheral signaling to the central nervous system (CNS) for food intake. It is not known whether these afferents linearly encode increasing contractions of the antrum during antral distension (AD). The aim of this study was to investigate effects of AD and electrically enhanced antral contractions on responses of vagal afferents innervating the antrum. Single-fiber recordings were made from the vagal afferents in anesthetized male Long-Evans rats. Antral contractions were measured with a solid-state probe placed in the antrum. A nonexcitatory electrical stimulation (NES) inducing no smooth muscle contractions was applied during the ascending phase of antral contractions to enhance subsequent antral contractions. Fifty-six fibers identified during AD (1 ml for 30 s) were studied through different types of mechanical stimuli. Under normal conditions, one group of fibers exhibited rhythmic firing in phase with antral contractions. Another group of fibers had nonrhythmic spontaneous firing. Responses of 15 fibers were tested with NES during multiple-step distension (MSD). NES produced a mean increase in antral contraction amplitude (177.1 +/- 35.3%) and vagal afferent firing (21.6 +/- 2.6%). Results show that both passive distension and enhanced antral contractions activate distension-sensitive vagal afferents. Responses of these fibers increase linearly to enhanced antral contraction induced by NES or MSD up to a distending volume of 0.6 ml. However, responses reached a plateau at a distending volume >0.8 ml. We concluded that enhanced contraction of the antrum can activate vagal afferents signaling to the CNS.     

The structure of the helically perturbed flagellar filament of Pseudomonas rhodos: implications for the absence of the outer domain in other complex flagellins and for the flexibility of the radial spokes

Bacterial flagella, the organelles of motility, are commonly divided into two classes: 'plain' and 'complex'. The complex filaments are pairwise, helically perturbed forms of the plain filaments and have been reported to occur only in Rhizobium and Pseudomonas. Previously, we reconstructed and analysed the structure of the complex filaments of Rhizobium lupini H13-3 and determined their unique symmetry and origin of the perturbations (Trachtenberg et al., 1986, J Mol Biol 190: 569-576; 1987, 195: 603-620; 1998, 276: 759-773; Cohen-Krausz and Trachtenberg, 1998, J Struct Biol 122: 267-282). Here, we analyse the structure of the flagellar filament of the other known complex filament, that of Pseudomonas rhodos, as reconstructed from electron microscope images. Compared with the filament of R. lupini, the filament of P. rhodos is more flexible, as implied from high-intensity darkfield light microscopy and, although constructed from flagellins of higher molecular weights (59 versus 41 kDa), has similar symmetry. Using cryonegative stained specimens and low-dose, field emission electron microscopy, we reconstructed and averaged 158 filaments each containing 170 statistically significant layer lines. The three-dimensional density maps of P. rhodos clearly suggest, when compared with those of R. lupini and the right-handed Salmonella typhimurium SJW1655, that R. lupini is missing the outer flagellin domain (D3), that the interior of the complex filament is rather similar to that of the plain filament and that the radial spokes (connecting domains D0 and D1), present in individual density maps, average out because of their variability and implied flexibility. Extending the three-start grooves and ridges on the propeller's surface, in the form of an Archimedean screw, may further improve the motility of the cell in viscous environments.     

Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas

Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease