Errors drive the evolution of biological signalling to costly codes

Reduction of costs in biological signalling seems an evolutionary advantage, but recent experiments have shown signalling codes shifted to signals of high cost with an underutilization of low-cost signals. Here I derive a theory for efficient signalling that includes both errors and costs as constraints and I show that errors in the efficient translation of biological states into signals can shift codes to higher costs, effectively performing a quality control. The statistical structure of signal usage is predicted to be of a generalized Boltzmann form that penalizes signals that are costly and sensitive to errors. This predicted distribution of signal usage against signal cost has two main features: an exponential tail required for cost efficiency and an underutilization of the low-cost signals required to protect the signalling quality from the errors. These predictions are shown to correspond quantitatively to the experiments in which gathering signal statistics is feasible as in visual cortex neurons.     

Rotatin is a novel gene required for axial rotation and left-right specification in mouse embryos

The genetic cascade that governs left-right (L-R) specification is starting to be elucidated. In the mouse, the lateral asymmetry of the body axis is revealed first by the asymmetric expression of nodal, lefty2 and pitx2 in the left lateral plate mesoderm of the neurulating embryo. Here we describe a novel gene, rotatin, essential for the correct expression of the key L-R specification genes nodal, lefty and Pitx2. Embryos deficient in rotatin show also randomized heart looping and delayed neural tube closure, and fail to undergo the critical morphogenetic step of axial rotation. The amino acid sequence deduced from the cDNA is predicted to contain at least three transmembrane domains. Our results show a novel key player in the genetic cascade that determines L-R specification, and suggest a causal link between this process and axial rotation.     

Racemochrysone,a dihydroanthracenone from Senna racemosa

From the hexane extract of the bark of the stems of Senna racemosa (syn. Cassia racemosa) a new dihydroanthracenone derivative, named racemochrysone, was isolated. Its structure was established as 8,9-dihydroxy-3-methoxy-2,2,6-trimethyl-(2H)-anthracen-1-one based on spectroscopical data, mainly 1D and 2D NMR experiments. In addition beta-sitosterol, stigmasterol, chrysophanol and physcion were obtained. From the leaves extracts the piperidine alkaloid cassine and the hexitol pinitol were obtained.     

Wnt signaling involvement in beta-amyloid-dependent neurodegeneration

Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-beta peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients.     

β1 Integrin triggering affects leukemic cell line sensitivity to natural killer cells

The role of beta1 (CD29) integrins in natural killer (NK) cell-target cell conjugation and cytotoxicity has not been clearly established. Ligation of beta1 integrins in NK cells can modulate the lytic capacity in both a positive and a negative manner; however, the contribution of the beta1 integrins present on target cells remains to be evaluated. Here, we analyzed the effect of beta1 integrins expressed by potential tumor target cells on conjugation and cytotoxicity. Using normalized flow cytometry binding assays, we demonstrated that the pretreatment of MOLT-4, K562, U-937 and HL-60 human leukemia target cell lines with selected anti-beta1 monoclonal antibodies (mAb) increased conjugation to human NK cell line NKL as well as to purified NK cells. Only mAb recognizing residues 207-218 of the beta1 subunit and functionally involved in the induction of homotypic adhesion (functional epitope A1) increased conjugation of all the target cells. Moreover, mAb to adhesion molecules different from beta1 but also inducers of homotypic adhesion of the target cells, i.e. CD43 and CD50 (ICAM-3), failed to increase conjugation to NKL cells. Cytotoxicity assays demonstrated that lysis of NK-sensitive target cells (MOLT-4) also increased after pretreatment with anti-beta1 epitope A1 mAb. Importantly, pretreatment of NK-resistant target cells (U-937 and HL-60) with anti-beta1 mAb was not able to outweigh the cytotoxic inhibitory mechanisms controlled by HLA class I molecules. However, simultaneous masking of HLA class I molecules with mAb and pretreatment with anti-beta1 mAb rendered NK-resistant cells susceptible to lysis, as predicted by the missing self hypothesis. Triggering of tumor target cells through beta1 integrins may thus play a role in conjugation to NK cells as well as in co-stimulation of cell-mediated cytotoxicity.     

Renal damage mediated by oxidative stress: a hypothesis of protective effects of red wine

Over the last decade, oxidative stress has been implicated in the pathogenesis of a wide variety of seemingly unrelated renal diseases. Epidemiological studies have documented an association of moderate wine consumption with a decreased risk of cardiovascular and neurological diseases; however, similar studies in the kidney are still lacking. The kidney is an organ highly vulnerable to damage caused by reactive oxygen species (ROS), likely due to the abundance of polyunsaturated fatty acids in the composition of renal lipids. ROS are involved in the pathogenic mechanism of conditions such as glomerulosclerosis and tubulointerstitial fibrosis. The health benefits of moderate consumption of red wine can be partly attributed to its antioxidant properties. Indeed, the kidney antioxidant defense system is enhanced after chronic exposure to moderate amounts of wine, a response arising from the combined effects of ethanol and the nonalcoholic components, mainly polyphenols. Polyphenols behave as potent ROS scavengers and metal chelators; ethanol, in turn, modulates the activity of antioxidant enzymes. Therefore, a hypothesis that red wine causes a decreased vulnerability of the kidney to the oxidative challenges could be proposed. This view is partly supported by direct evidences indicating that wine and antioxidants isolated from red wine, as well as other antioxidants, significantly attenuate or prevent the oxidative damage to the kidney. The present hypothesis paper provides a collective body of evidence suggesting a protective role of moderate wine consumption against the production and progression of renal diseases, based on the existing concepts on the pathophysiology of kidney injury mediated by oxidative stress.     

Beta 2-adrenergic receptor stimulated,G protein-coupled receptor kinase 2 mediated,phosphorylation of ribosomal protein P2

G protein-coupled receptor kinases are well characterized for their ability to phosphorylate and desensitize G protein-coupled receptors (GPCRs). In addition to phosphorylating the beta2-adrenergic receptor (beta2AR) and other receptors, G protein-coupled receptor kinase 2 (GRK2) can also phosphorylate tubulin, a nonreceptor substrate. To identify novel nonreceptor substrates of GRK2, we used two-dimensional gel electrophoresis to find cellular proteins that were phosphorylated upon agonist-stimulation of the beta2AR in a GRK2-dependent manner. The ribosomal protein P2 was identified as an endogenous HEK-293 cell protein whose phosphorylation was increased following agonist stimulation of the beta2AR under conditions where tyrosine kinases, PKC and PKA, were inhibited. P2 along with its other family members, P0 and P1, constitutes a part of the elongation factor-binding site connected to the GTPase center in the 60S ribosomal subunit. Phosphorylation of P2 is known to regulate protein synthesis in vitro. Further, P2 and P1 are shown to be good in vitro substrates for GRK2 with K(M) values approximating 1 microM. The phosphorylation sites in GRK2-phosphorylated P2 are identified (S102 and S105) and are identical to the sites known to regulate P2 activity. When the 60S subunit deprived of endogenous P1 and P2 is reconstituted with GRK2-phosphorylated P2 and unphosphorylated P1, translational activity is greatly enhanced. These findings suggest a previously unrecognized relationship between GPCR activation and the translational control of gene expression mediated by GRK2 activation and P2 phosphorylation and represent a potential novel signaling pathway responsible for P2 phosphorylation in mammals.     

Medroxyprogesterone priming and response to the ram effect in Corriedale ewes during the nonbreeding season

The "ram effect" (RE) is an inexpensive technique that allows farmers to obtain out-of-season lambs. Five hundred and ninety-six Corriedale ewes were used in three experiments to determine the effectiveness of different medroxyprogesterone (MAP) treatments associated with the ram effect during the nonbreeding season. The aim of the first experiment was to evaluate the effectiveness of short-term (6-day) MAP priming. We obtained similar results in estrus incidence and fertility after using MAP sponges for 6, 9, and 13 days. In the second experiment, we compared the effect of sponges containing 20, 40, or 60 mg of MAP used in 6-day priming. Estrous behavior and fertility were not affected by dosage. In the third experiment, 2.5mg of MAP was administered in single treatments 0, 1, 3, or 5 days before the introduction of the rams. Medroxyprogesterone administration 1, 3, or 5 days before the introduction of the rams concentrated estrus in ewes 17 to 20 days later.     

Additive polymorphisms and reticulation in an ITS phylogeny of thrifts (Armeria,Plumbaginaceae)

A parsimony analysis of 133 sequences of the nuclear ribosomal DNA ITS1+5.8S+ITS2 region from 71 taxa in Armeria was carried out. The presence of additive polymorphic sites (APS; occurring in 14 accessions) fits the reticulate scenario proposed in previous work for explaining the ITS pattern of variation on a much smaller scale and is based mainly on the geographical structure of the data, irrespective of taxonomic boundaries. Despite the relatively low bootstrap values and large polytomies, part of which are likely due to disruptive effects of reticulation and concerted evolution in these multicopy sequences, the ITS analysis has phylogenetic and biogeographic implications. APS detected in this study are consistent with hypothesized hybridization events, although biased concerted evolution, previously documented in the genus, needs to be invoked for specific cases and may be responsible for a possible "sink" effect in terminals from a large clade. The causes for sequences of the same species appearing in different clades (here termed transclade) are discussed.