BadiRate: estimating family turnover rates by likelihood-based methods

Motivation: The comparative analysis of gene gain and loss rates is critical for understanding the role of natural selection and adaptation in shaping gene family sizes. Studying complete genome data from closely related species allows accurate estimation of gene family turnover rates. Current methods and software tools, however, are not well designed for dealing with certain kinds of functional elements, such as microRNAs or transcription factor binding sites. Results: Here, we describe BadiRate, a new software tool to estimate family turnover rates, as well as the number of elements in internal phylogenetic nodes, by likelihood-based methods and parsimony. It implements two stochastic population models, which provide the appropriate statistical framework for testing hypothesis, such as lineage-specific gene family expansions or contractions. We have assessed the accuracy of BadiRate by computer simulations, and have also illustrated its functionality by analyzing a representative empirical dataset.

Carbon-isotope stratigraphy and ammonite faunal turnover for the Middle Jurassic in the Southern Iberian palaeomargin

Variations in the stable carbon-isotope ratio of marine and continental sediments can reflect changes in sink and flux modifications of the palaeocarbon cycle. Here we report carbon-isotope compositions of Middle Jurassic marine carbonates from the Betic Cordillera (southern Spain), which represents an ideal region to link the stable carbon-isotope curves directly to ammonite zones and subzones, and thereby for the first time achieve an accurate chronostratigraphic calibration. The five sections studied represent basin and high swell deposits of the Southern Iberian palaeomargin. We find a similar delta C-13 of carbonates between different oceanic areas, suggesting a homogeneous carbon-isotope oceanic reservoir through the Middle Jurassic. The Aalenian-Bajocian transition is a critical period in ammonite evolution; hence the Early Jurassic fauna are replaced by new ammonite families which become dominant throughout the Middle and Late Jurassic. For this reason, we compared the delta C-13 values of carbonates with ammonite diversity and extinction rates at different taxonomical levels in order to explore the possible relationship between the carbon cycle and ammonite evolution. The carbon-isotope values of carbonates are not exactly linearly correlated with the extinction rate and ammonite diversity, but the main faunal turnovers follow minimum delta C-13 values, where extinct taxa are replaced by new ones. Likewise, radiation episodes are associated with increasing delta C-13 values and with transgressive sea-level rise. All these data support the idea that perturbations in the global carbon cycle reflect rapid palaeoenvironmental changes. We made detailed analyses of these faunal turnovers, using them as a proxy to identify major palaeoenvironmental crises in their ecosystems forced by modification in the carbon cycle. (c) 2006 Elsevier B.V All rights reserved.

Context-dependent dual role of SKI8 homologs in mRNA synthesis and turnover.

Eukaryotic mRNA transcription and turnover is controlled by an enzymatic machinery that includes RNA polymerase II and the 3' to 5' exosome. The activity of these protein complexes is modulated by additional factors, such as the nuclear RNA polymerase II-associated factor 1 (Paf1c) and the cytoplasmic Superkiller (SKI) complex, respectively. Their components are conserved across uni- as well as multi-cellular organisms, including yeast, Arabidopsis, and humans. Among them, SKI8 displays multiple facets on top of its cytoplasmic role in the SKI complex. For instance, nuclear yeast ScSKI8 has an additional function in meiotic recombination, whereas nuclear human hSKI8 (unlike ScSKI8) associates with Paf1c. The Arabidopsis SKI8 homolog VERNALIZATION INDEPENDENT 3 (VIP3) has been found in Paf1c as well; however, whether it also has a role in the SKI complex remains obscure so far. We found that transgenic VIP3-GFP, which complements a novel vip3 mutant allele, localizes to both nucleus and cytoplasm. Consistently, biochemical analyses suggest that VIP3-GFP associates with the SKI complex. A role of VIP3 in the turnover of nuclear encoded mRNAs is supported by random-primed RNA sequencing of wild-type and vip3 seedlings, which indicates mRNA stabilization in vip3. Another SKI subunit homolog mutant, ski2, displays a dwarf phenotype similar to vip3. However, unlike vip3, it displays neither early flowering nor flower development phenotypes, suggesting that the latter reflect VIP3's role in Paf1c. Surprisingly then, transgenic ScSKI8 rescued all aspects of the vip3 phenotype, suggesting that the dual role of SKI8 depends on species-specific cellular context.

The evolution of trans-generational altruism: kin selection meets niche construction.

A cornerstone result of sociobiology states that limited dispersal can induce kin competition to offset the kin selected benefits of altruism. Several mechanisms have been proposed to circumvent this dilemma but all assume that actors and recipients of altruism interact during the same time period. Here, this assumption is relaxed and a model is developed where individuals express an altruistic act, which results in posthumously helping relatives living in the future. The analysis of this model suggests that kin selected benefits can then feedback on the evolution of the trait in a way that promotes altruistic helping at high rates under limited dispersal. The decoupling of kin competition and kin selected benefits results from the fact that by helping relatives living in the future, an actor is helping individuals that are not in direct competition with itself. A direct consequence is that behaviours which actors gain by reducing the common good of present and future generations can be opposed by kin selection. The present model integrates niche-constructing traits with kin selection theory and delineates demographic and ecological conditions under which altruism can be selected for; and conditions where the 'tragedy of the commons' can be reduced.

Effect of physical exercise on glycogen turnover and net substrate utilization according to the nutritional state.

To determine the metabolic effects of a single bout of exercise performed after a meal or in the fasting state, nine healthy subjects were studied over two 8-h periods during which net substrate oxidation was monitored by indirect calorimetry. On one occasion, exercise was performed 90 min after ingestion of a meal labeled with [U-13C]glucose [protocol meal-exercise (M-E)]. On the second occasion, exercise was performed after an overnight fast and was followed 30 min later by ingestion of an identical meal [protocol exercise-meal (E-M)]. Energy balances were similar in both protocols, but carbohydrate balance was positive (42.2 +/- 5.1 g), and lipid balance was negative (-11.1 +/- 2.0) during E-M, whereas they were nearly even during M-E. Total glycogen synthesis was calculated as carbohydrate intake minus oxidation of exogenous 13C-labeled carbohydrate (calculated from 13CO2 production). Total glycogen synthesis was increased by 90% (from 47.6 +/- 3.8 to 90.7 +/- 5.4 g, P < 0.0001) during E-M vs. M-E. Endogenous glycogen breakdown was calculated as net carbohydrate oxidation minus oxidation of exogenous carbohydrate and was increased by 44% (from 35.8 +/- 5.6 to 51.7 +/- 6.6 g, P < 0.004) during E-M. It is concluded that exercise performed in the fasting state stimulates glycogen turnover and fat oxidation.

On-Line Analytical Processing of Inventory Turnover

Operatiivisen tiedon tuottaminen loppukäyttäjille analyyttistä tarkastelua silmällä pitäen aiheuttaa ongelmia useille yrityksille. Diplomityö pyrkii ratkaisemaan ko. ongelman Teleste Oyj:ssä. Työ on jaettu kolmeen pääkappaleeseen. Kappale 2 selkiyttää On-Line Analytical Processing (OLAP)- käsitteen. Kappale 3 esittelee muutamia OLAP-tuotteiden valmistajia ja heidän arkkitehtuurejaan sekä tyypillisten sovellusalueiden lisäksi huomioon otettavia asioita OLAP käyttöönoton yhteydessä. Kappale 4, tuo esille varsinaisen ratkaisun. Teknisellä arkkitehtuurilla on merkittävä asema ratkaisun rakenteen kannalta. Tässä on sovellettu Microsoft:n tietovarasto kehysrakennetta. Kappaleen 4 edetessä, tapahtumakäsittelytieto muutetaan informaatioksi ja edelleen loppukäyttäjien tiedoksi. Loppukäyttäjät varustetaan tehokkaalla ja tosiaikaisella analysointityökalulla moniulotteisessa ympäristössä. Vaikka kiertonopeus otetaan työssä sovellusesimerkiksi, työ ei pyri löytämään optimaalista tasoa Telesten varastoille. Siitä huolimatta eräitä parannusehdotuksia mainitaan.

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a.

Reggies/flotillins are implicated in trafficking of membrane proteins to their target sites and in the regulation of the Rab11a-dependent targeted recycling of E-cadherin to adherens junctions (AJs). Here we demonstrate a function of reggies in focal adhesion (FA) formation and α5- and β1-integrin recycling to FAs. Downregulation of reggie-1 in HeLa and A431 cells by siRNA and shRNA increased the number of FAs, impaired their distribution and modified FA turnover. This was coupled to enhanced focal adhesion kinase (FAK) and Rac1 signaling and gain in plasma membrane motility. Wild type and constitutively-active (CA) Rab11a rescued the phenotype (normal number of FAs) whereas dominant-negative (DN) Rab11a mimicked the loss-of-reggie phenotype in control cells. That reggie-1 affects integrin trafficking emerged from the faster loss of internalized antibody-labeled β1-integrin in reggie-deficient cells. Moreover, live imaging using TIRF microscopy revealed vesicles containing reggie-1 and α5- or β1-integrin, trafficking close to the substrate-near membrane and making kiss-and-run contacts with FAs. Thus, reggie-1 in interaction with Rab11a controls Rac1 and FAK activation and coordinates the targeted recycling of α5- and β1-integrins to FAs to regulate FA formation and membrane dynamics.

The age of the"Grande Coupure" mammal turnover: New constraints from the Eocene Oligocene record of the Eastern Ebro Basin (NE Spain.)

The Grande Coupure represents a major terrestrial faunal turnover recorded in Eurasia associated with the overall climate shift at the Eocene-Oligocene transition. During this event, a large number of European Eocene endemic mammals became extinct and new Asian immigrants appeared. The absolute age of the Grande Coupure, however, has remained controversial for decades. The Late Eocene-Oligocene continental record of the Eastern Ebro Basin (NE Spain) constitutes a unique opportunity to build a robust magnetostratigraphy- based chronostratigraphy which can contribute with independent age constraints for this important turnover. This study presents new magnetostratigraphic data of a 495-m-thick section (Moià-Santpedor) that ranges from 36.1 Ma to 33.3 Ma. The integration of the new results with previous litho- bio- and magnetostratigraphic records of the Ebro Basin yields accurate ages for the immediately pre- and post-Grand Coupure mammal fossil assemblages found in the study area, bracketing the Grande Coupure to an age embracing the Eocene-Oligocene transition, with a maximum allowable lag of 0.5 Myr with respect to this boundary. The shift to drier conditions that accompanied the global cooling at the Eocene-Oligocene transition probably determined the sedimentary trends in the Eastern Ebro Basin. The occurrence and expansion of an amalgamated-channel sandstone unit is interpreted as the forced response of the fluvial fan system to the transient retraction of the central-basin lake systems. The new results from the Ebro Basin allow us to revisit correlations for the controversial Eocene-Oligocene record of the Hampshire Basin (Isle of Wight, UK), and their implications for the calibration of the Mammal Palaeogene reference levels MP18 to MP21.

Influência de contraceptivos hormonais sobre indicadores de homeostase de zinco e de turnover ósseo em mulheres adultas jovens

OBJETIVO: Investigar a influência de anticoncepcionais hormonais (ACH) orais em indicadores bioquímicos relacionados à utilização metabólica e distribuição de zinco e ao turnover ósseo em mulheres adultas jovens.MÉTODOS: Estudo transversal. Amostras de sangue e urina de não usuárias (-ACH; controle; n=69) e usuárias há pelo menos três meses de contraceptivos hormonais orais (+ACH; n=62) foram coletadas em condições padronizadas. Foram analisados os indicadores de homeostase de zinco e de turnoverósseo em soro ou plasma (zinco total e nas frações de albumina e α2-macroglobulina, albumina e atividade de fosfatase alcalina total e de origem óssea), em eritrócitos (zinco e metalotioneína) e em urina (zinco, cálcio e hidroxiprolina). Ingestões habituais de zinco e cálcio foram avaliadas por questionário de frequência de consumo.RESULTADOS: A ingestão alimentar de zinco foi semelhante nos grupos e, em média, acima do recomendado, enquanto que a ingestão de cálcio foi similarmente subadequada em +ACH e -ACH. Comparadas às controles, as +ACH apresentaram menores concentrações de zinco em soro, total e ligado à α2-macroglobulina (11 e 28,5%, respectivamente, p<0,001); albumina em soro (13%, p<0,001); atividade de fosfatase alcalina em plasma, total e de origem óssea (13 e 18%, respectivamente, p<0,05); metalotioneína em eritrócitos (13%, p<0,01) e zinco urinário (34%, p<0,05).CONCLUSÕES: O uso de ACH reduz o zinco sérico, altera a distribuição de zinco nas principais proteínas ligantes do soro com possíveis efeitos na captação tecidual, aumenta a retenção de zinco no organismo e reduz o turnover ósseo. O uso prolongado de ACH poderia levar a menor pico de massa óssea e/ou prejudicar a manutenção de massa óssea em mulheres jovens, principalmente com ingestão marginal de cálcio. Os efeitos de ACH verificados foram mais evidentes nas mulheres <25 anos de idade e nas nulíparas, as quais merecem especial atenção em estudos posteriores.

Markers of Bone Turnover In Preclinical Development of Drugs for Skeletal Diseases

Skeletal tissue is constantly remodeled in a process where osteoclasts resorb old bone and osteoblasts form new bone. Balance in bone remodeling is related to age, gender and genetic factors, but also many skeletal diseases, such as osteoporosis and cancer-induced bone metastasis, cause imbalance in bone turnover and lead to decreased bone mass and increased fracture risk. Biochemical markers of bone turnover are surrogates for bone metabolism and may be used as indicators of the balance between bone resorption and formation. They are released during the remodeling process and can be conveniently and reliably measured from blood or urine by immunoassays. Most commonly used bone formation markers include N-terminal propeptides of type I collagen (PINP) and osteocalcin, whereas tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) and C-terminal cross-linked telopeptide of type I collagen (CTX) are common resorption markers. Of these, PINP has been, until recently, the only marker not commercially available for preclinical use. To date, widespread use of bone markers is still limited due to their unclear biological significance, variability, and insufficient evidence of their prognostic value to reflect long term changes. In this study, the feasibility of bone markers as predictors of drug efficacy in preclinical osteoporosis models was elucidated. A non-radioactive PINP immunoassay for preclinical use was characterized and validated. The levels of PINP, N-terminal mid-fragment of osteocalcin, TRACP 5b and CTX were studied in preclinical osteoporosis models and the results were compared with the results obtained by traditional analysis methods such as histology, densitometry and microscopy. Changes in all bone markers at early timepoints correlated strongly with the changes observed in bone mass and bone quality parameters at the end of the study. TRACP 5b correlated strongly with the osteoclast number and CTX correlated with the osteoclast activity in both in vitro and in vivo studies. The concept “resorption index” was applied to the relation of CTX/TRACP 5b to describe the mean osteoclast activity. The index showed more substantial changes than either of the markers alone in the preclinical osteoporosis models used in this study. PINP was strongly associated with bone formation whereas osteocalcin was associated with both bone formation and resorption. These results provide novel insight into the feasibility of PINP, osteocalcin, TRACP 5b and CTX as predictors of drug efficacy in preclinical osteoporosis models. The results support clinical findings which indicate that short-term changes of these markers reflect long-term responses in bone mass and quality. Furthermore, this information may be useful when considering cost-efficient and clinically predictive drug screening and development assays for mining new drug candidates for skeletal diseases.

Obese women on a low energy rice and bean diet: effects of leucine, arginine or glycine supplementation on protein turnover

This study examined if leucine, arginine or glycine supplementation in adult obese patients (body mass index of 33 ± 4 kg/m²) consuming a Brazilian low energy and protein diet (4.2 MJ/day and 0.6 g protein/kg) affects protein and amino acid metabolism. After four weeks adaptation to this diet, each subject received supplements of these amino acids (equivalent to 0.2 g protein kg-1 day-1) in random order. On the seventh day of each amino acid supplementation, a single-dose 15N-glycine study was carried out. There were no significant differences in protein flux, synthesis or breakdown. The protein flux (grams of nitrogen, gN/9 h) was 55 ± 24 during the nonsupplemented diet intake and 39 ± 10, 44 ± 22 and 58 ± 35 during the leucine-, glycine- and arginine-supplemented diet intake, respectively; protein synthesis (gN/9 h) was 57 ± 24, 36 ± 10, 41 ± 22 and 56 ± 36, respectively; protein breakdown (gN/9 h) was 51 ± 24, 34 ± 10, 32 ± 28 and 53 ± 35, respectively; kinetic balance (gN/9 h) was 3.2 ± 1.8, 4.1 ± 1.7, 3.4 ± 2.9 and 3.9 ± 1.6. There was no difference in amino acid profiles due to leucine, arginine or glycine supplementation. The present results suggest that 0.6 g/kg of dietary protein is enough to maintain protein turnover in obese women consuming a reduced energy diet and that leucine, arginine or glycine supplementation does not change kinetic balance or protein synthesis.

Effect of dietary fat saturation on lipid metabolism, arachidonic acid turnover and peritoneal macrophage oxidative stress in mice

We investigated the effects of a saturated fat diet on lipid metabolism and arachidonic acid (AA) turnover in mouse resident peritoneal macrophages. The pro-oxidative effect of this diet was also studied. Female C57BL/6 mice were weaned at 21 days of age and assigned to either the experimental diet containing coconut oil (COCO diet), or the control diet containing soybean oil as fat source (10 mice per group). The fat content of each diet was 15% (w/w). Mice were fed for 6 weeks and then sacrificed. The concentration of total lipids, triglycerides, (LDL + VLDL)-cholesterol, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione were increased in the plasma of mice fed the COCO diet, without changes in phospholipid or total cholesterol concentrations compared to control. The concentrations of total cholesterol, free and esterified cholesterol, triglycerides, and TBARS were increased in the macrophages of COCO-fed mice, while the content of total phospholipids did not change. The phospholipid composition showed an increase of phosphatidylcholine and a decrease of phosphatidylethanolamine. The [³H]-AA distribution in the phospholipid classes showed an increase in phosphatidylcholine and phosphatidylethanolamine. Incorporation of [³H]-cholesterol into the macrophages of COCO-fed mice and into the cholesterol ester fraction was increased. The COCO diet did not affect [³H]-AA uptake but induced an increase in [³H]-AA release. The COCO diet also enhanced AA mobilization induced by lipopolysaccharide. These results indicate that the COCO diet, high in saturated fatty acids, alters the lipid metabolism and AA turnover of peritoneal macrophages in female mice and also produces a significant degree of oxidative stress.

Protein turnover, amino acid requirements and recommendations for athletes and active populations

Skeletal muscle is the major deposit of protein molecules. As for any cell or tissue, total muscle protein reflects a dynamic turnover between net protein synthesis and degradation. Noninvasive and invasive techniques have been applied to determine amino acid catabolism and muscle protein building at rest, during exercise and during the recovery period after a single experiment or training sessions. Stable isotopic tracers (13C-lysine, 15N-glycine, ²H5-phenylalanine) and arteriovenous differences have been used in studies of skeletal muscle and collagen tissues under resting and exercise conditions. There are different fractional synthesis rates in skeletal muscle and tendon tissues, but there is no major difference between collagen and myofibrillar protein synthesis. Strenuous exercise provokes increased proteolysis and decreased protein synthesis, the opposite occurring during the recovery period. Individuals who exercise respond differently when resistance and endurance types of contractions are compared. Endurance exercise induces a greater oxidative capacity (enzymes) compared to resistance exercise, which induces fiber hypertrophy (myofibrils). Nitrogen balance (difference between protein intake and protein degradation) for athletes is usually balanced when the intake of protein reaches 1.2 g·kg-1·day-1 compared to 0.8 g·kg-1·day-1 in resting individuals. Muscular activities promote a cascade of signals leading to the stimulation of eukaryotic initiation of myofibrillar protein synthesis. As suggested in several publications, a bolus of 15-20 g protein (from skimmed milk or whey proteins) and carbohydrate (± 30 g maltodextrine) drinks is needed immediately after stopping exercise to stimulate muscle protein and tendon collagen turnover within 1 h.