Novel method to estimate the phenotypic variation explained by genome-wide association studies reveals large fraction of the missing heritability.

Genome-wide association studies (GWAS) are conducted with the promise to discover novel genetic variants associated with diverse traits. For most traits, associated markers individually explain just a modest fraction of the phenotypic variation, but their number can well be in the hundreds. We developed a maximum likelihood method that allows us to infer the distribution of associated variants even when many of them were missed by chance. Compared to previous approaches, the novelty of our method is that it (a) does not require having an independent (unbiased) estimate of the effect sizes; (b) makes use of the complete distribution of P-values while allowing for the false discovery rate; (c) takes into account allelic heterogeneity and the SNP pruning strategy. We applied our method to the latest GWAS meta-analysis results of the GIANT consortium. It revealed that while the explained variance of genome-wide (GW) significant SNPs is around 1% for waist-hip ratio (WHR), the observed P-values provide evidence for the existence of variants explaining 10% (CI=[8.5-11.5%]) of the phenotypic variance in total. Similarly, the total explained variance likely to exist for height is estimated to be 29% (CI=[28-30%]), three times higher than what the observed GW significant SNPs give rise to. This methodology also enables us to predict the benefit of future GWA studies that aim to reveal more associated genetic markers via increased sample size.

Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial.

BACKGROUND: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab. METHODS: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595. FINDINGS: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]). INTERPRETATION: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable. FUNDING: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Testis size, sperm characteristics and testosterone concentrations in four species of shrews (Mammalia, Soricidae).

The aim of this study was to establish and compare the sperm characteristics in four shrew species in the context of the sperm competition hypothesis. As expected, the large relative testis size in promiscuous species was associated with a high number of cauda epididymal spermatozoa and a high concentration of circulating testosterone. In addition, in Sorex and Neomys, species with high intensity of sperm competition, the spermatozoa stored in cauda epididymis were characterized by high percentage of progressive motility whereas in Crocidura and Suncus, the cauda epididymal spermatozoa were motile but with very low percentage of progressive motility. This capability is achieved only following the passage through the vas gland, a specialized region for sperm storage located along the vas deferens in these shrew species. The hypothesis that sperm competition is positively correlated with spermatozoa length could not be confirmed. In Crocidura and Suncus, the total sperm length is increased by the large sperm head due to a big acrosome. This trait, specific to the subfamily Crocidurinae, may results from a selective pressure independent of the context of sperm competition, related to a specific, but as yet unclear role, for the acrosome during the fertilization.

Scales and causes of heterogeneity in bars in a large multi-channel river: Rio Parana, Argentina

To date, published studies of alluvial bar architecture in large rivers have been restricted mostly to case studies of individual bars and single locations. Relatively little is known about how the depositional processes and sedimentary architecture of kilometre-scale bars vary within a multi-kilometre reach or over several hundreds of kilometres downstream. This study presents Ground Penetrating Radar and core data from 11, kilometre-scale bars from the Rio Parana, Argentina. The investigated bars are located between 30km upstream and 540km downstream of the Rio Parana - Rio Paraguay confluence, where a significant volume of fine-grained suspended sediment is introduced into the network. Bar-scale cross-stratified sets, with lengths and widths up to 600m and thicknesses up to 12m, enable the distinction of large river deposits from stacked deposits of smaller rivers, but are only present in half the surface area of the bars. Up to 90% of bar-scale sets are found on top of finer-grained ripple-laminated bar-trough deposits. Bar-scale sets make up as much as 58% of the volume of the deposits in small, incipient mid-channel bars, but this proportion decreases significantly with increasing age and size of the bars. Contrary to what might be expected, a significant proportion of the sedimentary structures found in the Rio Parana is similar in scale to those found in much smaller rivers. In other words, large river deposits are not always characterized by big structures that allow a simple interpretation of river scale. However, the large scale of the depositional units in big rivers causes small-scale structures, such as ripple sets, to be grouped into thicker cosets, which indicate river scale even when no obvious large-scale sets are present. The results also show that the composition of bars differs between the studied reaches upstream and downstream of the confluence with the Rio Paraguay. Relative to other controls on downstream fining, the tributary input of fine-grained suspended material from the Rio Paraguay causes a marked change in the composition of the bar deposits. Compared to the upstream reaches, the sedimentary architecture of the downstream reaches in the top ca 5m of mid-channel bars shows: (i) an increase in the abundance and thickness (up to metre-scale) of laterally extensive (hundreds of metres) fine-grained layers; (ii) an increase in the percentage of deposits comprised of ripple sets (to >40% in the upper bar deposits); and (iii) an increase in bar-trough deposits and a corresponding decrease in bar-scale cross-strata (<10%). The thalweg deposits of the Rio Parana are composed of dune sets, even directly downstream from the Rio Paraguay where the upper channel deposits are dominantly fine-grained. Thus, the change in sedimentary facies due to a tributary point-source of fine-grained sediment is primarily expressed in the composition of the upper bar deposits.

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study.

BackgroundFacioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease. Methods A cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6¿10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers. Results Among the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6¿10 RUs. Penetrance was estimated at 62% in the range of 6¿8 RUs, and at 47% in the range of 9¿10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance. Conclusions Penetrance of FSHD1 is low for largest alleles in the range of 9¿10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families.

Information transfer between large and small two-dimensional polyacrylamide gel electrophoresis.

To determine the feasibility of data transfer, an interlaboratory comparison was conducted on colon carcinoma cell line (DLD-1) proteins resolved by two-dimensional polyacrylamide gel electrophoresis either on small (6 x 7 cm) or large (16x18 cm) gels. The gels were silver-stained and scanned by laser densitometry, and the image obtained was analyzed using Melanie software. The number of spots detected was 1337+/-161 vs. 2382+/-176 for small vs. large format gels, respectively. After gel calibration using landmarks determined using pl and Mr markers, large- and small-format gels were matched and 712+/-36 proteins were found on both types of gels. Having performed accurate gel matching it was possible to acquire additional information after accessing a 2-D PAGE reference database (http://www.expasy.ch/ cgibin/map2/def?DLD1_HUMAN). Thus, the difference in gel size is not an obstacle for data transfer. This will facilitate exchanges between laboratories or consultation concerning existing databases.

Local map update for large scale SLAM

A technique for simultaneous localisation and mapping (SLAM) for large scale scenarios is presented. This solution is based on the use of independent submaps of a limited size to map large areas. In addition, a global stochastic map, containing the links between adjacent submaps, is built. The information in both levels is corrected every time a loop is closed: local maps are updated with the information from overlapping maps, and the global stochastic map is optimised by means of constrained minimisation

Investigating the impact of small versus large firms on economic performance of countries and industries

Following earlier work by Audretsch et al. (2002), we assume that an optimal size-class structure exists, in terms of achieving maximal economic growth rates. Such an optimal structure is likely to exist as economies need a balance between the core competences of large firms (such as exploitation of economies of scale) and those of smaller firms (such as flexibility and exploration of new ideas). Accordingly, changes in size-class structure (i.e., changes in the relative shares in economic activity accounted for by micro, small, medium-sized and large firms) may affect macro-economic growth. Using a unique data base of the EU-27 countries for the period 2002-2008 for five broad sectors of economic activity and four size-classes, we find empirical support which suggests that, on average for these countries over this period, the share of micro and large firms may have been ‘above optimum’ (particularly in lower income EU countries) whereas the share of medium-sized firms may have been ‘below optimum’ (particularly in higher income EU countries). This evidence suggests that the transition from a ‘managed’ to an ‘entrepreneurial’ economy (Audretsch and Thurik, 2001) has not been completed yet in all countries of the EU-27. Keywords: small firms, large firms, size-classes, macro-economic performance

The Role of Firm Size in Training Provision Decisions: evidence from Spain

The level of training provided by small firms to their employees is below that provided by their larger counterparts. The provision of firm-related training is believed to be associated to certain characteristics of the firm. In this paper we argue that small firms provide fewer training opportunities as they are less likely to be associated with these characteristics than large firms. The suitability of estimating training decisions as a double-decision process is examined here: first, a firm has to decide whether to provide training or not and, second, having decided to do so, the amount of training to provide. The differences in training provision between small and large firms are decomposed in order to analyse the individual contribution of these characteristics to explaining the gap. The results show that small firms face greater obstacles in accessing training and that the main reasons for that are related to their technological activity and the geographical scope of the market in which they operate.

Decomposing differences in total factor productivity across firm size

This paper investigates the extent to which the gap in total factor productivity between small and large firms is due to differences in the endowment of factors determining productivity and to the returns associated with these factors. We place particular emphasis on the contribution of differences in the propensity to innovate and in the use of skilled labor across firms of different size. Empirical evidence from a representative sample of Spanish manufacturing firms corroborates that both differences in endowments and returns to innovation and skilled labor significantly contribute to the productivity gap between small and large firms. In addition, it is observed that the contribution of innovation to this gap is caused only by differences in quantity, while differences in returns have no effect; in the case of human capital, however, most of the effect can be attributed to increasing differences in returns between small and large firms.

Do innovation and human capital explain the productivity gap between small and large firms?

Empirical evidence is compelling that large firms are more productive than small firms. The hypothesis in this paper is that the productivity differences between small and large firms are associated with two of the main determinants of a firm’s performance: the human and technological capital that firms incorporate. We suggest that the contribution of these factors in explaining the productivity-size gap might not only be due to the fact that large firms make a more extensive use of them, but also because large firms obtain higher returns from their investment in human and technological capital. The evidence we obtain for a comprehensive sample of Spanish manufacturing firms (1990-2002) supports this hypothesis, which has important implications for the effectiveness of policies designed to improve productivity in SMEs by stimulating innovation and the use of more skilled workers.

Fish colonization of artificial reefs in a large Neotropical reservoir: material type and successional changes

Artificial reefs have barely been used in Neotropical reservoirs (about five studies in three reservoirs), despite their potential as a fishery management tool to create new habitats and also to understand fish ecology. We experimentally assessed how reef material (ceramic, concrete, and PVC) and time modulated fish colonization of artificial reefs deployed in Itaipu Reservoir, a large reservoir of the mainstem Parana´ River, Brazil. Fish richness, abundance, and biomass were significantly greater in the reef treatments than at control sites. Among the experimental reefs, ceramic followed by the concrete treatments were the materials most effectively colonized, harboring the majority of the 13 fish species recorded. Although dependent on material type, many of the regularities of ecological successions were also observed in the artificial reefs, including decelerating increases in species richness, abundance, mean individual size, and species loss rates with time and decelerating decreases of species gain and turnover rates. Species composition also varied with material type and time, together with suites of life history traits: more equilibrium species (i.e., fishes of intermediate size that often exhibit parental care and produce fewer but larger offspring) of the Winemiller-Rose model of fish life histories prevailed in later successional stages. Overall, our study suggests that experimental reefs are a promising tool to understand ecological succession of fish assemblages, particularly in tropical ecosystems given their high species richness and low seasonality

Size Effect and Notch Size Effect in Metal Fatigue

It is a well known phenomenon that the constant amplitude fatigue limit of a large component is lower than the fatigue limit of a small specimen made of the same material. In notched components the opposite occurs: the fatigue limit defined as the maximum stress at the notch is higher than that achieved with smooth specimens. These two effects have been taken into account in most design handbooks with the help of experimental formulas or design curves. The basic idea of this study is that the size effect can mainly be explained by the statistical size effect. A component subjected to an alternating load can be assumed to form a sample of initiated cracks at the end of the crack initiation phase. The size of the sample depends on the size of the specimen in question. The main objective of this study is to develop a statistical model for the estimation of this kind of size effect. It was shown that the size of a sample of initiated cracks shall be based on the stressed surface area of the specimen. In case of varying stress distribution, an effective stress area must be calculated. It is based on the decreasing probability of equally sized initiated cracks at lower stress level. If the distribution function of the parent population of cracks is known, the distribution of the maximum crack size in a sample can be defined. This makes it possible to calculate an estimate of the largest expected crack in any sample size. The estimate of the fatigue limit can now be calculated with the help of the linear elastic fracture mechanics. In notched components another source of size effect has to be taken into account. If we think about two specimens which have similar shape, but the size is different, it can be seen that the stress gradient in the smaller specimen is steeper. If there is an initiated crack in both of them, the stress intensity factor at the crack in the larger specimen is higher. The second goal of this thesis is to create a calculation method for this factor which is called the geometric size effect. The proposed method for the calculation of the geometric size effect is also based on the use of the linear elastic fracture mechanics. It is possible to calculate an accurate value of the stress intensity factor in a non linear stress field using weight functions. The calculated stress intensity factor values at the initiated crack can be compared to the corresponding stress intensity factor due to constant stress. The notch size effect is calculated as the ratio of these stress intensity factors. The presented methods were tested against experimental results taken from three German doctoral works. Two candidates for the parent population of initiated cracks were found: the Weibull distribution and the log normal distribution. Both of them can be used successfully for the prediction of the statistical size effect for smooth specimens. In case of notched components the geometric size effect due to the stress gradient shall be combined with the statistical size effect. The proposed method gives good results as long as the notch in question is blunt enough. For very sharp notches, stress concentration factor about 5 or higher, the method does not give sufficient results. It was shown that the plastic portion of the strain becomes quite high at the root of this kind of notches. The use of the linear elastic fracture mechanics becomes therefore questionable.

Small and Large Scale Dynamics in the Milky Way

This thesis contains dynamical analysis on four different scales: the Solar system, the Sun itself, the Solar neighbourhood, and the central region of the Milky Way galaxy. All of these topics have been handled through methods of potential theory and statistics. The central topic of the thesis is the orbits of stars in the Milky Way. An introduction into the general structure of the Milky Way is presented, with an emphasis on the evolution of the observed value for the scale-length of the Milky Way disc and the observations of two separate bars in the Milky Way. The basics of potential theory are also presented, as well as a developed potential model for the Milky Way. An implementation of the backwards restricted integration method is shown, rounding off the basic principles used in the dynamical studies of this thesis. The thesis looks at the orbit of the Sun, and its impact on the Oort cloud comets (Paper IV), showing that there is a clear link between these two dynamical systems. The statistical atypicalness of the orbit of the Sun is questioned (Paper I), concluding that there is some statistical typicalness to the orbit of the Sun, although it is not very significant. This does depend slightly on whether one includes a bar, or not, as a bar has a clear effect on the dynamical features seen in the Solar neighbourhood (Paper III). This method can be used to find the possible properties of a bar. Finally, we look at the effect of a bar on a statistical system in the Milky Way, seeing that there are not only interesting effects depending on the mass and size of the bar, but also how bars can capture disc stars (Paper II).

SPECIES RICHNESS AND ABUNDANCE OF LOW-TRUNK HERB EPIPHYTES IN RELATION TO HOST TREE SIZE AND BARK TYPE, EASTERN AMAZONIA

ABSTRACTThe composition and structure of the low-trunk epiphytic herb assembly as well as its vertical distribution were studied. DBH of host tree and bark type influence species richness and abundance in a nonlooded lowland tropical rainforest in Eastern Amazonia (1º57’36"S 51º36’55"W). A total of 37 epiphytic herb species were identified, among which 60% were Araceae. Species richness and abundance of epiphytic herbs showed tendency of positive correlation with host tree size and no relationships with bark type. Low positive correlation may be a by-product of the predominance of trees with smaller diameter in our sample rather than a reflection of neutral relationship. The absence of relationships with bark type may be partially explained by the large number of secondary, generalist, hemi-epiphytes and also may reflect the absence of suitable substrate in trees with smaller diameter.