Three-dimensional model for multi-component reactive transport with variable density groundwater flow

PHWAT is a new model that couples a geochemical reaction model (PHREEQC-2) with a density-dependent groundwater flow and solute transport model (SEAWAT) using the split-operator approach. PHWAT was developed to simulate multi-component reactive transport in variable density groundwater flow. Fluid density in PHWAT depends not on only the concentration of a single species as in SEAWAT, but also the concentrations of other dissolved chemicals that can be subject to reactive processes. Simulation results of PHWAT and PHREEQC-2 were compared in their predictions of effluent concentration from a column experiment. Both models produced identical results, showing that PHWAT has correctly coupled the sub-packages. PHWAT was then applied to the simulation of a tank experiment in which seawater intrusion was accompanied by cation exchange. The density dependence of the intrusion and the snow-plough effect in the breakthrough curves were reflected in the model simulations, which were in good agreement with the measured breakthrough data. Comparison simulations that, in turn, excluded density effects and reactions allowed us to quantify the marked effect of ignoring these processes. Next, we explored numerical issues involved in the practical application of PHWAT using the example of a dense plume flowing into a tank containing fresh water. It was shown that PHWAT could model physically unstable flow and that numerical instabilities were suppressed. Physical instability developed in the model in accordance with the increase of the modified Rayleigh number for density-dependent flow, in agreement with previous research. (c) 2004 Elsevier Ltd. All rights reserved.

The role of physiological understanding in plant breeding; From a breeding perspective

The role of physiological understanding in improving the efficiency of breeding programs is examined largely from the perspective of conventional breeding programs. Impact of physiological research to date on breeding programs, and the nature of that research, was assessed from (i) responses to a questionnaire distributed to plant breeders and physiologists, and (ii) a survey of literature abstracts. Ways to better utilise physiological understanding for improving breeding programs are suggested, together with possible constraints to delivering beneficial outcomes. Responses from the questionnaire indicated a general view that the contribution by crop physiology to date has been modest. However, most of those surveyed expected the contribution to be larger in the next 20 years. Some constraints to progress perceived by breeders and physiologists were highlighted. The survey of literature abstracts indicated that from a plant breeding perspective, much physiological research is not progressing further than making suggestions about possible approaches to selection. There was limited evidence in the literature of objective comparison of such suggestions with existing methodology, or of development and application of these within active breeding programs. It is argued in this paper that the development of outputs from physiological research for breeding requires a good understanding of the breeding program(s) being serviced and factors affecting its performance. Simple quantitative genetic models, or at least the ideas they represent, should be considered in conducting physiological research and in envisaging and evaluating outputs. The key steps of a generalised breeding program are outlined, and the potential pathways for physiological understanding to impact on these steps are discussed. Impact on breeding programs may arise through (i) better choice of environments in which to conduct selection trials, (ii) identification of selection criteria and traits for focused introgression programs, and (iii) identifying traits for indirect selection criteria as an adjunct to criteria already used. While many breeders and physiologists apparently recognise that physiological understanding may have a major role in the first area, there appears to be relatively Little research activity targeting this issue, and a corresponding bias, arguably unjustified, toward examining traits for indirect selection. Furthermore, research on traits aimed at crop improvement is often deficient because key genetic parameters, such as genetic variation in relevant breeding populations and genetic (as opposed to phenotypic) correlations with yield or other characters of economic importance, are not properly considered in the research. Some areas requiring special attention for successfully interfacing physiology research with breeding are discussed. These include (i) the need to work with relevant genetic populations, (ii) close integration of the physiological research with an active breeding program, and (iii) the dangers of a pre-defined or narrow focus in the physiological research.

THE TEMPO AND MODE OF EVOLUTION OF TRANSPOSABLE ELEMENTS AS REVEALED BY MOLECULAR PHYLOGENIES RECONSTRUCTED FROM MOSQUITO GENOMES

Although many mathematical models exist predicting the dynamics of transposable elements (TEs), there is a lack of available empirical data to validate these models and inherent assumptions. Genomes can provide a snapshot of several TE families in a single organism, and these could have their demographics inferred by coalescent analysis, allowing for the testing of theories on TE amplification dynamics. Using the available genomes of the mosquitoes Aedes aegypti and Anopheles gambiae, we indicate that such an approach is feasible. Our analysis follows four steps: (1) mining the two mosquito genomes currently available in search of TE families; (2) fitting, to selected families found in (1), a phylogeny tree under the general time-reversible (GTR) nucleotide substitution model with an uncorrelated lognormal (UCLN) relaxed clock and a nonparametric demographic model; (3) fitting a nonparametric coalescent model to the tree generated in (2); and (4) fitting parametric models motivated by ecological theories to the curve generated in (3).

Impact of Atypical Retardation Patterns on Detection of Glaucoma Progression using the GDx with Variable Corneal Compensation

PURPOSE: To evaluate the impact of atypical retardation patterns (ARP) on detection of progressive retinal nerve fiber layer (RNFL) loss using scanning laser polarimetry with variable corneal compensation (VCC). DESIGN: Observational cohort study. METHODS: The study included 377 eyes of 221 patients with a median follow-up of 4.0 years. Images were obtained annually with the GDx VCC (Carl Zeiss Med, itec Inc, Dublin, California, USA), along with optic disc stereophotographs and standard automated perimetry (SAP) visual fields. Progression was determined by the Guided Progression Analysis software for SAP and by masked assessment of stereophotographs by expert graders. The typical scan score (TSS) was used to quantify the presence of ARPs on GDx VCC images. Random coefficients models were used to evaluate the relationship between ARP and RNFL thickness measurements over time. RESULTS: Thirty-eight eyes (10%) showed progression over time on visual fields, stereophotographs, or both. Changes in TSS scores from baseline were significantly associated with changes in RNFL thickness measurements in both progressing and nonprogressing eyes. Each I unit increase in TSS score was associated with a 0.19-mu m decrease in RNFL thickness measurement (P < .001) over time. CONCLUSIONS: ARPs had a significant effect on detection of progressive RNFL loss with the GDx VCC. Eyes with large amounts of atypical patterns, great fluctuations on these patterns over time, or both may show changes in measurements that can appear falsely as glaucomatous progression or can mask true changes in the RNFL. (Am J Ophthalmol 2009;148:155-163. (C) 2009 by Elsevier Inc. All rights reserved.)

VKORC1 polymorphisms in Brazilians: comparison with the Portuguese and Portuguese-speaking Africans and pharmacogenetic implications

Aims: The heterogeneity of the Brazilian population renders the extrapolation of pharmacogenomic data derived from well-defined ethnic groups inappropriate. We investigated the influence of self-reported `race/color`, geographical origin and genetic ancestry on the distribution of four VKORC1 SNPs and haplotypes in Brazilians. Comparative data were obtained from two major ancestral roots of Brazilians: Portuguese and Africans from former Portuguese colonies. Materials & methods: A total of 1037 healthy adults Brazilians, recruited at four different geographical regions and self identified as white, brown or black (race/color categories), 89 Portuguese and 216 Africans from Angola and Mozambique were genotyped for the VKORC1 3673G>A (rs9923231), 5808T>G (rs2884737), 6853G>C (rs8050894) and 9041G>A (rs7294) polymorphisms using TaqMan (R) (Applied Biosystems, CA, USA) assays. VKORC1 haplotypes were statistically inferred using the haplo.stats software. We inferred the statistical association between the distribution of the VKORC1 polymorphisms among Brazilians and self-reported color, geographical region and genetic ancestry by fitting multinomial log linear models via neural networks. Individual proportions of European and African ancestry were used to assess the impact of genetic admixture on the frequency distribution of VKORC1 polymorphisms among Brazilians, and for the comparison of Brazilians with Portuguese and Africans. Results: The frequency distribution of the 3673G>A and 5808T>G polymorphisms, and VKORC1 haplotypes among Brazilians varies across geographical regions, within self-reported color categories and according to the individual proportions of European and African genetic ancestry. Notably, the frequency of the warfarin sensitive VKORC1 3673A allele and the distribution of VKORC1 haplotypes varied continuously as the individual proportion of European ancestry increased in the entire cohort, independently of race/color categorization and geographical origin. Brazilians with more than 80% African ancestry differ significantly from Angolans and Mozambicans in frequency of the 3673G>A, 5808T>G and 6853G>C polymorphisms and haplotype distribution, whereas no such differences are observed between Brazilians with more than 90% European ancestry and Portuguese individuals. Conclusion: The diversity of the Brazilian population, evident in the distribution of VKORC1 polymorphisms, must be taken into account in the design of pharmacogenetic clinical trials and dealt with as a continuous variable. Warfarin dosing algorithms that include `race` terms defined for other populations are clearly not applicable to the heterogeneous and extensively admixed Brazilian population.

Exploring the knowledge contained in neuroimages: Statistical discriminant analysis and automatic segmentation of the most significant changes

Objective: The aim of this article is to propose an integrated framework for extracting and describing patterns of disorders from medical images using a combination of linear discriminant analysis and active contour models. Methods: A multivariate statistical methodology was first used to identify the most discriminating hyperplane separating two groups of images (from healthy controls and patients with schizophrenia) contained in the input data. After this, the present work makes explicit the differences found by the multivariate statistical method by subtracting the discriminant models of controls and patients, weighted by the pooled variance between the two groups. A variational level-set technique was used to segment clusters of these differences. We obtain a label of each anatomical change using the Talairach atlas. Results: In this work all the data was analysed simultaneously rather than assuming a priori regions of interest. As a consequence of this, by using active contour models, we were able to obtain regions of interest that were emergent from the data. The results were evaluated using, as gold standard, well-known facts about the neuroanatomical changes related to schizophrenia. Most of the items in the gold standard was covered in our result set. Conclusions: We argue that such investigation provides a suitable framework for characterising the high complexity of magnetic resonance images in schizophrenia as the results obtained indicate a high sensitivity rate with respect to the gold standard. (C) 2010 Elsevier B.V. All rights reserved.

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra-and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Genetic association and cellular function of MC1R variant alleles in human pigmentation

We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.

Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome

Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth retardation in association with a typical small triangular face and other variable features. Genetic and epigenetic disturbances are detected in about 50% of the patients. Most frequently, SRS is caused by altered gene expression on chromosome 11p15 due to hypomethylation of the telomeric imprinting center (ICR1) that is present in at least 40% of the patients. Maternally inherited duplications encompassing ICR1 and ICR2 domains at 11p15 were found in a few patients, and a microduplication restricted to ICR2 was described in a single SRS child. We report on a microduplication of the ICR2 domain encompassing the KCNQ1, KCNQ1OT1, and CDKN1C genes in a three-generation family: there were four instances of paternal transmissions of the microduplication from a single male uniformly resulting in normal offspring, and five maternal transmissions, via two clinically normal sisters, with all the children exhibiting SRS. This report provides confirmatory evidence that a microduplication restricted to the ICR2 domain results in SRS when maternally transmitted. (C) 2011 Wiley-Liss, Inc.

Prenatal diagnosis and natural history of fetuses presenting with pleural effusion

Objective To describe the natural history of fetuses presenting with pleural effusion. Methods Between January 2005 and December 2009 all fetuses diagnosed with pleural effusion were followed up. Fetuses were divided into three groups: I, isolated pleural effusion; II, associated structural anomalies but normal karyotype; and III, chromosomal anomalies. Univariate and multivariate analyses were performed to determine the association between prenatal ultrasound findings and perinatal death. Results Fifty-six fetuses were included in the study. Associated structural or chromosomal anomalies occurred in 75.0% (42/56) of cases. Bilateral pleural effusion and fetal hydrops were associated with each other (p < 0.01) and with perinatal death (p < 0.05). Multivariate analysis indicated that only the presence of associated abnormalities was a statistical determinant of perinatal death (OR, 3.56; 95% CI, 1.48-5.64; p < 0.01). Conclusion Fetal pleural effusion is often associated with other abnormalities, and this association has poor perinatal outcome. Copyright (C) 2011 John Wiley & Sons, Ltd.

Assessing Individual Interethnic Admixture and Population Substructure Using a 48-Insertion-Deletion (INSEL) Ancestry-Informative Marker (AIM) Panel

Estimating the proportions of different ancestries in admixed populations is very important in population genetics studies, and it is particularly important for detecting population substructure effects in case-control association studies. In this work, a set of 48 ancestry, informative insertion, deletion polymorphisms (INDELs) were selected with the goal of efficiently measuring the proportions of three different ancestries (sub-Saharan African, European, and Native American) in mixed populations. All selected markers can be easily analyzed via multiplex PCR and detected with standard capillary electrophoresis. A total of 593 unrelated individuals representative of European, African, and Native American parental populations were typed, as were 380 individuals from three Brazilian populations with known admixture patterns. As expected, the interethnic admixture estimates show that individuals from southern Brazil present an almost exclusively European ancestry; Afro-descendant communities in the Amazon region, apart from the major African contribution, present some degree of admixture with Europeans and Native Americans; and a sample from Belem, in the northeastern Amazon, shows a significant contribution of the three ethnic groups, although with a greater European proportion. In summary, a panel of ancestry-informative INDELs was optimized and proven to be a variable tool for estimating individual and global ancestry proportions in admixed populations. The ability to accurately infer interethnic admixtures highlights the usefulness of this marker set for assessing population substructure in association studies, particularly those conducted in Brazilian and other Latin American populations sharing trihybrid ancestry patterns. Hum Mutat 31:184-190, 2010. (C) 2009 Wiley-Liss, Inc.

Mitochondrial population genomics supports a single pre-Clovis origin with a coastal route for the peopling of the Americas

It is well accepted that the Americas were the last continents reached by modern humans, most likely through Beringia. However, the precise time and mode of the colonization of the New World remain hotly disputed issues. Native American populations exhibit almost exclusively five mitochondrial DNA (mtDNA) haplogroups (A-D and X). Haplogroups A-D are also frequent in Asia, suggesting a northeastern Asian origin of these lineages. However, the differential pattern of distribution and frequency of haplogroup X led some to suggest that it may represent an independent migration to the Americas. Here we show, by using 86 complete mitochondrial genomes, that all Native American haplogroups, including haplogroup X, were part of a single founding population, thereby refuting multiple-migration models. A detailed demographic history of the mtDNA sequences estimated with a Bayesian coalescent method indicates a complex model for the peopling of the Americas, in which the initial differentiation from Asian populations ended with a moderate bottleneck in Beringia during the last glacial maximum (LGM), around similar to 23,000 to similar to 19,000 years ago. Toward the end of the LGM, a strong population expansion started similar to 18,000 and finished similar to 15,000 years ago. These results support a pre-Clovis occupation of the New World, suggesting a rapid settlement of the continent along a Pacific coastal route.

Ovarian reserve evaluation: state of the art

Purpose Revise role of hormonal basal and dynamic tests, as well as ultrasonographic measures as ovarian reserve markers, in order to provide better counseling to subfertile couples. Methods Review of publications on the topic, with an emphasis on recent well designed articles. Results Currently available ovarian reserve tests do not provide sufficient evidence to be solely considered ideal, even for premature ovarian senescence patients who do not present subfertility complaints. However, these markers occupy important place in initial approach to treatment of subfertile couples, predicting unsatisfactory results that could be improved by differentiated induction schemes and reducing excessive psychological and financial burdens, and adverse effects. Conclusions In order to remedy the limitations due to the scarcity of strong evidence about this topic, future studies should try to clarify predictive value of markers in groups of specific diseases-related subfertility and pay special attention to propaedeutic multivariate models including anti-Mullerian hormone and antral follicle count.

Bursts of transposition from non-long terminal repeat retrotransposon families of the RTE clade in Schistosoma mansoni

The genus Schistosoma is composed of blood flukes that infect vertebrates, from which three species are major causative agents of human schistosomiasis, a tropical disease that affects more than 200 million people. Current models of the recent evolution of Schistosoma indicate multiple events of migration and speciation from an Asian ancestral species. Transposable elements are important drivers of genome evolution and have been hypothesised to have an important role in speciation. In this work, we describe a comprehensive inventory of Schistosoma mansoni and Schistosoma japonicum retrotransposons, based on their recently published genomic data. We find a considerable difference in retrotransposon representation between the two species (22% and 13%, respectively). A large part of this difference can be attributed to higher representation of two previously described families of S. mansoni retrotransposons (SR2 and Perere-3/SR3), compared with the representation of their closest relative families in S. japonicum. A more detailed analysis suggests that these two S. mansoni families were the subject of recent bursts of transposition that were not paralleled by their S. japonicum counterparts. We hypothesise that these bursts could be a consequence of the evolutionary pressure resulting from migration of Schistosoma from Asia to Africa and their establishment in this new environment, helping both speciation and adaptation. (C) 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Genetic associations between age at first calving and heifer body weight and scrotal circumference in Nelore cattle

P>Age at first calving (AFC) measures the entry of heifers into the beef cattle production system. This trait can be used as a selection criterion for earlier reproductive performance. Using data from Nelore cattle participating in the `Program for Genetic Improvement of the Nelore Breed` (PMGRN-Nelore Brazil), bi-trait analyses were performed using the restricted maximum likelihood method, based on an AFC animal model and the following traits: female body weight adjusted to 365 (BW365) and 450 (BW450) days of age, and male scrotal circumference adjusted to 365 (SC365), 450 (SC450), 550 (SC550) and 730 (SC730) days of age. The heritability estimates for AFC ranged from 0.02 +/- 0.02 to 0.04 +/- 0.02. The estimates of additive direct heritabilities (with standard error) for BW365, BW450, SC365, SC450, SC550 and SC730 were 0.36 +/- 0.07, 0.38 +/- 0.07, 0.48 +/- 0.07, 0.65 +/- 0.07, 0.64 +/- 0.07 and 0.42 +/- 0.07, respectively, and the genetic correlations with AFC were -0.38, -0.33, 0.10, -0.13, -0.13 and 0.06, respectively. In the herds studied, selection for SC365, SC450, SC550 or SC730 should not cause genetic changes in AFC. Selection based on BW365 or BW450 would favor smaller AFC breeding values. However, the low magnitude of direct heritability estimates for AFC in these farms indicates that changes in phenotypical expression depend mostly on non-genetic factors.