Geographical variation in the penetrance of CDKN2A mutations for melanoma

Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

Effect of disrupted SOX18 transcription factor function on tumor growth, vascularization, and endothelial development

Background. The growth of solid tumors depends on establishing blood supply; thus, inhibiting tumor angiogenesis has been a long-term goal in cancer therapy. The SOX18 transcription factor is a key regulator of murine and human blood vessel formation. Methods: We established allograft melanoma tumors in wild-type mice, Sox18-null mice, and mice expressing a dominant-negative form of Sox18 (Sox18RaOp) (n = 4 per group) and measured tumor growth and microvessel density by immunohistochemical analysis with antibodies to the endothelial marker CD31 and the pericyte marker NG2. We also assessed the affects of disrupted SOX18 function on MCF-7 human breast cancer and human umbilical vein endothelial cell (HUVEC) proliferation by measuring BrdU incorporation and by MTS assay, cell migration using Boyden chamber assay, and capillary tube formation in vitro. All statistical tests were two-sided. Results: Allograft tumors in Sox18-null and Sox18RaOp mice grew more slowly than those in wild-type mice (tumor volume at day 14, Sox18 null, mean = 486 mm(3), 95% confidence interval [CI] = 345 mm(3) to 627 mm(3), p = .004; Sox18RaOp, mean = 233 mm(3), 95% CI = 73 mm(3) to 119 mm(3), p < .001; versus wild-type, mean = 817 mm(3), 95% CI = 643 mm(3) to 1001 mm(3)) and had fewer CD31- and NG2-expressing vessels. Expression of dominant-negative Sox18 reduced the proliferation of MCF-7 cells (BrdU incorporation: MCF-7(Ra) = 20%, 95% CI = 15% to 25% versus MCF-7 = 41%, 95% CI = 35% to 45%; P = .013) and HUVECs (optical density at 490 nm, empty vector, mean = 0.46 versus SOX18 mean = 0.29; difference = 0.17, 95% CI = 0.14 to 0.19; P = .001) compared with control subjects. Overexpression of wild-type SOX18 promoted capillary tube formation of HUVECs in vitro, whereas expression of dominant-negative SOX18 impaired tube formation of HUVECs and the migration of MCF-7 cells via the disruption of the actin cytoskeleton. Conclusions: SOX18 is a potential target for antiangiogenic therapy of human cancers.

Modelling of two-stage anaerobic digestion using the IWA Anaerobic Digestion Model No. 1 (ADM1)

The aim of the study presented was to implement a process model to simulate the dynamic behaviour of a pilot-scale process for anaerobic two-stage digestion of sewage sludge. The model implemented was initiated to support experimental investigations of the anaerobic two-stage digestion process. The model concept implemented in the simulation software package MATLAB(TM)/Simulink(R) is a derivative of the IWA Anaerobic Digestion Model No.1 (ADM1) that has been developed by the IWA task group for mathematical modelling of anaerobic processes. In the present study the original model concept has been adapted and applied to replicate a two-stage digestion process. Testing procedures, including balance checks and 'benchmarking' tests were carried out to verify the accuracy of the implementation. These combined measures ensured a faultless model implementation without numerical inconsistencies. Parameters for both, the thermophilic and the mesophilic process stage, have been estimated successfully using data from lab-scale experiments described in literature. Due to the high number of parameters in the structured model, it was necessary to develop a customised procedure that limited the range of parameters to be estimated. The accuracy of the optimised parameter sets has been assessed against experimental data from pilot-scale experiments. Under these conditions, the model predicted reasonably well the dynamic behaviour of a two-stage digestion process in pilot scale. (C) 2004 Elsevier Ltd. All rights reserved.

Drying process of microcrystalline cellulose studied by attenuated total reflection IR spectroscopy with two-dimensional correlation spectroscopy and principal component analysis

Molecular interactions between microcrystalline cellulose (MCC) and water were investigated by attenuated total reflection infrared (ATR/IR) spectroscopy. Moisture-content-dependent IR spectra during a drying process of wet MCC were measured. In order to distinguish overlapping O–H stretching bands arising from both cellulose and water, principal component analysis (PCA) and, generalized two-dimensional correlation spectroscopy (2DCOS) and second derivative analysis were applied to the obtained spectra. Four typical drying stages were clearly separated by PCA, and spectral variations in each stage were analyzed by 2DCOS. In the drying time range of 0–41 min, a decrease in the broad band around 3390 cm−1 was observed, indicating that bulk water was evaporated. In the drying time range of 49–195 min, decreases in the bands at 3412, 3344 and 3286 cm−1 assigned to the O6H6cdots, three dots, centeredO3′ interchain hydrogen bonds (H-bonds), the O3H3cdots, three dots, centeredO5 intrachain H-bonds and the H-bonds in Iβ phase in MCC, respectively, were observed. The result of the second derivative analysis suggests that water molecules mainly interact with the O6H6cdots, three dots, centeredO3′ interchain H-bonds. Thus, the H-bonding network in MCC is stabilized by H-bonds between OH groups constructing O6H6cdots, three dots, centeredO3′ interchain H-bonds and water, and the removal of the water molecules induces changes in the H-bonding network in MCC.

A two-phase approach for detecting recombination in nucleotide sequences

Genetic recombination can produce heterogeneous phylogenetic histories within a set of homologous genes. Delineating recombination events is important in the study of molecular evolution, as inference of such events provides a clearer picture of the phylogenetic relationships among different gene sequences or genomes. Nevertheless, detecting recombination events can be a daunting task, as the performance of different recombination-detecting approaches can vary, depending on evolutionary events that take place after recombination. We recently evaluated the effects of post-recombination events on the prediction accuracy of recombination-detecting approaches using simulated nucleotide sequence data. The main conclusion, supported by other studies, is that one should not depend on a single method when searching for recombination events. In this paper, we introduce a two-phase strategy, applying three statistical measures to detect the occurrence of recombination events, and a Bayesian phylogenetic approach in delineating breakpoints of such events in nucleotide sequences. We evaluate the performance of these approaches using simulated data, and demonstrate the applicability of this strategy to empirical data. The two-phase strategy proves to be time-efficient when applied to large datasets, and yields high-confidence results.

Two times three little pigs: Dysfluency, cognitive complexity and autism

This paper presents an analysis of dysfluencies in two oral tellings of a familiar children's story by a young boy with autism. Thurber & Tager-Flusberg (1993) postulate a lower degree of cognitive and communicative investment to explain a lower frequency of non-grammatical pauses observed in elicited narratives of children with autism in comparison to typically developing and intellectually disabled controls. we also found a very low frequency of non-grammatical pauses in our data, but indications of high engagement and cognitive and communicative investment. We point to a wider range of disfluencies as indicators of cognitive load, and show that the kind and location of dysfluencies produced may reveal which aspects of the narrative task are creating the greatest cognitive demand: here, mental state ascription, perspectivization, and adherence to story schema. This paper thus generates analytical options and hypotheses that can be explored further in a larger population of children with autism and typically developing controls.

Two-bedroom townhouses, Air Niugini Staff Housing, Papua New Guinea

As seen from road.

Bimanual aiming and overt attention: one law for two hands

Reaching to interact with an object requires a compromise between the speed of the limb movement and the required end-point accuracy. The time it takes one hand to move to a target in a simple aiming task can be predicted reliably from Fitts' law, which states that movement time is a function of a combined measure of amplitude and accuracy constraints (the index of difficulty, ID). It has been assumed previously that Fitts' law is violated in bimanual aiming movements to targets of unequal ID. We present data from two experiments to show that this assumption is incorrect: if the attention demands of a bimanual aiming task are constant then the movements are well described by a Fitts' law relationship. Movement time therefore depends not only on ID but on other task conditions, which is a basic feature of Fitts' law. In a third experiment we show that eye movements are an important determinant of the attention demands in a bimanual aiming task. The results from the third experiment extend the findings of the first two experiments and show that bimanual aiming often relies on the strategic co-ordination of separate actions into a seamless behaviour. A number of the task specific strategies employed by the adult human nervous system were elucidated in the third experiment. The general strategic pattern observed in the hand trajectories was reflected by the pattern of eye movements recorded during the experiment. The results from all three experiments demonstrate that eye movements must be considered as an important constraint in bimanual aiming tasks.

Local adaptation and species segregation in two mussel (Mytilus edulis X M. trossulus) hybrid zones

Few marine hybrid zones have been studied extensively, the major exception being the hybrid zone between the mussels Mytilus edulis and M. galloprovincialis in southwestern Europe. Here, we focus on two less studied hybrid zones that also involve Mytilus spp.; M. edulis and M. trossulus are sympatric and hybridize on both western and eastern coasts of the Atlantic Ocean. We review the dynamics of hybridization in these two hybrid zones and evaluate the role of local adaptation for maintaining species boundaries. In Scandinavia, hybridization and gene introgression is so extensive that no individuals with pure M. trossulus genotypes have been found. However, M. trossulus alleles are maintained at high frequencies in the extremely low salinity Baltic Sea for some allozyme genes. A synthesis of reciprocal transplantation experiments between different salinity regimes shows that unlinked Gpi and Pgm alleles change frequency following transplantation, such that post-transplantation allelic composition resembles native populations found in the same salinity. These experiments provide strong evidence for salinity adaptation at Gpi and Pgm (or genes linked to them). In the Canadian Maritimes, pure M. edulis and M. trossulus individuals are abundant, and limited data suggest that M. edulis predominates in low salinity and sheltered conditions, whereas M. trossulus are more abundant on the wave-exposed open coasts. We suggest that these conflicting patterns of species segregation are, in part, caused by local adaptation of Scandinavian M. trossulus to the extremely low salinity Baltic Sea environment.

Entangled States and Collective Nonclassical Effects in Two-Atom Systems

We propose a review of recent developments on entanglement and nonclassical effects in collective two-atom systems and present a uniform physical picture of the many predicted phenomena. The collective effects have brought into sharp focus some of the most basic features of quantum theory, such as nonclassical states of light and entangled states of multiatom systems. The entangled states are linear superpositions of the internal states of the system which cannot be separated into product states of the individual atoms. This property is recognized as entirely quantum-mechanical effect and have played a crucial role in many discussions of the nature of quantum measurements and, in particular, in the developments of quantum communications. Much of the fundamental interest in entangled states is connected with its practical application ranging from quantum computation, information processing, cryptography, and interferometry to atomic spectroscopy.

Two-wire waveguide and interferometer for cold atoms

A versatile miniature de Broglie waveguide is formed by two parallel current-carrying wires in the presence of a uniform bias field. We derive a variety of analytical expressions to describe the guide and present a quantum theory to show that it offers a remarkable range of possibilities for atom manipulation on the submicron scale. These include controlled and coherent splitting of the wave function as well as cooling, trapping, and guiding. In particular, we discuss a novel microscopic atom interferometer with the potential to be exceedingly sensitive.

A two-phase strategy for detecting recombination in nucleotide sequences

Genetic recombination can produce heterogeneous phylogenetic histories within a set of homologous genes. Delineating recombination events is important in the study of molecular evolution, as inference of such events provides a clearer picture of the phylogenetic relationships among different gene sequences or genomes. Nevertheless, detecting recombination events can be a daunting task, as the performance of different recombination-detecting approaches can vary, depending on evolutionary events that take place after recombination. We previously evaluated the effects of post-recombination events on the prediction accuracy of recombination-detecting approaches using simulated nucleotide sequence data. The main conclusion, supported by other studies, is that one should not depend on a single method when searching for recombination events. In this paper, we introduce a two-phase strategy, applying three statistical measures to detect the occurrence of recombination events, and a Bayesian phylogenetic approach to delineate breakpoints of such events in nucleotide sequences. We evaluate the performance of these approaches using simulated data, and demonstrate the applicability of this strategy to empirical data. The two-phase strategy proves to be time-efficient when applied to large datasets, and yields high-confidence results.

Lower Carboniferous microfloras of Spitsbergen, Part Two.

Second part (and conclusion) of a paper on dispersed microspores from Culm (Carboniferous) localities, mainly in Billefjorden sandstones. Macroscopic lithologic data for samples are appended. "The present study lends considerable support to the view . . . that terrestrial sequences of lower Carboniferous age may be subdivided precisely on the exclusive basis of their microspore content.