Differentiated evolutionary rates in alternative exons and the implications for splicing regulation

Background: Alternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences. Results: We find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values. Conclusion: We conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.

The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view

Objective: The importance of hemodynamics in the etiopathogenesis of intracranial aneurysms (IAs) is widely accepted.Computational fluid dynamics (CFD) is being used increasingly for hemodynamic predictions. However, alogn with thecontinuing development and validation of these tools, it is imperative to collect the opinion of the clinicians. Methods: A workshopon CFD was conducted during the European Society of Minimally Invasive Neurological Therapy (ESMINT) Teaching Course,Lisbon, Portugal. 36 delegates, mostly clinicians, performed supervised CFD analysis for an IA, using the @neuFuse softwaredeveloped within the European project @neurIST. Feedback on the workshop was collected and analyzed. The performancewas assessed on a scale of 1 to 4 and, compared with experts’ performance. Results: Current dilemmas in the management ofunruptured IAs remained the most important motivating factor to attend the workshop and majority of participants showedinterest in participating in a multicentric trial. The participants achieved an average score of 2.52 (range 0–4) which was 63% (range 0–100%) of an expert user. Conclusions: Although participants showed a manifest interest in CFD, there was a clear lack ofawareness concerning the role of hemodynamics in the etiopathogenesis of IAs and the use of CFD in this context. More effortstherefore are required to enhance understanding of the clinicians in the subject.

Development of In-Situ Detection Methods for Materials-Related Distress (MRD) in Concrete Pavements, July 2003

The purpose of this research was to summarize existing nondestructive test methods that have the potential to be used to detect materials-related distress (MRD) in concrete pavements. The various nondestructive test methods were then subjected to selection criteria that helped to reduce the size of the list so that specific techniques could be investigated in more detail. The main test methods that were determined to be applicable to this study included two stress-wave propagation techniques (impact-echo and spectral analysis of surface waves techniques), infrared thermography, ground penetrating radar (GPR), and visual inspection. The GPR technique was selected for a preliminary round of “proof of concept” trials. GPR surveys were carried out over a variety of portland cement concrete pavements for this study using two different systems. One of the systems was a state-of-the-art GPR system that allowed data to be collected at highway speeds. The other system was a less sophisticated system that was commercially available. Surveys conducted with both sets of equipment have produced test results capable of identifying subsurface distress in two of the three sites that exhibited internal cracking due to MRD. Both systems failed to detect distress in a single pavement that exhibited extensive cracking. Both systems correctly indicated that the control pavement exhibited negligible evidence of distress. The initial positive results presented here indicate that a more thorough study (incorporating refinements to the system, data collection, and analysis) is needed. Improvements in the results will be dependent upon defining the optimum number and arrangement of GPR antennas to detect the most common problems in Iowa pavements. In addition, refining highfrequency antenna response characteristics will be a crucial step toward providing an optimum GPR system for detecting materialsrelated distress.

Perfusion abnormalities in hemimegalencephaly

INTRODUCTION: Cerebrovascular changes are rarely discussed in patients with hemimegalencephaly. These alterations have previously been associated with epileptical activity. CASE: We report the case of a 36-week gestation neonate presenting with total right hemimegalencephaly, as demonstrated by a magnetic resonance imaging (MRI) performed in the first days of life. Perfusion-weighted imaging displayed a clear hypervascularization of the right hemisphere. Diffusion-tensor imaging showed an arrangement of white matter fibers concentrically around the ventricle on the right hemisphere. AngioMRI showed an obvious asymmetry in the size of the middle cerebral arteries, with the right middle cerebral artery being prominent. The baby was free of clinical seizures during his first week of life. An electroencephalogram at that time displayed an asymmetric background activity, but no electrical seizures. CONCLUSION: Perfusion anomalies in hemimegalencephaly may not necessarily be related to epileptical activity, but may be related to vessel alterations.

Catalytic and anticancer activities of sawhorse-type diruthenium tetracarbonyl complexes derived from fluorinated fatty acids

The reaction of fluorinated fatty acids, perfluorobutyric acid (C3F7CO2H), and perfluorododecanoic acid (C11F23CO2H), with dodecacarbonyltriruthenium (Ru-3(CO)(12)) under reflux in tetrahydrofuran, followed by addition of two-electron donors (L) such as pyridine, 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane, or triphenylphosphine, gives stable diruthenium complexes Ru-2(CO)(4)((2)-(2)-O2CC3F7)(2)(L)(2) (1a, L=C5H5N; 1b, L=PTA; 1c, L=PPh3) and Ru-2(CO)(4)((2)-(2)-O2CC11F23)(2)(L)(2) (2a, L=C5H5N; 2b, L=PTA; 2c, L=PPh3). The catalytic activity of the complexes for hydrogenation of styrene under supercritical carbon dioxide has been assessed and compared to the analogous triphenylphosphine complexes with non-fluorinated carboxylato groups Ru-2(CO)(4)((2)-(2)-O2CC3H7)(2)(PPh3)(2) (3) and Ru-2(CO)(4)((2)-(2)-O2CC11H23)(2)(PPh3)(2) (4). In addition, the cytotoxicities of the fluorinated complexes 1 were also evaluated on several human cancer cell lines (A2780, A549, Me300, HeLa). The complexes appear to be moderately cytotoxic, showing greater activity on the Me300 melanoma cells. Single-crystal X-ray structure analyses of 1a and 3 show the typical sawhorse-type arrangement of the diruthenium tetracarbonyl backbone with two bridging carboxylates and two terminal ligands occupying the axial positions.

The Standard Biplot

Biplots are graphical displays of data matrices based on the decomposition of a matrix as the product of two matrices. Elements of these two matrices are used as coordinates for the rows and columns of the data matrix, with an interpretation of the joint presentation that relies on the properties of the scalar product. Because the decomposition is not unique, there are several alternative ways to scale the row and column points of the biplot, which can cause confusion amongst users, especially when software packages are not united in their approach to this issue. We propose a new scaling of the solution, called the standard biplot, which applies equally well to a wide variety of analyses such as correspondence analysis, principal component analysis, log-ratio analysis and the graphical results of a discriminant analysis/MANOVA, in fact to any method based on the singular-value decomposition. The standard biplot also handles data matrices with widely different levels of inherent variance. Two concepts taken from correspondence analysis are important to this idea: the weighting of row and column points, and the contributions made by the points to the solution. In the standard biplot one set of points, usually the rows of the data matrix, optimally represent the positions of the cases or sample units, which are weighted and usually standardized in some way unless the matrix contains values that are comparable in their raw form. The other set of points, usually the columns, is represented in accordance with their contributions to the low-dimensional solution. As for any biplot, the projections of the row points onto vectors defined by the column points approximate the centred and (optionally) standardized data. The method is illustrated with several examples to demonstrate how the standard biplot copes in different situations to give a joint map which needs only one common scale on the principal axes, thus avoiding the problem of enlarging or contracting the scale of one set of points to make the biplot readable. The proposal also solves the problem in correspondence analysis of low-frequency categories that are located on the periphery of the map, giving the false impression that they are important.

Dual-wavelength digital holographic microscopy with sub-nanometer axial accuracy

We present dual-wavelength Digital Holographic Microscopy (DHM) measurements on a certified 8.9 nm high Chromium thin step sample and demonstrate sub-nanometer axial accuracy. We introduce a modified DHM Reference Calibrated Hologram (RCH) reconstruction algorithm taking into account amplitude contributions. By combining this with a temporal averaging procedure and a specific dual-wavelength DHM arrangement, it is shown that specimen topography can be measured with an accuracy, defined as the axial standard deviation, reduced to at least 0.9 nm. Indeed, it is reported that averaging each of the two wavefronts recorded with real-time dual-wavelength DHM can provide up to 30% spatial noise reduction for the given configuration, thanks to their non-correlated nature. ©2008 COPYRIGHT SPIE

The Role of Public Administration: A Global Perspective

From my experience with public administration in my country, Cape Verde, and through readings in the area of development administration, I have found that a distinctive role and specific societal goals are usually ascribed to public administration in developing country. In studying American public administration approaches and operation, I was stuck by the fact that the definition of roles and societal goals for public administration seems not to be a forefront concern in the field. How to do things and achieve efficiency, in a managerial and rational perspective, seemed to draw much more attention than the purpose of doing things. Somehow, the contrast with the concept of development administration seemed too sharp, and I became curious about the reasons for such disparate approaches. Historical, cultural, and environmental differences would probably not be the only explanation for that since the concept of development administration was shaped, in the late 50’s and 60’s, by American authors and institutional aid agencies, and then “offered” to developing countries. At the same time, looking to poor results of the successive prescriptions of the development administration movement, I was no sure that such a concept and the framework it establishes was worthwhile. What practical answers and arrangement did they bring to the needs and challenges of public administrations in developing countries? …

Living Snow Fences, 2006

Blowing snow can cause significant problems for mobility and safety during winter weather in three distinct ways. It may drift onto the road, thus requiring almost continuous plowing while the wind is blowing (which may occur when a given winter storm is over). Snow may drift onto wet pavement (perhaps caused by ice control chemicals) and dilute out the chemicals on the road, creating ice on the road. And sufficient blowing snow can cause a major deterioration in visibility on the road, a factor which has been shown to be significant in winter crashes. The problem of blowing snow can be very effectively addressed by creating a snow storage device upwind of the road that requires protection from snow drifting. Typically, these storage devices are fences. Extensive design guidance exists for the required height and placement of such fences for a given annual snowfall and given local topography. However, the design information on the placement of living snow fences is less complete. The purpose of this report is to present the results of three seasons of study on using standing corn as snow fences. In addition, the experience of using switch grass as a snow storage medium is also presented. On the basis of these experimental data, a design guide has been developed that makes use of the somewhat unique snow storage characteristics of standing corn snow fences. The results of the field tests on using standing corn showed that multiple rows of standing corn store snow rather differently than a traditional wooden snow fence. Specifically, while a traditional fence stores most of the snow downwind from the fence (and thus must be placed a significant distance upwind of the road to be protected, specifically at least 35 times the snow fence height) rows of standing corn store the majority of the snow within the rows. Results from the three winters of testing show that the standing corn snow fences can store as much snow within the rows of standing corn as a traditional fence of typical height for operation in Iowa (4 to 6 feet) can store. This finding is significant because it means that the snow fences can be placed at the edge of the farmer’s field closest to the road, and still be effective. This is typically much more convenient for the farmer and thus may mean that more farmers would be willing to participate in a program that uses standing corn than in traditional programs. ii On the basis of the experimental data, design guidance for the use of standing corn as a snow storage device in Iowa is given in the report. Specifically, it is recommended that if the fetch in a location to be protected is less than 5,000 feet, then 16 rows of standing corn should be used, at the edge of the field adjacent to the right of way. If the fetch is greater than 5,000 feet, then 24 rows of standing corn should be used. This is based on a row spacing of 22 inches. Further, it should be noted that these design recommendations are ONLY for the State of Iowa. Other states of course have different winter weather and without extensive further study, it cannot be said that these guidelines would be effective in other locations with other winter conditions.

Modeling of the TCR-MHC-peptide complex.

The methodology for generating a homology model of the T1 TCR-PbCS-K(d) class I major histocompatibility complex (MHC) class I complex is presented. The resulting model provides a qualitative explanation of the effect of over 50 different mutations in the region of the complementarity determining region (CDR) loops of the T cell receptor (TCR), the peptide and the MHC's alpha(1)/alpha(2) helices. The peptide is modified by an azido benzoic acid photoreactive group, which is part of the epitope recognized by the TCR. The construction of the model makes use of closely related homologs (the A6 TCR-Tax-HLA A2 complex, the 2C TCR, the 14.3.d TCR Vbeta chain, the 1934.4 TCR Valpha chain, and the H-2 K(b)-ovalbumine peptide), ab initio sampling of CDR loops conformations and experimental data to select from the set of possibilities. The model shows a complex arrangement of the CDR3alpha, CDR1beta, CDR2beta and CDR3beta loops that leads to the highly specific recognition of the photoreactive group. The protocol can be applied systematically to a series of related sequences, permitting the analysis at the structural level of the large TCR repertoire specific for a given peptide-MHC complex.

Adoption Subsidies and Environmental Impacts of Alternative Energy Crops, March 2007

We provide estimates of the costs associated with inducing substantial conversion of land from production of traditional crops to switchgrass. Higher traditional crop prices due to increased demand for corn from the ethanol industry has increased the relative advantage that row crops have over switchgrass. Results indicate that farmers will convert to switchgrass production only with significant conversion subsidies. To examine potential environmental consequences of conversion, we investigate three stylized landscape usage scenarios, one with an entire conversion of a watershed to switchgrass production, a second with the entire watershed planted to continuous corn under a 50% removal rate of the biomass, and a third scenario that places switchgrass on the most erodible land in the watershed and places continuous corn on the least erodible. For each of these illustrative scenarios, the watershed-scale Soil and Water Assessment Tool (SWAT) hydrological model (Arnold et al., 1998; Arnold and Forher, 2005) is used to evaluate the effect of these landscape uses on sediment and nutrient loadings in the Maquoketa Watershed in eastern Iowa.

Ratio maps and correspondence analysis

We compare two methods for visualising contingency tables and developa method called the ratio map which combines the good properties of both.The first is a biplot based on the logratio approach to compositional dataanalysis. This approach is founded on the principle of subcompositionalcoherence, which assures that results are invariant to considering subsetsof the composition. The second approach, correspondence analysis, isbased on the chi-square approach to contingency table analysis. Acornerstone of correspondence analysis is the principle of distributionalequivalence, which assures invariance in the results when rows or columnswith identical conditional proportions are merged. Both methods may bedescribed as singular value decompositions of appropriately transformedmatrices. Correspondence analysis includes a weighting of the rows andcolumns proportional to the margins of the table. If this idea of row andcolumn weights is introduced into the logratio biplot, we obtain a methodwhich obeys both principles of subcompositional coherence and distributionalequivalence.

Contribution biplots

In order to interpret the biplot it is necessary to know which points usually variables are the ones that are important contributors to the solution, and this information is available separately as part of the biplot s numerical results. We propose a new scaling of the display, called the contribution biplot, which incorporates this diagnostic directly into the graphical display, showing visually the important contributors and thus facilitating the biplot interpretation and often simplifying the graphical representation considerably. The contribution biplot can be applied to a wide variety of analyses such as correspondence analysis, principal component analysis, log-ratio analysis and the graphical results of a discriminant analysis/MANOVA, in fact to any method based on the singular-value decomposition. In the contribution biplot one set of points, usually the rows of the data matrix, optimally represent the spatial positions of the cases or sample units, according to some distance measure that usually incorporates some form of standardization unless all data are comparable in scale. The other set of points, usually the columns, is represented by vectors that are related to their contributions to the low-dimensional solution. A fringe benefit is that usually only one common scale for row and column points is needed on the principal axes, thus avoiding the problem of enlarging or contracting the scale of one set of points to make the biplot legible. Furthermore, this version of the biplot also solves the problem in correspondence analysis of low-frequency categories that are located on the periphery of the map, giving the false impression that they are important, when they are in fact contributing minimally to the solution.

Management of patient dose and image noise in routine pediatric CT abdominal examinations.

The aim was to propose a strategy for finding reasonable compromises between image noise and dose as a function of patient weight. Weighted CT dose index (CTDI(w)) was measured on a multidetector-row CT unit using CTDI test objects of 16, 24 and 32 cm in diameter at 80, 100, 120 and 140 kV. These test objects were then scanned in helical mode using a wide range of tube currents and voltages with a reconstructed slice thickness of 5 mm. For each set of acquisition parameter image noise was measured and the Rose model observer was used to test two strategies for proposing a reasonable compromise between dose and low-contrast detection performance: (1) the use of a unique noise level for all test object diameters, and (2) the use of a unique dose efficacy level defined as the noise reduction per unit dose. Published data were used to define four weight classes and an acquisition protocol was proposed for each class. The protocols have been applied in clinical routine for more than one year. CTDI(vol) values of 6.7, 9.4, 15.9 and 24.5 mGy were proposed for the following weight classes: 2.5-5, 5-15, 15-30 and 30-50 kg with image noise levels in the range of 10-15 HU. The proposed method allows patient dose and image noise to be controlled in such a way that dose reduction does not impair the detection of low-contrast lesions. The proposed values correspond to high- quality images and can be reduced if only high-contrast organs are assessed.

Optimal monetary and fiscal policy in a currency union

We lay out a tractable model for fiscal and monetary policy analysis in a currency union, and study its implications for the optimal design of such policies. Monetary policy is conducted by a common central bank, which sets the interest rate for the union as a whole. Fiscal policy is implemented at the countrylevel, through the choice of government spending. The model incorporates country-specific shocks and nominal rigidities. Under our assumptions, the optimal cooperative policy arrangement requires that inflation be stabilized at the union level by the common central bank, while fiscal policy is used by each country for stabilization purposes. By contrast, when the fiscal authorities act in a non-coordinated way, their joint actions lead to a suboptimal outcome, and make the common central bank face a trade-off between inflation and output gap stabilization at the union level.