SIMEX for correction of dietary exposure effects with Box-Cox transformed data

Modelling dietary data, and especially 24-hr dietary recall (24HDR) data, is a challenge. Ignoring the inherent measurement error (ME) leads to biased effect estimates when the association between an exposure and an outcome is investigated. We propose an adapted simulation extrapolation (SIMEX) algorithm for modelling dietary exposures. For this purpose, we exploit the ME model of the NCI method where we assume the assumption of normally distributed errors of the reported intake on the Box-Cox transformed scale and of unbiased recalls on the original scale. According to the SIMEX algorithm, remeasurements of the observed data with additional ME are generated in order to estimate the association between the level of ME and the resulting effect estimate. Subsequently, this association is extrapolated to the case of zero ME to obtain the corrected estimate. We show that the proposed method fulfils the key property of the SIMEX approach, that is, that the MSE of the generated data will converge to zero if the ME variance converges to zero. Furthermore, the method is applied to real 24HDR data of the I.Family study to correct the effects of salt and alcohol intake on blood pressure. In a simulation study, the method is compared with the NCI method resulting in effect estimates with either smaller MSE or smaller bias in certain situations. In addition, we found our method to be more informative and easier to implement. Therefore, we conclude that the proposed method is useful to promote the dissemination of ME correction methods in nutritional epidemiology.     

Linking the evolution of habitat choice to ecosystem functioning: direct and indirect effects of pond-reproducing fire salamanders on aquatic-terrestrial subsidies

Shifts in life history traits and in the behaviour of species can potentially alter ecosystem functioning. The reproduction of the central European fire salamander (Salamandra salamandra), which usually deposits its larvae in first-order streams, in small pool and pond-like habitats, is an example of a recent local adaptation in this species. Here we aimed to quantify the direct and indirect effects of the predatory larvae on the aquatic food webs in the ponds and on the flux of matter between the ponds and adjacent terrestrial habitats. Our estimates are based on biomass data of the present pond fauna as well as on the analysis of stomach content data, growth rates and population dynamics of the salamander larvae in pond habitats. By their deposition of larvae in early spring, female fire salamanders import between 0.07 and 2.86 g dry mass m^?2 larval biomass into the ponds. Due to high mortality rates in the larval phase and the relatively small size at metamorphosis of the pond-adapted salamanders compared to stream-adapted ones, the biomass export of the metamorphosed salamanders clearly falls below the initial biomass import. Catastrophic events such as high water temperatures and low oxygen levels may even occasionally result in mass mortalities of salamander larvae and thus in a net 100 % import of the salamander biomass into the pond food webs. Indirect effects further accelerate this net import of matter into the aquatic habitat, e.g. the feeding of salamanders on aquatic insect larvae with the emergence of terrestrial adults—thus preventing export—and on terrestrial organisms that fall on the water surface (supporting import). This study demonstrates that the adaptation of salamanders to pond reproduction can alter food web linkages across ecosystem boundaries by enhancing the flux of materials and energy from terrestrial (i.e. forest) to the aquatic (i.e. pond) habitat.     

Critical thermal maxima of juvenile alligator gar (Atractosteus spatula,Lacépède, 1803) from three Mississippi‐drainage populations acclimated to three temperatures

Local adaptation may cause thermal tolerance to vary between nearby but distinct populations of a species. During the summer of 2013, alligator gar Atractosteus spatula spawned from broodstock collected from three populations within the Mississippi River drainage separated by a 5° latitudinal gradient were acclimated to three temperatures (25, 30, and 35°C). Ten fish from each population were acclimated at each temperature. CT_Max was determined at each temperature for each population, using five fish for each population‐acclimation temperature pairing. CT_Max for each population‐acclimation temperature pairing was compared using two‐factor anova . CT_Max increased significantly with acclimation temperature (F_2,40 = 600.5, P < 0.001) but population had no significant effect (F_2,40 = 1.882, P = 0.166). Temperature tolerance appears to be consistent across populations of alligator gar, with no evidence of local adaptation.     

Validated numerical fluid simulation of a thin‐layer cascade photobioreactor in OpenFOAM

Recently, microalgae have been considered as a promising alternative for the production of biofuels from CO₂. For the efficient cultivation of these microalgae, several types of photobioreactors have been designed and Pilot scale photobioreactors have been used to assess the performance of these reactors. Therein the primarily investigated reactor type is the Raceway Pond. However, the less researched Thin‐Layer Cascade Photobioreactor (TLC) shows a high potential for efficient production processes. Unfortunately, for low‐value products like biofuels costs must be kept to a minimum for an economic operation. To facilitate this, 3D Computational Fluid Dynamic simulations can be employed to estimate performance of reactor variants e.g. with respect to power input and mixing. Since up to now little effort has been put into the modelling of TLC reactors, this report aims to present a simulation approach for these reactors types that allows simple adaptation to different geometric or operational boundary conditions. All models have been generated for a two‐phase mixture in OpenFOAM. To demonstrate its applicability, validation measurements with a physical unit have been performed and were compared to the simulation results. With errors in the order of 10 % a successful simulation of the reactor geometry could be proven.     

Half a century of oligochaete research in Estonian running waters

About 51500 specimens from 1542 samples, collected over the years 1954–1975 and 1986–1999 in different running water bodies throughout Estonia, were identified. Tubificidae prevailed in the material, with Limnodrilus hoffmeisteri forming about 40%. This species was followed by the tubificids Tubifex tubifex, Potamothrix hammoniensis, Psammoryctides barbatus, L. udekemianus and Spirosperma ferox, the naidid Stylaria lacustris, and the lumbriculid Stylodrilus heringianus. Two main ecological assemblages were distinguished: the pelophilous assemblage, dominated by L. hoffmeisteri, and the psammophilous one, where usually P. barbatus was dominant. The relationships between different species and the chemical parameters of water were usually weak but in contrast, correlated well with sediment preferences. In organically enriched reaches, L. hoffmeisteri usually dominated. The fauna of the streams of the islands was poorer in species due to their small size rather than geographical isolation. Some recent antropochorous Ponto-Caspian invaders have only reached the lowermost reaches of the two largest rivers. Some brackish water species were found in the mouth of the Pärnu River. No essential differences were found between the comparable sets of oligochaete samples collected in 1954–1975 and 1987–1997 in the Estonian running waters.     

Structural and functional analysis of missense mutations in fumarylacetoacetate hydrolase, the gene deficient in hereditary tyrosinemia type 1

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by a deficiency of the enzyme involved in the last step of tyrosine degradation, fumarylacetoacetate hydrolase (FAH). Thus far, 34 mutations in the FAH gene have been reported in various HT1 patients. Site-directed mutagenesis of the FAH cDNA was used to investigate the effects of eight missense mutations found in HTI patients on the structure and activity of FAH. Mutated FAH proteins were expressed in Escherichia coli and in mammalian CV-1 cells. Mutations N16I, F62C, A134D, C193R, D233V, and W234G lead to enzymatically inactive FAH proteins. Two mutations (R341W, associated with the pseudo-deficiency phenotype, and Q279R) produced proteins with a level of activity comparable to the wild-type enzyme. The N16I, F62C, C193R, and W234G variants were enriched in an insoluble cellular fraction, suggesting that these amino acid substitutions interfere with the proper folding of the enzyme. Based on the tertiary structure of FAH, on circular dichroism data, and on solubility measurements, we propose that the studied missense mutations cause three types of structural effects on the enzyme: 1) gross structural perturbations, 2) limited conformational changes in the active site, and 3) conformational modifications with no significant effect on enzymatic activity.     

P3 cap modified Phe*-Ala series BACE inhibitors

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).     

Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors. Part 1: Design, synthesis, and biological evaluation

We have identified a novel structural class of protein serine/threonine kinase inhibitors comprised of an aminoimidazo[1,2-a]pyridine nucleus. Compounds from this family are shown to potently inhibit cyclin-dependent kinases by competing with ATP for binding to a catalytic subunit of the protein. Structure-based design approach was used to direct this chemical scaffold toward generating potent and selective CDK2 inhibitors. The discovery of this new class of ATP-site directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis of new medicinal chemistry tool in search for an effective treatment of cancer and other diseases that involve protein kinase signaling pathways.