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The evolution of complex phenotypes like reproductive strategies is challenging to understand, as they often depend on multiple adaptations that only jointly result in a specific functionality. Sulawesi ricefishes (Adrianichthyidae) evolved a reproductive strategy termed as pelvic brooding. In contrast to the more common transfer brooding, female pelvic brooders carry an egg bundle connected to their body for weeks until the fry hatches. To examine the genetic architecture of pelvic brooding, we crossed the pelvic brooding Oryzias eversi and the transfer brooding Oryzias nigrimas (species divergence time: ∼3.6 my). We hypothesize, that a low number of loci and modularity have facilitated the rapid evolution of pelvic brooding. Traits associated to pelvic brooding, like rib length, pelvic fin length, and morphology of the genital papilla, were correlated in the parental species but correlations were reduced or lost in their F1 and F2 hybrids. Using the Castle-Wright estimator, we found that generally few loci underlie the studied traits. Further, both parental species showed modularity in their body plans. In conclusion, morphological traits related to pelvic brooding were based on a few loci and the mid-body region likely could evolve independently from the remaining body parts. Both factors presumably facilitated the evolution of pelvic brooding.

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Hybridization can induce transposons to jump into new genomic positions, which may result in their accumulation across the genome. Alternatively, transposon copy numbers may increase through non-allelic (ectopic) homologous recombination in highly repetitive regions of the genome. The relative contribution of transposition bursts versus recombination-based mechanisms to evolutionary processes remains unclear because studies on transposon dynamics in natural systems are rare. We assessed the genome-wide distribution of transposon insertions in a young hybrid lineage ("invasive Cottus", n=11) and its parental species Cottus rhenanus (n=17) and Cottus perifretum (n=9) using a reference genome assembled from long single molecule PacBio reads. An inventory of transposable elements was reconstructed from the same data and annotated. Transposon copy numbers in the hybrid lineage increased in 120 (15.9%) out of 757 transposons studied here. The copy number increased on average by 69% (range: 10 - 197%). Given the age of the hybrid lineage, this suggests that they have proliferated within a few hundred generations since admixture began. However, frequency spectra of transposon insertions revealed no increase of novel and rare insertions across assembled parts of the genome. This implies that transposons were added to repetitive regions of the genome that remain difficult to assemble. Future studies will need to evaluate whether recombination-based mechanisms rather than genome-wide transposition may explain the majority of the recent transposon proliferation in the hybrid lineage. Irrespectively of the underlying mechanism, the observed over-abundance in repetitive parts of the genome suggests that gene-rich regions are unlikely to be directly affected. This article is protected by copyright. All rights reserved.

Ecological speciation and adaptive radiation are key processes shaping northern temperate freshwater fish diversity. Both often involve parapatric differentiation between stream and lake populations and less often, sympatric intralacustrine diversification into habitat- and resource-associated ecotypes. However, few taxa have been studied, calling for studies of others to investigate the generality of these processes. Here, we test for diversification within catchments in freshwater sculpins in a network of peri-Alpine lakes and streams. Using 8047 and 13 182 restriction site-associated (RADseq) SNPs, respectively, we identify three deeply divergent phylogeographic lineages associated with different major European drainages. Within the Aare catchment, we observe populations from geographically distant lakes to be genetically more similar to each other than to populations from nearby streams. This pattern is consistent with two distinct colonization waves, rather than by parapatric ecological speciation after a single colonization wave. We further find two distinct depth distribution modes in three lakes of the Aare catchment, one in very shallow and one in very deep water, and significant genomewide differentiation between these in one lake. Sculpins in the Aare catchment appear to represent an early-stage adaptive radiation involving the evolution of a lacustrine lineage distinct from parapatric stream sculpins and the repeated onset of depth-related intralacustrine differentiation.

When a lineage originates from hybridization genomic blocks of contiguous ancestry from different ancestors are fragmented through genetic recombination. The resulting blocks are delineated by so called junctions, which accumulate with every generation that passes. Modeling the accumulation of ancestry block junctions can elucidate processes and timeframes of genomic admixture. Previous models have not addressed ancestry block dynamics for chromosomes that consist of a finite number of recombination sites. However, genomic data typically consist of informative markers that are interspersed with fragments for which no ancestry information is available. Hence, repeated recombination events may occur between markers, effectively removing existing junctions. Here, we present an analytical treatment of the dynamics of the mean number of junctions over time, taking into account the number of recombination sites per chromosome, population size, genetic map length, and the frequency of the ancestral species in the founding hybrid swarm. We describe the expected number of junctions using equidistant molecular markers and estimate the number of junctions using random markers. This extended theory of junctions thus reflects properties of empirical data and can serve to study the genomic patterns following admixture.

Biomass fast pyrolysis is a technology that is able to convert biomass, a low-density solid, into primarily a liquid bio-oil product that is denser and more easily storable and transportable. However, utilizing raw bio-oil is difficult, mainly due to its high oxygen content. Bio-oil must be upgraded and deoxygenated first before it can be co-fed into a petroleum refinery. One method of upgrading involves condensing the pyrolysis vapors into bio-oil and then hydrotreating the bio-oil. Significant deoxygenation can be achieved; however, the hydrotreatment is typically performed under high pressure (>6900 kPa) and with multiple temperature stages. Also, lignin-derived phenolic compounds can be prone to polymerize and plug reactors. Generally, the catalysts that have been tested are expensive noble metals or transition metal sulfides. Another upgrading approach is to react the pyrolysis vapors over a catalyst to produce a deoxygenated liquid product upon condensation. Common petroleum refining catalysts, such as zeolites, have been found to produce hydrocarbons although their yields are generally low to moderate whereas the yields of solids (char/coke) and gases (CO and CO2) can be high. In addition, zeolites can suffer rapid deactivation through coking and loss of acidity. Other, new catalysts that have been tested for vapor-phase deoxygenation include noble-metal and transition-metal catalysts. Noble metals are active but are also prone to saturating aromatic rings. More cost-effective catalysts, that is, transition metal-based catalysts, have also been tested for hydrodeoxygenation efficacy. Particularly, two molybdenum-based catalysts, MoO3 and Mo2C, were found to deoxygenate biomass model compounds under low pressure and moderate temperatures. In addition, MoO3 has been shown to deoxygenate pyrolysis vapors obtained from complete biomass. From our perspective, the most feasible upgrading strategy would likely involve catalytically upgrading pyrolysis vapors under low pressure, moderate temperature, and with minimal hydrogen consumption to produce unsaturated alkenes and aromatics, which can then be further processed and refined in a traditional petroleum refinery.

OBJECTIVE: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.METHODS: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.RESULTS: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.INTERPRETATION: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. Ann Neurol 2016;79:970-982. (Less)

Sodium ions, one of the natural inorganic constituents in lignocellulosic biomass, significantly alter pyrolysis behavior and resulting chemical speciation. Here, experiments were conducted using a micropyrolyzer to investigate the catalytic effects of NaCl on fast pyrolysis of glucose-based carbohydrates (glucose, cellobiose, maltohexaose, and cellulose), and on a major product of cellulose pyrolysis, levoglucosan (LVG). A mechanistic model that addressed the significant catalytic effects of NaCl on the product distribution was developed. The model incorporated interactions of Na+ with cellulosic chains and low molecular weight species, reactions mediated by Na+ including dehydration, cyclic/Grob fragmentation, ring-opening/closing, isomerization, and char formation, and a degradation network of LVG in the presence of Na+. Rate coefficients of elementary steps were specified based on Arrhenius parameters. The mechanistic model for cellulose included 768 reactions of 222 species, which included 252 reactions of 150 species comprising the mechanistic model of glucose decomposition in the presence of NaCl. © 2015 American Institute of Chemical Engineers AIChE J, 62: 766–777, 2016

A mechanistic model considering the significant catalytic effects of Na+ on fast pyrolysis of glucose-based carbohydrates was developed in Part 1 of this study. A computational framework based on continuous distribution kinetics and mass action kinetics was constructed to solve the mechanistic model. Agreement between model yields of various pyrolysis products with experimental data from fast pyrolysis of glucose-based carbohydrates dosed with NaCl ranging from 0–0.34 mmol/g at 500 °C validated the model and demonstrated the robustness and extendibility of the mechanistic model. The model was able to capture the yields of major and minor products as well as their trends across NaCl concentrations. Modeling results showed that Na+ accelerated the rate of decomposition and reduced the time for complete thermoconversion of carbohydrates. The sharp reduction in the yield of levoglucosan (LVG) from fast pyrolysis of cellulose in the presence of NaCl was mainly caused by reduced decomposition of cellulose chains via end-chain initiation and depropagation due to Na+ favoring competing dehydration reactions. Analysis of the contributions of reaction pathways showed that the decomposition of LVG made a minor contribution to its yield reduction and contributed less than 0.5% to the final yield of glycolaldehyde from fast pyrolysis of glucose-based carbohydrates in the presence of NaCl. © 2015 American Institute of Chemical Engineers AIChE J, 62: 778–791, 2016

Summary The analysis of transcriptomes is well-established and increasingly affordable in studies at the interface of ecology and evolution. Expression analysis of thousands of genes in parallel reveals functions and pathways involved in relevant phenotypic differentiation. The application of such methods typically involves the sacrifice of the analysed organisms, which is potentially subject to ethical and legal constraints. As an alternative to lethal sampling, transcriptome analyses can be performed using small biopsies of dispensable tissues. It has to be verified, however, to what extent such results are representative of the whole organism. Here, we use a custom microarray to compare transcriptomes of tail-clip samples with those of the remaining whole body of fire salamander larvae (Salamandra salamandra). The microarray was calibrated using target RNA to validate the performance of each probe. We varied water temperature to test whether the thermal response in gene expression can be characterized in both types of sample. A large fraction (51%) of the differentially expressed genes showed parallel changes for both tail clips and whole bodies in response to temperature. While sets of differentially expressed were not identical, they largely belonged to the same functional categories. The gene functions thus revealed a common thermal response of larvae irrespective of the sampled tissue. This included an overexpression of mitochondrial transcripts, an expected thermal acclimatization response of ectotherms. Hence, ecological transcriptomics based on small biopsies represent an alternative to the analysis of lethally sampled tissues in situations where the sacrifice of individuals is not an option.

Purpose: Physical phantoms are essential for the development, optimization, and evaluation of x-ray breast imaging systems. Recognizing the major effect of anatomy on image quality and clinical performance, such phantoms should ideally reflect the three-dimensional structure of the human breast. Currently, there is no commercially available three-dimensional physical breast phantom that is anthropomorphic. The authors present the development of a new suite of physical breast phantoms based on human data. Methods: The phantoms were designed to match the extended cardiac-torso virtual breast phantoms that were based on dedicated breast computed tomography images of human subjects. The phantoms were fabricated by high-resolution multimaterial additive manufacturing (3D printing) technology. The glandular equivalency of the photopolymer materials was measured relative to breast tissue-equivalent plastic materials. Based on the current state-of-the-art in the technology and available materials, two variations were fabricated. The first was a dual-material phantom, the Doublet. Fibroglandular tissue and skin were represented by the most radiographically dense material available; adipose tissue was represented by the least radiographically dense material. The second variation, the Singlet, was fabricated with a single material to represent fibroglandular tissue and skin. It was subsequently filled with adipose-equivalent materials including oil, beeswax, and permanent urethane-based polymer. Simulated microcalcification clusters were further included in the phantoms via crushed eggshells. The phantoms were imaged and characterized visually and quantitatively. Results: The mammographic projections and tomosynthesis reconstructed images of the fabricated phantoms yielded realistic breast background. The mammograms of the phantoms demonstrated close correlation with simulated mammographic projection images of the corresponding virtual phantoms. Furthermore, power-law descriptions of the phantom images were in general agreement with real human images. The Singlet approach offered more realistic contrast as compared to the Doublet approach, but at the expense of air bubbles and air pockets that formed during the filling process. Conclusions: The presented physical breast phantoms and their matching virtual breast phantoms offer realistic breast anatomy, patient variability, and ease of use, making them a potential candidate for performing both system quality control testing and virtual clinical trials.

Aim Glacial cycles during the Pleistocene may have frequently contributed to parallel evolution of phenotypes across independently evolving genetic lineages associated with separate glacial refugia. Previous studies based on morphology suggested that the prickly sculpin (Cottus asper) survived the Last Glacial Maximum (LGM) in southern coastal and inland refugia, favouring allopatric divergence between coastal and inland prickling phenotypes, which vary in the degree to which spine-like scales cover the body of the fish. Herein, we aimed to test whether parallel evolution across multiple genetic lineages rather than a single-lineage origin of highly prickled inland sculpins could serve as an explanation for the biogeographical distribution of prickling phenotypes. Location North-western North America, Southeast Alaska and Canada (British Columbia). Methods We used data from mitochondrial haplotypes and 19 microsatellite loci to identify distinct genetic lineages as a basis to interpret patterns of phenotypic evolution. Results The occurrence of multiple mtDNA groups suggests that highly prickled inland phenotypes comprise more than one genetic lineage. Both mtDNA and microsatellite data are consistent with post-glacial dispersal along the coast and repeated coastal to inland colonization events, as opposed to inland dispersal of a single lineage from a southern refugium to northern regions. Main conclusions Our results suggest that highly prickled inland phenotypes evolved repeatedly following multiple inland colonization events, probably via coastal rivers. The prickly sculpin therefore provides an example of recent (post-glacial) parallel evolution, potentially facilitated by standing genetic variation already present in the ancestral coastal populations.

Models on hybrid speciation assume that hybridization generates increased phenotypic variance that is utilized to invade new adaptive peaks. We test to what extent this prediction can be traced using gene expression data in the fish species Cottus perifretum and Cottus rhenanus as well as a natural hybrid lineage referred to as invasive sculpins. In addition, interspecies crosses were used to explore evolutionary trajectories from initial stages to the hybrid lineage. EST (expressed sequence tag) libraries were sequenced to design an oligonucleotide microarray that was calibrated for probe-specific differences in binding behaviour. Levels of gene expression divergence between species correlate with genetic divergence at neutral markers and, accordingly, invasive sculpins were intermediate between the parental species overall. However, the hybrid lineage is distinguished through unique patterns of gene expression that are enriched for biological functions which represent candidates for the fitness properties of invasive sculpins. We compare F(2) crosses with natural invasive sculpins to show that the variance in gene expression decreases in invasives. Moreover, few of the transgressive patterns of gene expression that distinguish invasives can be directly observed in F(2) crosses. This suggests that the invasive transcriptome was subject to secondary changes after admixture. The result is in line with an evolutionary process that reduces maladaptive variance and optimizes the phenotype of an emerging hybrid lineage.

Homoploid hybridization after secondary contact between related species can lead to mixtures of genotypes which have the potential for rapid adaptation to new environmental conditions. Here, we focus on a case where anthropogenic changes within the past 200 years have allowed the hybridization between two fish species (Cottus rhenanus and Cottus perifretum) in the Netherlands. Specifically, we address the question of the dynamics of the emergence of these hybrids and invasion of the river systems. Using a set of 81 mostly ancestry-informative SNP markers, as well as broad sample coverage in and around the area of the initial contact, we find a structured hybrid swarm with at least three distinct hybrid lineages that have emerged out of this secondary contact situation. We show that genetically coherent groups can occur at geographically distant locations, while geographically adjacent groups can be genetically different, indicating that some form of reproductive isolation between the lineages is already effective. Using a newly developed modelling approach, we test the relative influence of founding admixture, drift and migration on the allele compositions of the sampling sites. We find that the allele frequency distributions can best be explained if continued gene flow between the parental species and the hybrid lineages is invoked. Genome mapping of the invasive lineage in the Rhine shows that major chromosomal rearrangements were not involved in creating this distinct lineage. Our results show that hybridization after secondary contact can quickly lead to multiple independent new lineages that have the capacity to form hybrid species.

As populations adapt to novel environments, divergent selection will promote heterogeneous genomic differentiation via reductions in gene flow for loci underlying adaptive traits. Using a data set of over 100 SNP markers, genome scans were performed to investigate the effect of natural selection maintaining differentiation in five lakes harbouring sympatric pairs of normal and dwarf lake whitefish (Coregonus clupeaformis). A variable proportion of SNPs (between 0% and 12%) was identified as outliers, which corroborated the predicted intensity of competitive interactions unique to each lake. Moreover, strong reduction in heterozygosity was typically observed for outlier loci in dwarf but not in normal whitefish, indicating that directional selection has been acting on standing genetic variation more intensively in dwarf whitefish. SNP associations in backcross hybrid progeny identified 16 genes exhibiting genotype-phenotype associations for four adaptive traits (growth, swimming activity, gill rakers and condition factor). However, neither simple relationship between elevated levels of genetic differentiation with adaptive phenotype nor conspicuous genetic signatures for parallelism at outlier loci were detected, which underscores the importance of independent evolution among lakes. The integration of phenotypic, transcriptomic and functional genomic information identified two candidate genes (sodium potassium ATPase and triosephosphate isomerase) involved in the recent ecological divergence of lake whitefish. Finally, the identification of several markers under divergent selection suggests that many genes, in an environment-specific manner, are recruited by selection and ultimately contributed to the repeated ecological speciation of a dwarf phenotype.

Gene expression divergence is one of the mechanisms thought to be involved in the emergence of incipient species. Next-generation sequencing has become an extremely valuable tool for the study of this process by allowing whole transcriptome sequencing, or RNA-Seq. We have conducted a 454 GS-FLX pyrosequencing experiment to refine our understanding of adaptive divergence between dwarf and normal lake whitefish species (Coregonus clupeaformis spp.). The objectives were to: (i) investigate transcriptomic divergence as measured by liver RNA-Seq; (ii) test the correlation between divergence in expression and sequence polymorphism; and (iii) investigate the extent of allelic imbalance. We also compared the results of RNA-seq with those of a previous microarray study performed on the same fish. Following de novo assembly, results showed that normal whitefish overexpressed more contigs associated with protein synthesis while dwarf fish overexpressed more contigs related to energy metabolism, immunity and DNA replication and repair. Moreover, 63 SNPs showed significant allelic imbalance, and this phenomenon prevailed in the recently diverged dwarf whitefish. Results also showed an absence of correlation between gene expression divergence as measured by RNA-Seq and either polymorphism rate or sequence divergence between normal and dwarf whitefish. This study reiterates an important role for gene expression divergence, and provides evidence for allele-specific expression divergence as well as evolutionary decoupling of regulatory and coding sequences in the adaptive divergence of normal and dwarf whitefish. It also demonstrates how next-generation sequencing can lead to a more comprehensive understanding of transcriptomic divergence in a young species pair.

[ ∗] P. W Nolte , . Dr. D. Pergande , Dr. S. L. Schweizer , Prof. R. B. Wehrspohn Martin-Luther-Univesity Halle-Wittenberg Heinrich Damerow Str. 4, 06120 Halle (Germany) E-mail: peter.nolte@physik.uni-halle.de M. Geuss , B. Makowski , Prof. C. Weder Adolphe Merkle Institute and Fribourg Center for NanomaterialsUniversity of Fribourg P.O. Box 209, CH-1723 Marly (Switzerland) B. Makowski , Prof. C. Weder Case Western Reserve University Department of Macromolecular Science and Engineering 2100 Adelbert Rd., Cleveland, OH 44107–7202 (USA) R. Salzer , Prof. R. B. Wehrspohn Fraunhofer Institute for Mechanics of Materials Walter-Hulse-Strase 1, 06120 Halle (Germany) P. Mack Institut fur Nanotechnologie Karlsruhe Institute of Technology (KIT) Hermann-von-Helmholtz-Platz 176344 Eggenstein-Leopoldshafen (Germany) Dr. D. Hermann , Prof. K. Busch Institut fur Theoretische Festkorperphysik and DFG-Center for Functional Nanostructures (CFN) Karlsruhe Institute of Technology (KIT) Wolfgang-Gaede-Strasse 1, 76131 Karlsruhe (Germany) M. Geuss , Prof. M. Steinhart Max Planck Institute of Microstructure Physics Weinberg 2, 06114 Halle (Germany) Prof. M. Steinhart Institute for ChemistryUniversity of Osnabruck 49069 Osnabruck (Germany)

As more diagnostic testing options become available to physicians, it becomes more difficult to combine various types of medicalinformation together in order to optimize the overall diagnosis. To improve diagnostic performance, here we introduce an approach to optimize a decision-fusion technique to combine heterogeneous information, such as from different modalities, feature categories, or institutions. For classifier comparison we used two performance metrics: The receiving operator characteristic (ROC) area under the curve [area under the ROC curve (AUC)] and the normalized partial area under the curve (pAUC). This study used four classifiers: Linear discriminant analysis (LDA), artificial neural network (ANN), and two variants of our decision-fusion technique, AUC-optimized (DF-A) and pAUC-optimized (DF-P) decision fusion. We applied each of these classifiers with 100-fold cross-validation to two heterogeneous breast cancerdata sets: One of mass lesion features and a much more challenging one of microcalcification lesion features. For the calcification data set, DF-A outperformed the other classifiers in terms of AUC ( p 0.02 ) and achieved AUC = 0.85 ± 0.01 . The DF-P surpassed the other classifiers in terms of pAUC ( p 0.01 ) and reached pAUC = 0.38 ± 0.02 . For the mass data set, DF-A outperformed both the ANN and the LDA ( p 0.04 ) and achieved AUC = 0.94 ± 0.01 . Although for this data set there were no statistically significant differences among the classifiers’ pAUC values ( pAUC = 0.57 ± 0.07 to 0.67 ± 0.05 , p > 0.10 ), the DF-P did significantly improve specificity versus the LDA at both 98% and 100% sensitivity ( p 0.04 ) . In conclusion, decision fusion directly optimized clinically significant performance measures, such as AUC and pAUC, and sometimes outperformed two well-known machine-learning techniques when applied to two different breast cancerdata sets.

Hybrid zones are commonly studied to dissect the processes that drive divergence among lineages, which have incomplete barriers of reproduction. Most hybrid zones have existed for an extended time making inferences on the initial mode of formation difficult. It is a priori unclear how fast a nascent hybrid zone would form as a response to endogenous and exogenous factors. We have studied several hybrid zones between two lineages of sculpins (Cottus spp.), which emerged due to a recent range expansion of one of the lineages along the river Rhine in the early 1990s. Applying a dense sampling across two contact areas and using a highly informative set of 45 microsatellite markers we found pronounced genetic structure. Steep genetic clines suggest that strong selective forces have shaped the respective hybrid zones from the beginning. We find that the zones are coupled to ecological transitions from small streams to larger rivers. The width of these zones is much smaller than estimates of annual individual dispersal distances, as estimated outside of the hybrid zones. The pattern is apparently not strongly affected by pre- or postzygotic reproductive isolation because numerous backcross hybrids occur within the zones. This suggests that strong natural selection acts against immigrant genotypes. The study exemplifies how local adaptation can play a key role in preventing admixture in dependence of the ecological context.

To initiate QTL studies in the nonmodel fish Cottus gobio we constructed a genetic map based on 171 microsatellite markers. The mapping panel consisted of F1 intercrosses between two divergent Cottus lineages from the River Rhine System. Basic local alignment search tool (BLAST) searches with the flanking sequences of the microsatellite markers yielded a significant (e

Applying a simplified enrichment procedure, we have isolated and characterized 177 microsatellite markers for Cottus gobio L., 1758 (Cottidae, Scorpaeniformes, Teleostei). In contrast to using specific probes for the enrichment, we use genomic DNAs of unrelated organisms for cross-hybridization. This takes advantage of the fact that simple sequences are the only repetitive elements that are abundantly found in all eukaryotic genomes and that any genome usually contains all permutations of microsatellite motifs. This cross-hybridization principle was employed to enrich genomic libraries of Cottus DNA to obtain a large number of nonredundant microsatellite markers without further screening procedures.

The likelihood ratio (LR) is an optimal approach for deciding which of two alternate hypotheses best describes a given situation. We adopted this formalism for predicting whether biopsy results of mammographic masses will be benign or malignant, aiming to reduce the number of biopsies performed on benign lesions. We compared the performance of this LR-based algorithm (LRb) to a case-based reasoning (CBR) classifier, which provides a solution to a new problem using past similiar cases. Each classifier used mammographers’ BI-RADS™ descriptions of mammographic masses as input. The database consisted of 646 biopsy-proven mammography cases. Performance was evaluated using Receiver Operating Characteristic (ROC) analysis, Round Robin sampling, and bootstrap. The ROC areas (AUC) for the LRb and CBR were 0.91±0.01 and 0.92±0.01, respectively. The partial ROC area index ( 0.90 AUC ) was the same for both classifiers, 0.59±0.05. At a sensitivity of 98%, the CBR would spare 204 (49%) of benign lesions from biopsy; the LRb would spare 209 (51%) benign lesions. The performance of the two classifiers was very similar, with no statistical differences in AUC or 0.90 AUC . Although the CBR and LRb originate from different fields of study, their implementations differ only in the estimation of the probability density functions(PDFs) of the feature distributions. The CBR performs this estimation implicitly, while using various similarity metrics. On the other hand, the estimation of the PDFs is specified explicitly in the LRb implementation. This difference in the estimation of the PDFs results in the very small difference in performance, and at 98% sensitivity, both classifiers would spare about half of the benign mammographic masses from biopsy. The CBR and LRb are equivalent methods in implementation and performance.

Summary objective We observed the new onset of severe obstructive sleep apnoea syndrome (OSAS) in an adult male patient during human growth hormone (hGH) replacement therapy. This prompted us to evaluate the potential influence of hGH substitution therapy on sleep in middle-aged men. design A longitudinal study. subjects Five male patients (aged 44–56 years, median age 54 years) with postoperative pituitary insufficiency given hGH replacement therapy for 1–2 years (median dose 2·0 U/day; median IGF-I serum concentration 351 µg/l) and 6 months after cessation of hGH treatment (median IGF-I level 77 µg/l – 1 µg/l = 0·131 nmol/l). measurements Polysomnographic studies were performed, and the following parameters were determined: time in bed (TIB), sleep period time (SPT), total sleep time (TST), sleep efficiency (SE = TST/TIB), sleep stage 1 onset latency (SL), different sleep stages [W (wake), S1, S2, SWS (slow wave sleep = S3 + S4) and REM; % of SPT], stage shifts per hour of SPT (SS/h), stage shifts to W/h of SPT [A/h (awakening)], index of apnoea and hypopnoea events per hour of TST (AH/h), arousals from apnoea and hypopnoea per hour of TST (Ar/h), index of obstructive (OAH/h), central (CAH/h) and mixed (MAH/h) events of apnoea and hypopnoea per hour of TST and minimal desaturation (MD). results Median baseline results were: TIB, 479 min; SPT, 465 min; TST, 405 min; SE, 77%; SL, 8·5 min; W, 18·9%; S1, 8·2%; S2, 52·7%; REM, 13·5%; SS/h, 17·7; A/h, 2·8; AH/h, 11·9; Ar/h, 4·4; MD, 80%. These parameters did not change significantly after cessation of hGH treatment. In contrast, median SWS decreased significantly from 33 min (7·1%) to 7·5 min (1·8%; P = 0·03). Median OAH/h decreased significantly from 4·4 to 0·1 (P = 0·03) whereas CAH/h increased from 6·3 to 14·6 (P = 0·03) after cessation of hGH. Correspondingly, one patient with OSAS improved markedly whereas another patient developed new and asymptomatic central SAS after cessation of hGH. conclusion This study showed that hGH replacement therapy influenced sleep reaction in a complex way in middle-aged men; cessation of treatment was associated with a significant decrease in slow wave sleep and a shift from obstructive to central apnoea and hypopnoea.

Eric Mohler, Arthur Nikkel, Richard Radek, Holly Robb, Michael Schrimpf, Jeffrey Waring, Chih-Hung Lee, Murali Gopalakrishnan, AbbVie Inc., North Chicago, Illinois, United States; AbbVie, North Chicago, Illinois, United States; AbbVie Inc., North Chicago, Illinois, United States; AbbVie Inc., North Chicago, Illinois, United States; AbbVie, North Chicago, Illinois, United States. Contact e-mail: robert.s.bitner@abbvie.com

reduced (ps 0.05) in the 33, 54, and 62 week APP/PS1 animals as compared to age-matched PS1 animals. The perfusion reduction was also observed in 8 week old animals but genotype effect just failed to reach statistical significance at this age (p 0.0505). Hypoperfusion was detected in the medial posterior cortex of the 33 and 62 week old APP/PS1 (p 0.01). A trend for hypoperfusion was noted in the 54 week old animals but was not statistically significant (p 0.06). At the level of the thalamus, hypoperfusion, was only seen in 8 week old APP/PS1 mice (p 0.05). Conclusions: Our longitudinal study showed a hypoperfusion in cortical regions from APP/PS1 mice. As perfusion can be measured non-invasively both in humans and animals, it might be used as a translational marker to follow drug effects both in animals and humans. Acknowledgments: Sanofi-Aventis Neurodegenerative Disease Group for the gift of the animals, French ‘Federation-for-Brain-Research’, ‘Neuroscience-ACI-programs’ French Ministry of Research.

Invasive species receive attention as manifestations of global ecological change and because of the effects that they may have on other organisms. They are commonly discussed in the context of the ecological perturbations or the human activities that permitted the invasion. There is also evidence, that there is an intrinsic component to biological invasions in that evolutionary changes of the invaders themselves can facilitate or limit invasions (Lee 2002; Urban et al. 2007; Van Bocxlaer et al. 2010). Hence, teasing apart whether environmental change or changes of the organism foster invasions is an interesting field of research. Ample evidence for plants and animals documents that ecological change and human activities trigger range expansions and invasions, but questions regarding evolutionary change of invaders remain less explored although there are several reasons to believe it matters. Firstly, rapid evolutionary change is possible in time-frames relevant for contemporary biological invasions(Hendry et al. 2007). Furthermore, population genetic modelling suggests that there are circumstances where the range expansion and colonization of empty spaces in the course of an invasion can induce evolutionary change in a way that is specific to invaders: the process of repeated founding out of marginal populations in the course of a range expansion can shift allele frequencies and has been referred to as allele surfing, which not only affects neutral genetic variance, but also fitness relevant traits (Klopfstein et al. 2006; Travis et al. 2007; Burton & Travis 2008). Importantly, this process poses a null model for evolutionary inference in invasive populations. It predicts conspicuous allele frequency changes in an expanding metapopulation unless migration homogenizes the gene pool. Despite this relevance, ideas about allele surfing rely heavily on modelling although some experimental evidence comes from studies that document the segregation of genetic variants in growing plaques of bacteria (Hallatschek et al. 2007). To date, little empirical data is available that would reveal the migration processes that affect the establishment of gene pools at invasion fronts in natural systems. This aspect sets the study of Bronnenhuber et al. (2011) apart. They quantify migration behind the expansion front of an invading fish and thus provide important baseline data for the interpretation of the emerging patterns of genetic differentiation.