Cycles of fusion and fission enabled rapid parallel adaptive radiations in African cichlids.

Although some lineages of animals and plants have made impressive adaptive radiations when provided with ecological opportunity, the propensities to radiate vary profoundly among lineages for unknown reasons. In Africa's Lake Victoria region, one cichlid lineage radiated in every lake, with the largest radiation taking place in a lake less than 16,000 years old. We show that all of its ecological guilds evolved in situ. Cycles of lineage fusion through admixture and lineage fission through speciation characterize the history of the radiation. It was jump-started when several swamp-dwelling refugial populations, each of which were of older hybrid descent, met in the newly forming lake, where they fused into a single population, resuspending old admixture variation. Each population contributed a different set of ancient alleles from which a new adaptive radiation assembled in record time, involving additional fusion-fission cycles. We argue that repeated fusion-fission cycles in the history of a lineage make adaptive radiation fast and predictable.

New phylogenetic insights into the African catfish families Mochokidae and Austroglanididae.

Several hundred catfish species (order: Siluriformes) belonging to 11 families inhabit Africa, of which at least six families are endemic to the continent. Although four of those families are well-known to belong to the 'Big-Africa clade', no previous study has addressed the phylogenetic placement of the endemic African catfish family Austroglanididae in a comprehensive framework with molecular data. Furthermore, interrelationships within the 'Big-Africa clade', including the most diverse family Mochokidae, remain unclear. This study was therefore designed to help reconstruct inter- and intrarelationships of all currently valid mochokid genera, to infer their position within the 'Big Africa clade' and to establish a first molecular phylogenetic hypothesis of the relationships of the enigmatic Austroglanididae within the Siluriformes. We assembled a comprehensive mitogenomic dataset comprising all protein coding genes and representing almost all recognized catfish families (N = 33 of 39) with carefully selected species (N = 239). We recovered the monophyly of the previously identified multifamily clades 'Big Asia' and 'Big Africa' and determined Austroglanididae to be closely related to Pangasiidae, Ictaluroidea and Ariidae. Mochokidae was recovered as the sister group to a clade encompassing Auchenoglanididae, Claroteidae, Malapteruridae and the African Schilbeidae, albeit with low statistical support. The two mochokid subfamilies Mochokinae and Chiloglanidinae as well as the chiloglanid tribe Atopochilini were recovered as reciprocally monophyletic. The genus Acanthocleithron forms the sister group of all remaining Mochokinae, although with low support. The genus Atopodontus is the sister group of all remaining Atopochilini. In contrast to morphological reconstructions, the monophyly of the genus Chiloglanis was strongly supported in our analysis, with Chiloglanis macropterus nested within a Chiloglanis sublineage encompassing only other taxa from the Congo drainage. This is an important result because the phylogenetic relationships of C. macropterus have been controversial in the past, and because we and other researchers assumed that this species would be resolved as sister to most or all other members of Chiloglanis. The apparent paraphyly of Synodontis with respect to Microsynodontis provided an additional surprise, with Synodontis punu turning out to be the sister group of the latter genus.

Prescriptive analytics in public-sector decision-making: A framework and insights from charging infrastructure planning.

In this work, we investigate the challenges public-sector organizations face when seeking to leverage prescriptive analytics and provide insights into the public value such data-driven tools and methods can provide. Using the strategic triangle of value, legitimacy, and operational capacity as a starting point, we derive a framework to assess public-sector prescriptive analytics initiatives, along with six guiding questions that structure the assessment process. We present a case study applying prescriptive analytics to the placement of charge points in urban areas, a critical challenge many municipalities are currently facing in the transition towards electric mobility. Reflecting on the analytics application as well as its development and implementation process through the guiding questions, we derive key lessons for public-sector organizations seeking to apply prescriptive analytics.

106Ruthenium eye plaque brachytherapy in the management of medium sized uveal melanoma.

BACKGROUND: To evaluate 106Ruthenium Brachytherapy in management of medium sized uveal melanoma, with emphasis on 5-year outcome and toxicity. METHODS: From April 2007 to October 2015, 39 patients with medium sized uveal melanoma were treated with 106 Ru eye plaques brachytherapy. At the time of diagnosis, the mean tumor depth was 3.7 mm (±SD:1.6 mm). The mean dose at the tumor apex was 141.4 Gy (± SD: 12.1 Gy) and 557.7 Gy (± SD: 257.3 Gy) to the sclera. RESULTS: Mean follow-up was 69.5 months (± SD: 53.8 months). Thirty-four patients (87.1%) remained free of recurrence. Twenty-six patients (66.7%) demonstrated a complete tumor regression after a median period of 12 months (3-60 mon.). By the final examination, the visual acuity of 26 patients (66.7%) was better than 20/200, and 12 patients (30.7%) had a visual acuity better than 20/40. Retinopathy was detected in 11 patients (28.2%). After treatments only one patient (5.1%) had active vascular changes by the last examination. Moderate optic neuropathy was observed in 4 patients (10.3%). Cataract development was diagnosed in 21 patients (53.8%), and 16 patients (41%) had bilateral cataract development. Special emphasis was made on patients with larger tumors. Twelve out of the 39 patients had a tumor with a depth of 5 mm or more. There was no significant difference in local control or in side effects between both groups observed. CONCLUSIONS: Our study proved 106Ru -brachytherapy to be an excellent treatment option with regard to tumor control and preservation of the visual acuity in well-selected patients. Our data suggested that this treatment is also suitable for tumors with a depth of more than 5 mm.

Micro-scale solubility assessments and prediction models for active pharmaceutical ingredients in polymeric matrices.

The number of models for assessing the solubility of active pharmaceutical ingredients (APIs) in polymeric matrices on the one hand and the extent of available associated data on the other hand has been rising steadily in the past few years. However, according to our knowledge an overview on the methods used for prediction and the respective experimental data is missing. Therefore, we compiled experimental data, the techniques used for their determination and the models used for estimating the solubility. Our focus was on polymers commonly used in spray drying and hot-melt extrusion to form amorphous solid dispersions (ASDs), namely polyvinylpyrrolidone grades (PVP), polyvinyl acetate (PVAc), vinylpyrrolidone-vinyl acetate copolymer (copovidone, COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft polymer (Soluplus®, SOL), different types of methacrylate copolymers (PMMA), polyethylene glycol grades (PEG) and hydroxypropyl-methylcellulose grades (HPMC). The literature data were further supplemented by our own results. The final data set included 37 APIs and two sugar derivatives. The majority of the prediction models was constituted by the melting point depression method, dissolution endpoint measurements, indirect solubility determination by Tg and the use of low molecular weight analogues. We observed that the API solubility depended more on the working group which conducted the experiments than on the measuring technique used. Furthermore, this compilation should assist researchers in choosing a prediction method suited for their investigations. Furthermore, a statistical assessment using recursive feature elimination was performed to identify descriptors of molecules, which are connected to the API solubility in polymeric matrices. It is capable of predicting the criterium 20% API soluble at 100 °C (Yes/No) for an unknown compound with a balanced accuracy of 71%. The identified 8 descriptors to be connected to API solubility in polymeric matrices were the number of hydrogen bonding donors, three descriptors related to the hydrophobicity of the molecule, glass transition temperature, fractional negative polar van der Waals surface area, out-of-plane potential energy and the fraction of rotatable bonds. Finally, in addition to our own model, the data set should help researchers in training their own solubility prediction models.

Statistical inferences for polarity identification in natural language.

Information forms the basis for all human behavior, including the ubiquitous decision-making that people constantly perform in their every day lives. It is thus the mission of researchers to understand how humans process information to reach decisions. In order to facilitate this task, this work proposes LASSO regularization as a statistical tool to extract decisive words from textual content in order to study the reception of granular expressions in natural language. This differs from the usual use of the LASSO as a predictive model and, instead, yields highly interpretable statistical inferences between the occurrences of words and an outcome variable. Accordingly, the method suggests direct implications for the social sciences: it serves as a statistical procedure for generating domain-specific dictionaries as opposed to frequently employed heuristics. In addition, researchers can now identify text segments and word choices that are statistically decisive to authors or readers and, based on this knowledge, test hypotheses from behavioral research.

Micro-scale prediction method for API-solubility in polymeric matrices and process model for forming amorphous solid dispersion by hot-melt extrusion.

A new predictive micro-scale solubility and process model for amorphous solid dispersions (ASDs) by hot-melt extrusion (HME) is presented. It is based on DSC measurements consisting of an annealing step and a subsequent analysis of the glass transition temperature (Tg). The application of a complex mathematical model (BCKV-equation) to describe the dependency of Tg on the active pharmaceutical ingredient (API)/polymer ratio, enables the prediction of API solubility at ambient conditions (25°C). Furthermore, estimation of the minimal processing temperature for forming ASDs during HME trials could be defined and was additionally confirmed by X-ray powder diffraction data. The suitability of the DSC method was confirmed with melt rheological trials (small amplitude oscillatory system). As an example, ball milled physical mixtures of dipyridamole, indomethacin, itraconazole and nifedipine in poly(vinylpyrrolidone-co-vinylacetate) (copovidone) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) were used.

Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder.

Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD.

Biodiversity inventories in high gear: DNA barcoding facilitates a rapid biotic survey of a temperate nature reserve.

BACKGROUND: Comprehensive biotic surveys, or 'all taxon biodiversity inventories' (ATBI), have traditionally been limited in scale or scope due to the complications surrounding specimen sorting and species identification. To circumvent these issues, several ATBI projects have successfully integrated DNA barcoding into their identification procedures and witnessed acceleration in their surveys and subsequent increase in project scope and scale. The Biodiversity Institute of Ontario partnered with the rare Charitable Research Reserve and delegates of the 6th International Barcode of Life Conference to complete its own rapid, barcode-assisted ATBI of an established land trust in Cambridge, Ontario, Canada. NEW INFORMATION: The existing species inventory for the rare Charitable Research Reserve was rapidly expanded by integrating a DNA barcoding workflow with two surveying strategies - a comprehensive sampling scheme over four months, followed by a one-day bioblitz involving international taxonomic experts. The two surveys resulted in 25,287 and 3,502 specimens barcoded, respectively, as well as 127 human observations. This barcoded material, all vouchered at the Biodiversity Institute of Ontario collection, covers 14 phyla, 29 classes, 117 orders, and 531 families of animals, plants, fungi, and lichens. Overall, the ATBI documented 1,102 new species records for the nature reserve, expanding the existing long-term inventory by 49%. In addition, 2,793 distinct Barcode Index Numbers (BINs) were assigned to genus or higher level taxonomy, and represent additional species that will be added once their taxonomy is resolved. For the 3,502 specimens, the collection, sequence analysis, taxonomic assignment, data release and manuscript submission by 100+ co-authors all occurred in less than one week. This demonstrates the speed at which barcode-assisted inventories can be completed and the utility that barcoding provides in minimizing and guiding valuable taxonomic specialist time. The final product is more than a comprehensive biotic inventory - it is also a rich dataset of fine-scale occurrence and sequence data, all archived and cross-linked in the major biodiversity data repositories. This model of rapid generation and dissemination of essential biodiversity data could be followed to conduct regional assessments of biodiversity status and change, and potentially be employed for evaluating progress towards the Aichi Targets of the Strategic Plan for Biodiversity 2011-2020.

Mathematical models for dermal drug absorption.

INTRODUCTION: Mathematical models of dermal transport offer the advantages of being much faster and less expensive than in vitro or in vivo studies. The number of methods used to create such models has been increasing rapidly, probably due to the steady rise in computational power. Although each of the various approaches has its own virtues and limitations, it may be difficult to decide which approach is best suited to address a given problem. AREAS COVERED: Here we outline the basic ideas, drawbacks and advantages of compartmental and quantitative structure-activity relationship models, as well as of analytical and numerical approaches for solving the diffusion equation. Examples of special applications of the different approaches are given. EXPERT OPINION: Although some models are sophisticated and might be used in future to predict transport through damaged or diseased skin, the comparatively low availability of suitable and accurate experimental data limits extensive usage of these models and their predictive accuracy. Due to the lack of experimental data, the possibility of validating mathematical models is limited.

A strategy for in-silico prediction of skin absorption in man.

For some time, in-silico models to address substance transport into and through the skin are gaining more and more importance in different fields of science and industry. In particular, the mathematical prediction of in-vivo skin absorption is of great interest to overcome ethical and economical issues. The presented work outlines a strategy to address this problem and in particular, investigates in-vitro and in-vivo skin penetration experiments of the model compound flufenamic acid solved in an ointment by means of a mathematical model. Experimental stratum corneum concentration-depth profiles (SC-CDP) for various time intervals using two different in-vitro systems (Franz diffusion cell, Saarbruecken penetration model) were examined and simulated with the help of a highly optimized three compartment numerical diffusion model and compared to the findings of SC-CDPs of the in-vivo scenario. Fitted model input parameters (diffusion coefficient and partition coefficient with respect to the stratum corneum) for the in-vitro infinite dose case could be used to predict the in-use conditions in-vitro. Despite apparent differences in calculated partition coefficients between in-vivo and in-vitro studies, prediction of in-vivo scenarios from input parameters calculated from the in-vitro case yielded reasonable results.

Patterns of Sensitivity to Emotion in Children with Williams Syndrome and Autism: Relations Between Autonomic Nervous System Reactivity and Social Functioning.

Williams syndrome (WS) and autism spectrum disorder (ASD) are associated with atypical social-emotional functioning. Affective visual stimuli were used to assess autonomic reactivity and emotion identification, and the social responsiveness scale was used to determine the level social functioning in children with WS and ASD contrasted with typical development (TD), to examine syndrome-specific and syndrome-general features. Children with ASD exhibited the highest arousal in response to faces, with a lack of difference in autonomic sensitivity across different emotional expressions, unlike in WS and TD. The WS group demonstrated unique deficits in identifying neutral stimuli. While autonomic responsivity to neutral faces was associated with social functioning in all children, converging profiles characterized children with WS contrasted with TD and ASD.

Molecular diversity of Germany's freshwater fishes and lampreys assessed by DNA barcoding.

This study represents the first comprehensive molecular assessment of freshwater fishes and lampreys from Germany. We analysed COI sequences for almost 80% of the species mentioned in the current German Red List. In total, 1056 DNA barcodes belonging to 92 species from all major drainages were used to (i) build a reliable DNA barcode reference library, (ii) test for phylogeographic patterns, (iii) check for the presence of barcode gaps between species and (iv) evaluate the performance of the barcode index number (BIN) system, available on the Barcode of Life Data Systems. For over 78% of all analysed species, DNA barcodes are a reliable means for identification, indicated by the presence of barcode gaps. An overlap between intra- and interspecific genetic distances was present in 19 species, six of which belong to the genus Coregonus. The Neighbour-Joining phenogram showed 60 nonoverlapping species clusters and three singleton species, which were related to 63 separate BIN numbers. Furthermore, Barbatula barbatula, Leucaspius delineatus, Phoxinus phoxinus and Squalius cephalus exhibited remarkable levels of cryptic diversity. In contrast, 11 clusters showed haplotype sharing, or low levels of divergence between species, hindering reliable identification. The analysis of our barcode library together with public data resulted in 89 BINs, of which 56% showed taxonomic conflicts. Most of these conflicts were caused by the use of synonymies, inadequate taxonomy or misidentifications. Moreover, our study increased the number of potential alien species in Germany from 14 to 21 and is therefore a valuable groundwork for further faunistic investigations.

A "drug cocktail" delivered by microspheres for the local treatment of rat glioblastoma.

For the treatment of glioblastoma multiforme, an "anticancer drug cocktail" delivered by biodegradable poly-lactide-co-glycolide (PLGA)-microspheres is proposed. Celecoxib, etoposide, and elacridar were encapsulated by an oil/water emulsification solvent evaporation method. Drug-loaded microspheres were analyzed for their physicochemical properties and evaluated in a rat glioblastoma model. Microspheres had a mean diameter 10-20 µm, and encapsulation rates varied upon lipophilicity of the drug (celecoxib: 97.4 ± 0.4%; elacridar: 98.1 ± 0.3%; and etoposide: 38.7 ± 8.3%). Drug release of celecoxib and elacridar resulted in a burst (t50: 3.1 h and 1.0 h, respectively) while etoposide release was slower (t50: 45.3 h). The comparison of celecoxib (p = 0.021) and etoposide microspheres (p = 0.002) as well as their combination (p = 0.011) led to a significant increase in the probability of survival compared to blank microspheres. Local delivery of celecoxib and etoposide microspheres was found to be suitable for the treatment of glioblastoma in rats although simultaneous drug administration did not improve the therapeutic outcome.

Finite and infinite dosing: difficulties in measurements, evaluations and predictions.

Due to the increased demand for reliable data regarding penetration into and permeation across human skin, assessment of the absorption of xenobiotics has been gaining in importance steadily. In vitro experiments allow for determining these data faster and more easily than in vivo experiments. However, the experiments described in literature and the subsequent evaluation procedures differ considerably. Here we will give an overview on typical finite and infinite dose experiments performed in fundamental research and on the evaluation of the data. We will point out possible difficulties that may arise and give a short overview on attempts at predicting skin absorption in vitro and in vivo.

Sensitivity of the autonomic nervous system to visual and auditory affect across social and non-social domains in williams syndrome.

Although individuals with Williams syndrome (WS) typically demonstrate an increased appetitive social drive, their social profile is characterized by dissociations, including socially fearless behavior coupled with anxiousness, and distinct patterns of "peaks and valleys" of ability. The aim of this study was to compare the processing of social and non-social visually and aurally presented affective stimuli, at the levels of behavior and autonomic nervous system (ANS) responsivity, in individuals with WS contrasted with a typically developing (TD) group, with the view of elucidating the highly sociable and emotionally sensitive predisposition noted in WS. Behavioral findings supported previous studies of enhanced competence in processing social over non-social stimuli by individuals with WS; however, the patterns of ANS functioning underlying the behavioral performance revealed a surprising profile previously undocumented in WS. Specifically, increased heart rate (HR) reactivity, and a failure for electrodermal activity to habituate were found in individuals with WS contrasted with the TD group, predominantly in response to visual social affective stimuli. Within the auditory domain, greater arousal linked to variation in heart beat period was observed in relation to music stimuli in individuals with WS. Taken together, the findings suggest that the pattern of ANS response in WS is more complex than previously noted, with increased arousal to face and music stimuli potentially underpinning the heightened behavioral emotionality to such stimuli. The lack of habituation may underlie the increased affiliation and attraction to faces characterizing individuals with WS. Future research directions are suggested.

Influence of the application area on finite dose permeation in relation to drug type applied.

For finite dose skin absorption experiments, a homogeneous donor distribution over the skin surface is usually assumed. However, the influence of the surface distribution on skin absorption is still unknown. The aim of this study was to evaluate the influence of the application area on the permeation of drugs during finite dose skin absorption experiments in static Franz diffusion cells. Permeation experiments with stained aqueous drug formulations were conducted, and the application area was determined by a suitable, objective, automated computational approach. The permeation of caffeine is strongly dependent on the application area. The variability between single experiments decreased when including the application area. For the lipophilic flufenamic acid, this was not the case. The variability highly increased after inclusion of the application area. Thus, a correction of the area is misleading. In summary, depending on the drug's physicochemical characteristics, the application area may influence skin absorption.

Single-unit responses selective for whole faces in the human amygdala.

The human amygdala is critical for social cognition from faces, as borne out by impairments in recognizing facial emotion following amygdala lesions [1] and differential activation of the amygdala by faces [2-5]. Single-unit recordings in the primate amygdala have documented responses selective for faces, their identity, or emotional expression [6, 7], yet how the amygdala represents face information remains unknown. Does it encode specific features of faces that are particularly critical for recognizing emotions (such as the eyes), or does it encode the whole face, a level of representation that might be the proximal substrate for subsequent social cognition? We investigated this question by recording from over 200 single neurons in the amygdalae of seven neurosurgical patients with implanted depth electrodes [8]. We found that approximately half of all neurons responded to faces or parts of faces. Approximately 20% of all neurons responded selectively only to the whole face. Although responding most to whole faces, these neurons paradoxically responded more when only a small part of the face was shown compared to when almost the entire face was shown. We suggest that the human amygdala plays a predominant role in representing global information about faces, possibly achieved through inhibition between individual facial features.

Lipid nanocapsules for dermal application: a comparative study of lipid-based versus polymer-based nanocarriers.

Lipid nanocapsules (LNC) are colloidal carriers providing controlled release profiles and improved bioavailability for many drug substances and diverse administration routes. However, they have not been explored before for transdermal application. Here, we study the behavior of LNC as a transdermal drug delivery system using ibuprofen as a model drug. A comparison to other lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and polymeric nanocarriers has been made. It was found that LNC could increase the flux rate of ibuprofen 21.9±0.5 compared to 5.8±0.4 µg/cm(2)h in case of drug solution. Similar flux rates were obtained for SLN and NLC with average values of 22.9±0.5 and 22.5±2.0 µg/cm(2)h, respectively. On the other side, comparison to polymeric nanoparticles showed that the polymer-based carriers of the same particle size had lower permeation-enhancing effect with a flux rate of 10.62±1.84 µg/cm(2)h. Polymeric carriers had fourfold higher accumulation in the skin compared to that of the LNC and twice the accumulation of SLN and NLC. These results would suggest that the LNC can be considered as efficient as SLN and NLC for the transdermal drug delivery while polymeric nanoparticles are more suitable for localized drug delivery to the skin.

Anti-idiotypic Fab Fragments Image a Conserved N-terminal Epitope Patch of Grass Pollen Allergen Phl p 1.

BACKGROUND AND AIMS: Naturally occurring anti-idiotypic antibodies structurally mimic the original antibody epitope. Anti-idiotypes, therefore, are interesting tools for the portrayal of conformational B-cell epitopes of allergens. In this study we used this strategy particularly for major timothy grass pollen (Phleum pratense) allergen Phl p 1. METHODS AND RESULTS: We used a combinatorial phage display library constructed from the peripheral IgG repertoire of a grass pollen allergic patient which was supposed to contain anti-idiotypic Fab specificities. Using purified anti-Phl p 1 IgG for biopanning, several Fab displaying phage clones could be isolated. 100 amplified colonies were screened for their binding capacity to anti-Phl p 1-specific antibodies, finally resulting in four distinct Fab clones according to sequence analysis. Interestingly, heavy chains of all clones derived from the same germ line sequence and showed high homology in their CDRs. Projecting their sequence information on the surface of the natural allergen Phl p 1 (PDB ID: 1N10) indicated matches on the N-terminal domain of the homo-dimeric allergen, including the bridging region between the two monomers. The resulting epitope patches were formed by spatially distant sections of the primary allergen sequence. CONCLUSION: In this study we report that anti-idiotypic specificities towards anti-Phl p 1 IgG, selected from a Fab library of a grass pollen allergic patient, mimic a conformational epitope patch being distinct from a previously reported IgE epitope area.