Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

Vine-cacti pitayas: the new crops of the world

Until 1994, only scarce research existed on these plants; however the worldwide interest in this novel fruit crop is evident, as numbers of pitaya-related publications have grown rapidly, especially during the past decade .There is a big confusion about both botanical and commercial names and there is a need to clear this point. Herein, we attempt to review existing knowledge on the taxonomy, breeding and other horticultural characteristics of this unique crop. This paper comments abou taxonomy,breeding,physiology and horticultura e chatera ristics,postsharvest and uses.

Identification of novel HIV restriction factors

To efficiently replicate within mammalian cells, viruses have to manoeuvre through complex host mechanisms, hijacking a network of host proteins to achieve successful propagation. To prevent this invasion, cells have evolved over time to efficiently block the incursing pathogen by direct or indirect targeting. Human immunodeficiency virus (HIV) is a retrovirus of major global public health issue. In the last decade, extensive focus on innate immune proteins has been given, and particularly restriction factors, proteins inhibiting HIV replication by affecting various stages of the viral cycle. Because of the importance of developing new HIV therapies that are associated with reduced side effects and resistances, there is an urge to understand the antiviral response against HIV. Using common features of known restriction factors as a signature to identify new anti-HIV factors, candidates were identified. Particularly multiple members of the apolipoproteins L (APOL) family were found. Cotransfection experiments confirmed very potent inhibitory effects on HIV-1 expression. Further characterization of APOL6, the best candidate, was carried out. APOL6 was not able to inhibit HIV specifically but rather inhibited any gene-encoded DNA that was cotransfected and therefore APOL6 does not classify as a bona fide restriction factor. In addition, we were able to map the activity of APOL6 to the MAD domain and mainly to residue 174. We also found that other members of the family identified in the screen, APOL1 and 3, could have similar mechanism of action as APOL6. Finally, although the complete mechanism of action of APOL6 has yet to be elucidated, it might be blocked during transfections, potentially improving transfection of primary cells. -- Pour se répliquer efficacement dans les cellules de mammifères, les virus doivent manoeuvrer à travers des mécanismes cellulaires complexes et détourner un réseau de protéines de l'hôte. Pour empêcher cette invasion, les gènes de l'hôte ont évolué dans le temps pour cibler efficacement, directement ou indirectement, l'agent pathogène. Le virus de l'immunodéficience humaine (VIH) est un rétrovirus de problème majeur de santé publique mondiale, mais le faible risque de transmission du virus pourrait être expliqué par la présence d'un système antiviral de l'hôte qui, en cas d'échec, conduit à une infection productive. Durant la dernière décennie, il y a eu un intérêt spécial porté sur les protéines immunitaires innées appelé facteurs de restriction présentant des effets inhibiteurs puissants sur la réplication du VIH en affectant différentes étapes du cycle viral. En raison de l'importance de la recherche de nouvelles thérapies anti-VIH associées à des effets secondaires et des résistances réduites comparé aux traitements actuels, il existe un besoin de comprendre la réponse antivirale innée contre le VIH. Basé sur des caractéristiques communes des facteurs de restriction connus, nous avons proposé d'identifier de nouveaux facteurs anti-VIH. Nous avons trouvé une famille de protéines, les apolipoprotéines L (APOL) montrant les effets inhibiteurs très puissants contre l'expression du VIH-1 dans des expériences de co-transfection. Nous avons décidé d'approfondir le rôle de ces protéines dans l'immunité innée et de se concentrer sur le meilleur candidat APOL6. Nous avons en outre établi qu'APOL6 n'a pas d'activité anti-virale spécifique et donc pas classé comme un facteur de bonne foi de restriction. Par ailleurs, APOL6 est capable d'inhiber fortement l'expression de tout Plasmide cotransfecté. En outre, nous avons été en mesure de cartographier l'activité d'APOL6 au domaine MAD et principalement au résidu 174. Nous avons également constaté que d'autres membres de la famille identifiés dans l'étude, APOL1 et 3, pourraient avoir le même mécanisme d'action qu'APOL6. Enfin, bien que le mécanisme d'action complet d'APOL6 reste à être élucidé, il pourrait être d'une importance biotechnologique car il pourrait potentiellement faciliter la transfection de cellules primaires après l'inhibition d'APOL6.

Protein homology reveals new targets for bioactive small molecules.

MOTIVATION: The functional impact of small molecules is increasingly being assessed in different eukaryotic species through large-scale phenotypic screening initiatives. Identifying the targets of these molecules is crucial to mechanistically understand their function and uncover new therapeutically relevant modes of action. However, despite extensive work carried out in model organisms and human, it is still unclear to what extent one can use information obtained in one species to make predictions in other species. RESULTS: Here, for the first time, we explore and validate at a large scale the use of protein homology relationships to predict the targets of small molecules across different species. Our results show that exploiting target homology can significantly improve the predictions, especially for molecules experimentally tested in other species. Interestingly, when considering separately orthology and paralogy relationships, we observe that mapping small molecule interactions among orthologs improves prediction accuracy, while including paralogs does not improve and even sometimes worsens the prediction accuracy. Overall, our results provide a novel approach to integrate chemical screening results across multiple species and highlight the promises and remaining challenges of using protein homology for small molecule target identification. AVAILABILITY AND IMPLEMENTATION: Homology-based predictions can be tested on our website http://www.swisstargetprediction.ch. CONTACT: david.gfeller@unil.ch or vincent.zoete@isb-sib.ch. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Phylogeography and population genetics of north European Atlantic salmon (Salmo salar L.)

Although abundant in the number of individuals, the Atlantic salmon may be considered as a threatened species in many areas of its native distribution range. Human activities such as building of power plant dams, offshore overfishing, pollution, clearing of riverbeds for timber floating and badly designed stocking regimes have diminished the distribution of Atlantic salmon. As a result of this, many of the historical populations both in Europe and northern America have gone extinct or are severely depressed. In fact, only 1% of Atlantic salmon existing today are of natural origin, the rest being farmed salmon. All of this has lead to a vast amount of research and many restoration programmes aiming to bring Atlantic salmon back to rivers from where it has vanished. However, many of the restoration programmes conducted thus far have been unsuccessful due to inadequate scientific research or lack of its implementation, highlighting the fact that more research is needed to fully understand the biology of this complex species. The White and Barents Seas in northwest Russia are among the last regions in Europe where Atlantic salmon populations are still stable, thus forming an important source of biodiversity for the entire European region. Salmon stocks from this area are also of immense economic and social importance for the local people in the form of fishing tourism. The main aim of this thesis was to elucidate the post-glacial history and population genetic structure of north European and particularly northwest Russian Atlantic salmon, both of which are aspects of great importance for the management and conservation of the species. Throughout the whole thesis, these populations were studied by utilizing microsatellites as the main molecular tool. One of the most important discoveries of the thesis was the division of Atlantic salmon from the White and Barents Seas into four separate clusters, which has not been observed in previous studies employing nuclear markers although is supported by mtDNA studies. Populations from the western Barents Sea clustered together with the northeast Atlantic populations into a clearly distinguishable group while populations from the White Sea and eastern Barents Sea were separated into three additional groups. This has important conservation implications as this thesis clearly indicates that conservation of populations from all of the observed clusters is warranted in order to conserve as much of the genetic diversity as possible in this area. The thesis also demonstrates how differences in population life histories within a species, migratory behaviour in this case, and in their phylogeographic origin affect the genetic characteristics of populations, namely diversity and divergence levels. The anadromous populations from the Atlantic Ocean, White Sea and Barents Sea possessed higher levels of genetic diversity than the anadromous populations form the Baltic Sea basin. Among the non-anadromous populations the result was the opposite: the Baltic freshwater populations were more variable. This emphasises the importance of taking the life history of a population into consideration when developing conservation strategies: due to the limited possibilities for new genetic diversity to be generated via gene flow, it is expected that freshwater Atlantic salmon populations would be more vulnerable to extinction following a population crash and thus deserve a high conservation status. In the last chapter of this thesis immune relevant marker loci were developed and screened for signatures of natural selection along with loci linked to genes with other functions or no function at all. Also, a novel landscape genomics method, which combines environmental information with molecular data, was employed to investigate whether immune relevant markers displayed significant correlations to various environmental variables more frequently than other loci. Indications of stronger selection pressure among immune-relevant loci compared to non-immune relevant EST-linked loci was found but further studies are needed to evaluate whether it is a common phenomenon in Atlantic salmon.

New kernel functions and learning methods for text and data mining

Recent advances in machine learning methods enable increasingly the automatic construction of various types of computer assisted methods that have been difficult or laborious to program by human experts. The tasks for which this kind of tools are needed arise in many areas, here especially in the fields of bioinformatics and natural language processing. The machine learning methods may not work satisfactorily if they are not appropriately tailored to the task in question. However, their learning performance can often be improved by taking advantage of deeper insight of the application domain or the learning problem at hand. This thesis considers developing kernel-based learning algorithms incorporating this kind of prior knowledge of the task in question in an advantageous way. Moreover, computationally efficient algorithms for training the learning machines for specific tasks are presented. In the context of kernel-based learning methods, the incorporation of prior knowledge is often done by designing appropriate kernel functions. Another well-known way is to develop cost functions that fit to the task under consideration. For disambiguation tasks in natural language, we develop kernel functions that take account of the positional information and the mutual similarities of words. It is shown that the use of this information significantly improves the disambiguation performance of the learning machine. Further, we design a new cost function that is better suitable for the task of information retrieval and for more general ranking problems than the cost functions designed for regression and classification. We also consider other applications of the kernel-based learning algorithms such as text categorization, and pattern recognition in differential display. We develop computationally efficient algorithms for training the considered learning machines with the proposed kernel functions. We also design a fast cross-validation algorithm for regularized least-squares type of learning algorithm. Further, an efficient version of the regularized least-squares algorithm that can be used together with the new cost function for preference learning and ranking tasks is proposed. In summary, we demonstrate that the incorporation of prior knowledge is possible and beneficial, and novel advanced kernels and cost functions can be used in algorithms efficiently.

Combining niche modelling and landscape genetics to study local adaptation: A novel approach illustrated using alpine plants

Understanding the factors that shape adaptive genetic variation across species niches has become of paramount importance in evolutionary ecology, especially to understand how adaptation to changing climate affects the geographic range of species. The distribution of adaptive alleles in the ecological niche is determined by the emergence of novel mutations, their fitness consequences and gene flow that connects populations across species niches. Striking demographical differences and source sink dynamics of populations between the centre and the margin of the niche can play a major role in the emergence and spread of adaptive alleles. Although some theoretical predictions have long been proposed, the origin and distribution of adaptive alleles within species niches remain untested. In this paper, we propose and discuss a novel empirical approach that combines landscape genetics with species niche modelling, to test whether alleles that confer local adaptation are more likely to occur in either marginal or central populations of species niches. We illustrate this new approach by using a published data set of 21 alpine plant species genotyped with a total of 2483 amplified fragment length polymorphisms (AFLP), distributed over more than 1733 sampling sites across the Alps. Based on the assumption that alleles that were statistically associated with environmental variables were adaptive, we found that adaptive alleles in the margin of a species niche were also present in the niche centre, which suggests that adaptation originates in the niche centre. These findings corroborate models of species range evolution, in which the centre of the niche contributes to the emergence of novel adaptive alleles, which diffuse towards niche margins and facilitate niche and range expansion through subsequent local adaptation. Although these results need to be confirmed via fitness measurements in natural populations and functionally characterised genetic sequences, this study provides a first step towards understanding how adaptive genetic variation emerges and shapes species niches and geographic ranges along environmental gradients.

The effect of learning on the evolution of new courtship behavior: a simulation model

The fact that individuals learn can change the relationship between genotype and phenotype in the population, and thus affect the evolutionary response to selection. Here we ask how male ability to learn from female response affects the evolution of a novel male behavioral courtship trait under pre-existing female preference (sensory drive). We assume a courtship trait which has both a genetic and a learned component, and a two-level female response to males. With individual-based simulations we show that, under this scenario, learning generally increases the strength of selection on the genetic component of the courtship trait, at least when the population genetic mean is still low. As a consequence, learning not only accelerates the evolution of the courtship trait, but also enables it when the trait is costly, which in the absence of learning results in an adaptive valley. Furthermore, learning can enable the evolution of the novel trait in the face of gene flow mediated by immigration of males that show superior attractiveness to females based on another, non-heritable trait. However, rather than increasing monotonically with the speed of learning, the effect of learning on evolution is maximized at intermediate learning rates. This model shows that, at least under some scenarios, the ability to learn can drive the evolution of mating behaviors through a process equivalent to Waddington's genetic assimilation.

Economic Methodology: A Historical Introduction.

Ever since the inception of economics over two hundred years ago, the tools at the discipline's disposal have grown more and more more sophisticated. This book provides a historical introduction to the methodology of economics through the eyes of economists. The story begins with John Stuart Mill's seminal essay from 1836 on the definition and method of political economy, which is then followed by an examination of how the actual practices of economists changed over time to such an extent that they not only altered their methods of enquiry, but also their self-perception as economists. Beginning as intellectuals and journalists operating to a large extent in the public sphere, they then transformed into experts who developed their tools of research increasingly behind the scenes. No longer did they try to influence policy agendas through public discourse; rather they targeted policymakers directly and with instruments that showed them as independent and objective policy advisors, the tools of the trade changing all the while. In order to shed light on this evolution of economic methodology, this book takes carefully selected snapshots from the discipline's history. It tracks the process of development through the nineteenth and twentieth centuries, analysing the growth of empirical and mathematical modelling. It also looks at the emergence of the experiment in economics, in addition to the similarities and differences between modelling and experimentation. This book will be relevant reading for students and academics in the fields of economic methodology, history of economics, and history and philosophy of the social sciences.

The awr gene family encodes a novel class of Ralstonia solanacearum type III effectors displaying virulence and avirulence activities

We present here the characterization of a new gene family, awr, found in all sequenced Ralstonia solanacearum strains and in other bacterial pathogens. We demonstrate that the five paralogues in strain GMI1000 encode type III-secreted effectors and that deletion of all awr genes severely impairs its capacity to multiply in natural host plants. Complementation studies show that the AWR (alanine-tryptophanarginine tryad) effectors display some functional redundancy, although AWR2 is the major contributor to virulence. In contrast, the strain devoid of all awr genes (¿awr1-5) exhibits enhanced pathogenicity on Arabidopsis plants. A gain-of-function approach expressing AWR in Pseudomonas syringae pv. tomato DC3000 proves that this is likely due to effector recognition, because AWR5 and AWR4 restrict growth of this bacterium in Arabidopsis. Transient overexpression of AWR in nonhost tobacco species caused macroscopic cell death to varying extents, which, in the case of AWR5, shows characteristics of a typical hypersensitive response. Our work demonstrates that AWR, which show no similarity to any protein with known function, can specify either virulence or avirulence in the interaction of R. solanacearum with its plant hosts.

A novel approach to analysing the regimes of temporary streams in relation to their controls on the composition and structure of aquatic biota

Temporary streams are those water courses that undergo the recurrent cessation of flow or the complete drying of their channel. The structure and composition of biological communities in temporary stream reaches are strongly dependent on the temporal changes of the aquatic habitats determined by the hydrological conditions. Therefore, the structural and functional characteristics of aquatic fauna to assess the ecological quality of a temporary stream reach cannot be used without taking into account the controls imposed by the hydrological regime. This paper develops methods for analysing temporary streams' aquatic regimes, based on the definition of six aquatic states that summarize the transient sets of mesohabitats occurring on a given reach at a particular moment, depending on the hydrological conditions: Hyperrheic, Eurheic, Oligorheic, Arheic, Hyporheic and Edaphic. When the hydrological conditions lead to a change in the aquatic state, the structure and composition of the aquatic community changes according to the new set of available habitats. We used the water discharge records from gauging stations or simulations with rainfall-runoff models to infer the temporal patterns of occurrence of these states in the Aquatic States Frequency Graph we developed. The visual analysis of this graph is complemented by the development of two metrics which describe the permanence of flow and the seasonal predictability of zero flow periods. Finally, a classification of temporary streams in four aquatic regimes in terms of their influence over the development of aquatic life is updated from the existing classifications, with stream aquatic regimes defined as Permanent, Temporary-pools, Temporary-dry and Episodic. While aquatic regimes describe the long-term overall variability of the hydrological conditions of the river section and have been used for many years by hydrologists and ecologists, aquatic states describe the availability of mesohabitats in given periods that determine the presence of different biotic assemblages. This novel concept links hydrological and ecological conditions in a unique way. All these methods were implemented with data from eight temporary streams around the Mediterranean within the MIRAGE project. Their application was a precondition to assessing the ecological quality of these streams.

Identification of new transformation products during enzymatic treatment of tetracycline and erythromycin antibiotics at laboratory scale by an on-line turbulent flow liquid-chromatography coupled to a high resolution mass spectrometer LTQ-Orbitrap

This work describes the formation of transformation products (TPs) by the enzymatic degradation at laboratory scale of two highly consumed antibiotics: tetracycline (Tc) and erythromycin (ERY). The analysis of the samples was carried out by a fast and simple method based on the novel configuration of the on-line turbulent flow system coupled to a hybrid linear ion trap – high resolution mass spectrometer. The method was optimized and validated for the complete analysis of ERY, Tc and their transformation products within 10 min without any other sample manipulation. Furthermore, the applicability of the on-line procedure was evaluated for 25 additional antibiotics, covering a wide range of chemical classes in different environmental waters with satisfactory quality parameters. Degradation rates obtained for Tc by laccase enzyme and ERY by EreB esterase enzyme without the presence of mediators were ∼78% and ∼50%, respectively. Concerning the identification of TPs, three suspected compounds for Tc and five of ERY have been proposed. In the case of Tc, the tentative molecular formulas with errors mass within 2 ppm have been based on the hypothesis of dehydroxylation, (bi)demethylation and oxidation of the rings A and C as major reactions. In contrast, the major TP detected for ERY has been identified as the “dehydration ERY-A”, with the same molecular formula of its parent compound. In addition, the evaluation of the antibiotic activity of the samples along the enzymatic treatments showed a decrease around 100% in both cases

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis.

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases.

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Cyanobacterial diversity and a new Acaryochloris-like symbiont from Bahamian sea-squirts

Symbiotic interactions between ascidians (sea-squirts) and microbes are poorly understood. Here we characterized the cyanobacteria in the tissues of 8 distinct didemnid taxa from shallow-water marine habitats in the Bahamas Islands by sequencing a fragment of the cyanobacterial 16S rRNA gene and the entire 16S-23S rRNA internal transcribed spacer region (ITS) and by examining symbiont morphology with transmission electron (TEM) and confocal microscopy (CM). As described previously for other species, Trididemnum spp. mostly contained symbionts associated with the Prochloron-Synechocystis group. However, sequence analysis of the symbionts in Lissoclinum revealed two unique clades. The first contained a novel cyanobacterial clade, while the second clade was closely associated with Acaryochloris marina. CM revealed the presence of chlorophyll d (chl d) and phycobiliproteins (PBPs) within these symbiont cells, as is characteristic of Acaryochloris species. The presence of symbionts was also observed by TEM inside the tunic of both the adult and larvae of L. fragile, indicating vertical transmission to progeny. Based on molecular phylogenetic and microscopic analyses, Candidatus Acaryochloris bahamiensis nov. sp. is proposed for this symbiotic cyanobacterium. Our results support the hypothesis that photosymbiont communities in ascidians are structured by host phylogeny, but in some cases, also by sampling location.