Animal modelling for inherited central vision loss.

Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans.

Welfare loss with municipal amalgamations and the willingness-to-pay for the municipality name

Functional advantages and drawbacks are commonly mentioned to rationally justify or condemn municipality amalgamations. However, many consolidation projects are resisted by local governments or citizens on the grounds that amalgamation would dampen local identity. A municipality's name change is probably the most visible sign of the loss of community bond experienced by citizens at amalgamation time. This article aims to put a value on this loss by measuring citizen willingness to pay for their city name. This methodological approach innovates upon the literature on municipal amalgamation and place branding by exploiting the versatility of the so-called contingent valuation method (CVM). CVM confronts respondents, in a survey setting, with a hypothetical market in which a characteristic of interest is exchanged. Here the characteristic is the possibility to retain one's city name for an amalgamated jurisdiction. The article presents the estimates provided by a survey conducted in four Swiss cities.

The EXS Domain of PHO1 Participates in the Response of Shoots to Phosphate Deficiency via a Root-to-Shoot Signal.

The response of shoots to phosphate (Pi) deficiency implicates long-distance communication between roots and shoots, but the participating components are poorly understood. We have studied the topology of the Arabidopsis (Arabidopsis thaliana) PHOSPHATE1 (PHO1) Pi exporter and defined the functions of its different domains in Pi homeostasis and signaling. The results indicate that the amino and carboxyl termini of PHO1 are both oriented toward the cytosol and that the protein spans the membrane twice in the EXS domain, resulting in a total of six transmembrane α-helices. Using transient expression in Nicotiana benthamiana leaf, we demonstrated that the EXS domain of PHO1 is essential for Pi export activity and proper localization to the Golgi and trans-Golgi network, although the EXS domain by itself cannot mediate Pi export. In contrast, removal of the amino-terminal hydrophilic SPX domain does not affect the Pi export capacity of the truncated PHO1 in N. benthamiana. While the Arabidopsis pho1 mutant has low shoot Pi and shows all the hallmarks associated with Pi deficiency, including poor shoot growth and overexpression of numerous Pi deficiency-responsive genes, expression of only the EXS domain of PHO1 in the roots of the pho1 mutant results in a remarkable improvement of shoot growth despite low shoot Pi. Transcriptomic analysis of pho1 expressing the EXS domain indicates an attenuation of the Pi signaling cascade and the up-regulation of genes involved in cell wall synthesis and the synthesis or response to several phytohormones in leaves as well as an altered expression of genes responsive to abscisic acid in roots.

Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes

Genome duplications increase genetic diversity and may facilitate the evolution of gene subfunctions. Little attention, however, has focused on the evolutionary impact of lineage-specific gene loss. Here, we show that identifying lineage-specific gene loss after genome duplication is important for understanding the evolution of gene subfunctions in surviving paralogs and for improving functional connectivity among human and model organism genomes. We examine the general principles of gene loss following duplication, coupled with expression analysis of the retinaldehyde dehydrogenase Aldh1a gene family during retinoic acid signaling in eye development as a case study. Humans have three ALDH1A genes, but teleosts have just one or two. We used comparative genomics and conserved syntenies to identify loss of ohnologs (paralogs derived from genome duplication) and to clarify uncertain phylogenies. Analysis showed that Aldh1a1 and Aldh1a2 form a clade that is sister to Aldh1a3-related genes. Genome comparisons showed secondarily loss of aldh1a1 in teleosts, revealing that Aldh1a1 is not a tetrapod innovation and that aldh1a3 was recently lost in medaka, making it the first known vertebrate with a single aldh1a gene. Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival. We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications. Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

Iterative reconstruction in CT : using mathematical model observers to determine low dose images' trustworthiness

La tomodensitométrie (TDM) est une technique d'imagerie pour laquelle l'intérêt n'a cessé de croitre depuis son apparition au début des années 70. De nos jours, l'utilisation de cette technique est devenue incontournable, grâce entre autres à sa capacité à produire des images diagnostiques de haute qualité. Toutefois, et en dépit d'un bénéfice indiscutable sur la prise en charge des patients, l'augmentation importante du nombre d'examens TDM pratiqués soulève des questions sur l'effet potentiellement dangereux des rayonnements ionisants sur la population. Parmi ces effets néfastes, l'induction de cancers liés à l'exposition aux rayonnements ionisants reste l'un des risques majeurs. Afin que le rapport bénéfice-risques reste favorable au patient il est donc nécessaire de s'assurer que la dose délivrée permette de formuler le bon diagnostic tout en évitant d'avoir recours à des images dont la qualité est inutilement élevée. Ce processus d'optimisation, qui est une préoccupation importante pour les patients adultes, doit même devenir une priorité lorsque l'on examine des enfants ou des adolescents, en particulier lors d'études de suivi requérant plusieurs examens tout au long de leur vie. Enfants et jeunes adultes sont en effet beaucoup plus sensibles aux radiations du fait de leur métabolisme plus rapide que celui des adultes. De plus, les probabilités des évènements auxquels ils s'exposent sont également plus grandes du fait de leur plus longue espérance de vie. L'introduction des algorithmes de reconstruction itératifs, conçus pour réduire l'exposition des patients, est certainement l'une des plus grandes avancées en TDM, mais elle s'accompagne de certaines difficultés en ce qui concerne l'évaluation de la qualité des images produites. Le but de ce travail est de mettre en place une stratégie pour investiguer le potentiel des algorithmes itératifs vis-à-vis de la réduction de dose sans pour autant compromettre la qualité du diagnostic. La difficulté de cette tâche réside principalement dans le fait de disposer d'une méthode visant à évaluer la qualité d'image de façon pertinente d'un point de vue clinique. La première étape a consisté à caractériser la qualité d'image lors d'examen musculo-squelettique. Ce travail a été réalisé en étroite collaboration avec des radiologues pour s'assurer un choix pertinent de critères de qualité d'image. Une attention particulière a été portée au bruit et à la résolution des images reconstruites à l'aide d'algorithmes itératifs. L'analyse de ces paramètres a permis aux radiologues d'adapter leurs protocoles grâce à une possible estimation de la perte de qualité d'image liée à la réduction de dose. Notre travail nous a également permis d'investiguer la diminution de la détectabilité à bas contraste associée à une diminution de la dose ; difficulté majeure lorsque l'on pratique un examen dans la région abdominale. Sachant que des alternatives à la façon standard de caractériser la qualité d'image (métriques de l'espace Fourier) devaient être utilisées, nous nous sommes appuyés sur l'utilisation de modèles d'observateurs mathématiques. Nos paramètres expérimentaux ont ensuite permis de déterminer le type de modèle à utiliser. Les modèles idéaux ont été utilisés pour caractériser la qualité d'image lorsque des paramètres purement physiques concernant la détectabilité du signal devaient être estimés alors que les modèles anthropomorphes ont été utilisés dans des contextes cliniques où les résultats devaient être comparés à ceux d'observateurs humain, tirant profit des propriétés de ce type de modèles. Cette étude a confirmé que l'utilisation de modèles d'observateurs permettait d'évaluer la qualité d'image en utilisant une approche basée sur la tâche à effectuer, permettant ainsi d'établir un lien entre les physiciens médicaux et les radiologues. Nous avons également montré que les reconstructions itératives ont le potentiel de réduire la dose sans altérer la qualité du diagnostic. Parmi les différentes reconstructions itératives, celles de type « model-based » sont celles qui offrent le plus grand potentiel d'optimisation, puisque les images produites grâce à cette modalité conduisent à un diagnostic exact même lors d'acquisitions à très basse dose. Ce travail a également permis de clarifier le rôle du physicien médical en TDM: Les métriques standards restent utiles pour évaluer la conformité d'un appareil aux requis légaux, mais l'utilisation de modèles d'observateurs est inévitable pour optimiser les protocoles d'imagerie. -- Computed tomography (CT) is an imaging technique in which interest has been quickly growing since it began to be used in the 1970s. Today, it has become an extensively used modality because of its ability to produce accurate diagnostic images. However, even if a direct benefit to patient healthcare is attributed to CT, the dramatic increase in the number of CT examinations performed has raised concerns about the potential negative effects of ionising radiation on the population. Among those negative effects, one of the major risks remaining is the development of cancers associated with exposure to diagnostic X-ray procedures. In order to ensure that the benefits-risk ratio still remains in favour of the patient, it is necessary to make sure that the delivered dose leads to the proper diagnosis without producing unnecessarily high-quality images. This optimisation scheme is already an important concern for adult patients, but it must become an even greater priority when examinations are performed on children or young adults, in particular with follow-up studies which require several CT procedures over the patient's life. Indeed, children and young adults are more sensitive to radiation due to their faster metabolism. In addition, harmful consequences have a higher probability to occur because of a younger patient's longer life expectancy. The recent introduction of iterative reconstruction algorithms, which were designed to substantially reduce dose, is certainly a major achievement in CT evolution, but it has also created difficulties in the quality assessment of the images produced using those algorithms. The goal of the present work was to propose a strategy to investigate the potential of iterative reconstructions to reduce dose without compromising the ability to answer the diagnostic questions. The major difficulty entails disposing a clinically relevant way to estimate image quality. To ensure the choice of pertinent image quality criteria this work was continuously performed in close collaboration with radiologists. The work began by tackling the way to characterise image quality when dealing with musculo-skeletal examinations. We focused, in particular, on image noise and spatial resolution behaviours when iterative image reconstruction was used. The analyses of the physical parameters allowed radiologists to adapt their image acquisition and reconstruction protocols while knowing what loss of image quality to expect. This work also dealt with the loss of low-contrast detectability associated with dose reduction, something which is a major concern when dealing with patient dose reduction in abdominal investigations. Knowing that alternative ways had to be used to assess image quality rather than classical Fourier-space metrics, we focused on the use of mathematical model observers. Our experimental parameters determined the type of model to use. Ideal model observers were applied to characterise image quality when purely objective results about the signal detectability were researched, whereas anthropomorphic model observers were used in a more clinical context, when the results had to be compared with the eye of a radiologist thus taking advantage of their incorporation of human visual system elements. This work confirmed that the use of model observers makes it possible to assess image quality using a task-based approach, which, in turn, establishes a bridge between medical physicists and radiologists. It also demonstrated that statistical iterative reconstructions have the potential to reduce the delivered dose without impairing the quality of the diagnosis. Among the different types of iterative reconstructions, model-based ones offer the greatest potential, since images produced using this modality can still lead to an accurate diagnosis even when acquired at very low dose. This work has clarified the role of medical physicists when dealing with CT imaging. The use of the standard metrics used in the field of CT imaging remains quite important when dealing with the assessment of unit compliance to legal requirements, but the use of a model observer is the way to go when dealing with the optimisation of the imaging protocols.

Effects of iodinated contrast agent, xylocaine and gadolinium concentration on the signal emitted in magnetic resonance arthrography: a samples study

Objective:To investigate the effects of dilution of paramagnetic contrast agent with iodinated contrast and xylocaine on the signal intensity during magnetic resonance arthrography, and to improve the paramagnetic contrast agent concentration utilized in this imaging modality.Materials and Methods:Samples specially prepared for the study with three different concentrations of paramagnetic contrast agent diluted in saline, iodinated contrast agent and xylocaine were imaged with fast spin echo T1-weighted sequences with fat saturation. The samples were placed into flasks and graphical analysis of the signal intensity was performed as a function of the paramagnetic contrast concentration.Results:As compared with samples of equal concentrations diluted only with saline, the authors have observed an average signal intensity decrease of 20.67% for iodinated contrast agent, and of 28.34% for xylocaine. However, the increased gadolinium concentration in the samples caused decrease in signal intensity with all the dilutions.Conclusion:Minimizing the use of iodinated contrast media and xylocaine and/or the use of a gadolinium concentration of 2.5 mmol/L diluted in saline will improve the sensitivity of magnetic resonance arthrography.

Job loss among immigrant and native workers: evidence from Spain's economic downturn

The profound crisis that has affected the Spanish economy since mid - 2008 has been characterized by significant job losses and a marked rise in the country´s unemployment rate. However, unemployment has had a differential impact on different population groups. Compared to native, immigrant workers have experienced higher rates of job loss. Against this backdrop, this paper examines the differences between immigrants and natives (distinguished by gender) in terms of their probability of suffering job loss in the downturn of late 2008 and 2009. Our results indicate that the higher rate of job loss among female immigrant workers can be fully explained by their lower endowment of human capital. By contrast, human capital endowment and over-representation in certain occupations, sectors and regions in which the crisis had greatest impact do not appear to be the only reason for the penalty suffered by immigrant males in terms of their chances of losing their job in the downturn.

Population connectivity buffers genetic diversity loss in a seabird

Background Ancient DNA has revolutionized conservation genetic studies as it allows monitoring of the genetic variability of species through time and predicting the impact of ecosystems" threats on future population dynamics and viability. Meanwhile, the consequences of anthropogenic activities and climate change to island faunas, particularly seabirds, remain largely unknown. In this study, we examined temporal changes in the genetic diversity of a threatened seabird, the Cory"s shearwater (Calonectris borealis). Findings We analysed the mitochondrial DNA control region of ancient bone samples from the late-Holocene retrieved from the Canary archipelago (NE Atlantic) together with modern DNA sequences representative of the entire breeding range of the species. Our results show high levels of ancient genetic diversity in the Canaries comparable to that of the extant population. The temporal haplotype network further revealed rare but recurrent long-distance dispersal between ocean basins. The Bayesian demographic analyses reveal both regional and local population size expansion events, and this is in spite of the demographic decline experienced by the species over the last millennia. Conclusions Our findings suggest that population connectivity of the species has acted as a buffer of genetic losses and illustrate the use of ancient DNA to uncover such cryptic genetic events.

Lamellarin D bioconjugates II: synthesis and cellular internalization of dendrimer and nuclear location signal derivatives

The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.4 to 3.3-fold more cytotoxic than the parent compound against three human tumor cell lines(MDA-MB-231 breast, A-549 lung, and HT-29 colon). Besides, conjugates 3, 4 showed a decrease in activity potency in BJ skin fibroblasts, a normal cell culture. Cellular internalization was analyzed and nuclear distribution pattern was observed for 4, which contains a nuclear localization signalling sequence.

Her onginþ seo boc: On the loss and retention of grammatical gender in Early Middle English

Tutkielma käsittelee kieliopillisen suvun säilymistä myöhäisessä muinaisenglannissa (Late Old English) ja varhaiskeskienglannissa (Early Middle English). Tutkielman tavoitteena on päätellä, kuinka kieliopillinen suku säilyy kolmessa muinaisenglannin/varhaiskeskienglannin aikakautta edustavassa tekstissä. Lähdeaineisto on valittu edustamaan aikaa (1150-1225), jolloin kieliopillisen suvun on sanottu kadonneen englannin kielestä. Lähdeaineisto myös edustaa kahta eri tekstilajia, ja tarjoaa siten aineistoa niiden väliseen vertailuun. Aineistosta on analysoitu nominien päätteitä, demonstratiivipronomineja sekä anaforisia persoonapronomineja, joissa substantiivien kieliopillinen suku näkyy. Osa anaforisista viittauksista on selitettävissä personifikaatiolla, jolloin elottomiin objekteihin tai käsitteisiin on liitetty inhimillistäviä piirteitä. Tutkimuksen perusteella kieliopillinen suku säilyy vielä joissakin muodoissa 1200- luvulle saakka. Merkittävää on aineistossa esiintyvä runsas vaihtelu ja pyhimyselämänkertojen ja lääketieteellisen tekstin väliset erot.

Loss of intestinal epithelial barrier function in Salmonella Enteritidis infection

Intestinal infection with Salmonella enterica serotype Enteritidis, a food-borne infection spread to humans especially through contaminated eggs and egg-products as well as undercooked contaminated fresh meat, is the most common cause of intestinal inflammation in the European Union. Enteritis caused by Salmonella Enteritidis is characterized by fever, diarrhoea and abdominal pain. The disruption of the intestinal epithelial barrier function contributes to diarrhoea and is responsible for the perpetuation of the inflammatory process. In this sense, oxidative stress and the proinflammatory cytokines TNF-α, IFN-γ and IL-1β are described to induce the disorganization of the tight junctions (TJ), the most apical epithelial intercellular junctions and responsible for the paracellular permeability. The interest of this chapter relies not only in the investigation dealing with the mechanisms of TJ regulation but also in the contribution to the development of new tools for the prevention of epithelial barrier disruption in enteritis caused by Salmonella Enteritidis.

Invasive species and habitat degradation in Iberian streams: an analysis of their role in freshwater fish diversity loss

Mediterranean endemic freshwater fish are among the most threatened biota in the world. Distinguishing the role of different extinction drivers and their potential interactions is crucial for achieving conservation goals. While some authors argue that invasive species are a main driver of native species declines, others see their proliferation as a co-occurring process to biodiversity loss driven by habitat degradation. It is difficult to discern between the two potential causes given that few invaded ecosystems are free from habitat degradation, and that both factors may interact in different ways. Here we analyze the relative importance of habitat degradation and invasive species in the decline of native fish assemblages in the Guadiana River basin (southwestern Iberian Peninsula) using an information theoretic approach to evaluate interaction pathways between invasive species and habitat degradation (structural equation modeling, SEM). We also tested the possible changes in the functional relationships between invasive and native species, measured as the per capita effect of invasive species, using ANCOVA. We found that the abundance of invasive species was the best single predictor of natives’ decline and had the highest Akaike weight among the set of predictor variables examined. Habitat degradation neither played an active role nor influenced the per capita effect of invasive species on natives. Our analyses indicated that downstream reaches and areas close to reservoirs had the most invaded fish assemblages, independently of their habitat degradation status. The proliferation of invasive species poses a strong threat to the persistence of native assemblages in highly fluctuating environments. Therefore, conservation efforts to reduce native freshwater fish diversity loss in Mediterranean rivers should focus on mitigating the effect of invasive species and preventing future invasions

Alternative Techniques of Neural Signal Processing in Neuroengineering

Neural signal processing is a discipline within neuroengineering. This interdisciplinary approach combines principles from machine learning, signal processing theory, and computational neuroscience applied to problems in basic and clinical neuroscience. The ultimate goal of neuroengineering is a technological revolution, where machines would interact in real time with the brain. Machines and brains could interface, enabling normal function in cases of injury or disease, brain monitoring, and/or medical rehabilitation of brain disorders. Much current research in neuroengineering is focused on understanding the coding and processing of information in the sensory and motor systems, quantifying how this processing is altered in the pathological state, and how it can be manipulated through interactions with artificial devices including brain–computer interfaces and neuroprosthetics.

Effects of Weight Loss on Adipose Tissue, Liver and Heart Metabolism in Humans

Obesity has become the leading cause of many chronic diseases, such as type 2 diabetes and cardiovascular diseases. The prevalence of obesity is high in developed countries and it is also a major cause of the use of health services. Ectopic fat accumulation in organs may lead to metabolic disturbances, such as insulin resistance.Weight loss with very-low-energy diet is known to be safe and efficient. Weight loss improves whole body insulin sensitivity, but its effects on tissue and organ level in vivo are not well known. The aims of the studies were to investigate possible changes of weight loss in glucose and fatty acid uptake and perfusion and fat distribution at tissue and organ level using positron emission tomography and magnetic resonance imaging and spectroscopy in 34 healthy obese subjects. The results showed that whole-body insulin sensitivity increased after weight loss with very-low-energy diet and this is associated with improved skeletal muscle insulin-stimulated glucose uptake, but not with adipose tissue, liver or heart glucose uptake. Liver insulin resistance decreased after weight loss. Liver and heart free fatty acid uptakes decreased concomitantly with liver and heart triglyceride content. Adipose tissue and myocardial perfusion decreased. In conclusion, enhanced skeletal muscle glucose uptake leads to increase in whole-body insulin sensitivity when glucose uptake is preserved in other organs studied. These findings suggest that lipid accumulation found in the liver and the heart in obese subjects without co-morbidies is in part reversible by reduced free fatty acid uptake after weight loss. Reduced lipid accumulation in organs may improve metabolic disturbances, e.g. decrease liver insulin resistance. Keywords: Obesity, weight loss, very-low-energy diet, adipose tissue metabolism, liver metabolism, heart metabolism, positron emission tomography