Primetime for antiangiogenic therapy.

PURPOSE OF REVIEW: To review the current experience with angiogenesis inhibitors in the treatment of gliomas. RECENT FINDINGS: Antiangiogenic therapy has recently reached the clinic with the approval of bevacizumab for recurrent glioblastomas. A number of promising antiangiogenic and vasculature-modifying agents are under investigation for newly diagnosed and recurrent malignant gliomas. A recurrence under ongoing or after antiangiogenic therapy is often characterized by a more aggressive and, in particular, invasive phenotype. SUMMARY: Despite impressively high radiological response rates in patients with recurrent malignant glioma, the duration of response is usually short-lived, and the observed effect to a large extent may be due to normalization of the disrupted blood-brain barrier and less due to a direct antitumor effect. Overall survival remains poor. Induction of invasive phenotypes and escape with proangiogenic alternative pathways are contributing to resistance. Investigation of combination regimes targeting several pathways will determine the possibilities to overcome the resistance to antiangiogenic therapy in malignant gliomas. This article summarizes the results of recent clinical trials in this field, points towards mechanisms of resistance arising under angiogenesis inhibition and discusses the challenges for the future.

Oligopotent stem cells are distributed throughout the mammalian ocular surface.

The integrity of the cornea, the most anterior part of the eye, is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of loss of corneal transparency; treatments range from local medications to corneal transplants, and more recently to stem cell therapy. The corneal epithelium is a squamous epithelium that is constantly renewing, with a vertical turnover of 7 to 14 days in many mammals. Identification of slow cycling cells (label-retaining cells) in the limbus of the mouse has led to the notion that the limbus is the niche for the stem cells responsible for the long-term renewal of the cornea; hence, the corneal epithelium is supposedly renewed by cells generated at and migrating from the limbus, in marked opposition to other squamous epithelia in which each resident stem cell has in charge a limited area of epithelium. Here we show that the corneal epithelium of the mouse can be serially transplanted, is self-maintained and contains oligopotent stem cells with the capacity to generate goblet cells if provided with a conjunctival environment. Furthermore, the entire ocular surface of the pig, including the cornea, contains oligopotent stem cells (holoclones) with the capacity to generate individual colonies of corneal and conjunctival cells. Therefore, the limbus is not the only niche for corneal stem cells and corneal renewal is not different from other squamous epithelia. We propose a model that unifies our observations with the literature and explains why the limbal region is enriched in stem cells.

Amoeba/amoebal symbiont genetic transfers: lessons from giant virus neighbours.

Free-living amoebae serve as hosts for a variety of amoebae-resisting microorganisms, including giant viruses and certain bacteria. The latter include symbiotic bacteria as well as bacteria exhibiting a pathogenic phenotype towards amoebae. Amoebae-resisting bacteria have been shown to be widespread in water and to use the amoebae as a reservoir, a replication niche, a protective armour as well as a training ground to select virulence traits allowing survival in the face of microbicidal effects of macrophages, the first line of defense against invading pathogens. More importantly, amoebae play a significant role as a melting pot for genetic exchanges. These ecological and evolutionary roles of amoebae might also be at play for giant viruses and knowledge derived from the study of amoebae-resisting bacteria is useful for the study and understanding of interactions between amoebae and giant viruses. This is especially important since some genes have spread in all domains of life and the exponential availability of eukaryotic genomes and metagenomic sequences will allow researchers to explore these genetic exchanges in a more comprehensive way, thus completely changing our perception of the evolutionary history of organisms. Thus, a large part of this review is dedicated to report current known gene exchanges between the different amoebae-resisting organisms and between amoebae and the internalized bacteria.

Parachlamydia acanthamoebae, an emerging agent of pneumonia.

Parachlamydia acanthamoebae is a Chlamydia-like organism that easily grows within Acanthamoeba spp. Thus, it probably uses these widespread free-living amoebae as a replicative niche, a cosmopolite aquatic reservoir and a vector. A potential role of P. acanthamoebae as an agent of lower respiratory tract infection was initially suggested by its isolation within an Acanthamoeba sp. recovered from the water of a humidifier during the investigation of an outbreak of fever. Additional serological and molecular-based investigations further supported its pathogenic role, mainly in bronchiolitis, bronchitis, aspiration pneumonia and community-acquired pneumonia. P. acanthamoebae was shown to survive and replicate within human macrophages, lung fibroblasts and pneumocytes. Moreover, this strict intracellular bacterium also causes severe pneumonia in experimentally infected mice, thus fulfilling the third and fourth Koch criteria for a pathogenic role. Consequently, new tools have been developed for the diagnosis of parachlamydial infections. It will be important to routinely search for this emerging agent of pneumonia, as P. acanthamoebae is apparently resistant to quinolones, which are antibiotics often used for the empirical treatment of atypical pneumonia. Other Chlamydia-related bacteria, including Protochlamydia naegleriophila, Simkania negevensis and Waddlia chondrophila, might also cause lung infections. Moreover, several additional novel chlamydiae, e.g. Criblamydia sequanensis and Rhabdochlamydia crassificans, have been discovered and are now being investigated for their human pathogenicity.

Loss of interactions with ants under cold climate in a regional myrmecophilous butterfly fauna

Aim Specialized mutualistic clades may revert and thus increase their autonomy and generalist characteristics. However, our understanding of the drivers that trigger reductions in mutualistic traits and of the consequences for the tolerance of these species to various environmental conditions remains limited. This study investigates the relationship between the environmental niche and the degree of myrmecophily (i.e. the ability to interact with ants) among members of the Lycaenidae. Location The western Swiss Alps. Methods We measured the tolerance of Lycaenidae species to low temperatures by comparing observations from a random stratified field sampling with climatic maps. We then compared the species-specific degree of myrmecophily with the species range limits at colder temperatures while controlling for phylogenetic dependence. We further evaluated whether the community-averaged degree of myrmecophily increases with temperature, as would be expected in the case of environmental filters acting on myrmecophilous species. Results Twenty-nine Lycaenidae species were found during sampling. Ancestral state reconstruction indicated that the 24 species of Polyommatinae displayed both strong myrmecophily and secondary loss of mutualism; these species were used in the subsequent statistical analyses. Species with a higher degree of ant interaction were, on average, more likely to inhabit warmer sites. Species inhabiting the coldest environments displayed little or no interaction with ants. Main conclusions Colder climates at high elevations filter out species with a high degree of myrmecophily and may have been the direct evolutionary force that promoted the loss of mutualism. A larger taxon sampling across the Holarctic may help to distinguish between the ecological and evolutionary effects of climate.

O Turismo de Cruzeiros na Ilha de São Vicente - Harmonia entre a Procura e Oferta Turística

Este trabalho aborda o sector do Turismo de Cruzeiros Marítimos na ilha de São Vicente, visando aferir em que medida a oferta turística da ilha encontra-se equilibrada com a procura dos navios de cruzeiros. O turismo em Cabo Verde é considerado como o sector central de desenvolvimento da economia do país e o mercado do turismo de cruzeiros marítimos apresenta uma excelente alternativa para a maximização dos impactos socioeconómicos na ilha de São Vicente. Quanto à metodologia, a pesquisa foi caracterizada como exploratória e descritiva, com uma abordagem tanto qualitativa como quantitativa. O uso da técnica da observação directa, como recurso metodológico na colecta dos dados, levou a concluir que a estrutura portuária da cidade é bastante atractiva no que tange à questão de segurança, da paisagem e dos recursos naturais oferecidos na ilha. Também a utilização do programa SPSS no tratamento dos inquéritos recolhidos possibilitou a realização de várias análises o que permitiu chegar a conclusões importantes da investigação. A pesquisa foi desenvolvida com base a pesquisa bibliográfica, consulta em sites de Internet e acesso a documentos que possuem informações sobre a evolução do turismo de cruzeiros em São Vicente. This work intends to study the sector of Cruise Tourism in São Vicente Island, in Cape Verde. Its main objective is to gauge to what extent the touristic offer is balanced with the demand for this specific niche of tourism. Tourism in Cape Verde is being considered as a central sector for economic growth, and this type of tourism surely presents itself as an excellent alternative for the maximization of social and economic impacts, in the island. In terms of methodology used, this research is seen as both exploratory and descriptive; hence, it has a qualitative and a quantitative approach. Direct observation as a methodological resource has allowed us to conclude that the island’s port infrastructure is very attractive in terms of safety, landscape, and natural resources the island has to offer its visitors. The use of SPSS for data treatment, in terms of our survey, allowed the realization of many analyses that lead to very important conclusions to this research. The research also relied on bibliographic review, web surfing for information, and analyses of documentation related to the evolution of cruise tourism in São Vicente.

Costly search and design

Firms compete by choosing both a price and a design from a family of designs thatcan be represented as demand rotations. Consumers engage in costly sequential searchamong firms. Each time a consumer pays a search cost he observes a new offering. Anoffering consists of a price quote and a new good, where goods might vary in the extentto which they are good matches for the consumer. In equilibrium, only two design-styles arise: either the most niche where consumers are likely to either love or loathethe product, or the broadest where consumers are likely to have similar valuations. Inequilibrium, different firms may simultaneously offer both design-styles. We performcomparative statics on the equilibrium and show that a fall in search costs can lead tohigher industry prices and profits and lower consumer surplus. Our analysis is relatedto discussions of how the internet has led to the prevalence of niche goods and the"long tail" phenomenon.

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Studies aiming at explaining specialization along latitudinal gradients of plant-herbivore interactions have, to date, yielded inconclusive results. Here we propose the use of steep altitudinal gradients for dissecting factors driving evolution of polyphagy in insect herbivores. First, we test whether colonization of high elevation environment favours increased niche-breadth in two disparate insect groups - the wood-boring beetles and the pollinator group of bees - and show increased polyphagy at higher altitudes in both groups. We then assess classic assumptions transferred from the 'latitude-niche-breadth hypothesis', particularly the increase in environmental variability at high, compared to low, altitude. Finally, we discuss alternative mechanisms shaping the observed pattern of increased polyphagy in altitude, including variation in plant quality and predator pressure at different altitudes. We thus suggest evidence for the 'altitude niche-breadth hypothesis', in which both abiotic and biotic conditions, including increased variability and an increase of the potential feeding niche-breadth, promote evolution for increased insect polyphagy in altitude.

Expression of apoptosis and survival genes in human memory T cell populations

RESUME Introduction: Les cellules T mémoires humaines sont classées en trois sous-populations sur la base de l'expression d'un marqueur de surface cellulaire, CD45RA, et du récepteur aux chimiokines, CCR7. Ces sous-populations, nommées cellules mémoires centrales (TcM), mémoires effectrices (TEM) et mémoires effectrices terminales (ITEM), ont des rôles fonctionnels distincts, ainsi que des capacités de prolifération et de régénération différentes. Cependant, la génération de ces différences reste encore mal comprise et on ignore les mécanismes moléculaires impliqués. Matériaux et Méthodes: Des cellules mononucléaires humaines du sang périphérique ont été séparées par cytométrie de flux selon leur expression de CD4, CD8, CD45RA et CCR7 en sous-populations de cellules CD4+ ou CD8+ naïves, TcM, TEM ou ITEM. Dans chacune de ces sous-populations, 14 gènes impliqués dans l'apoptose, la survie ou la capacité proliférative des cellules T ont été quantifiés par RT-PCR en temps réel, relativement à l'expression d'un gène de référence endogène. L'ARN provenant de 450 cellules T a été utilisé par gène et par sous-population. Les gènes analysés (cibles) comprenaient des gènes de survie (BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα, IL-7Rα), des gènes anti-apoptotiques (Bcl-2, BclxL, FLIP), des gènes pro-apoptotiques (Bad, Bax, Fast) et le gène anti-prolifératif, Tob. A l'aide de la méthode comparative delta-delta-CT, le taux d'expression des gènes cibles de chaque sous-population des cellules T mémoires CD4+ et CD8+, à été comparée à leur taux d'expression dans les cellules T naïves CD4+ et CD8+. Résultats: Dans les cellules CD8+, les gènes pro-apoptotiques Bax et Fast étaient surexprimés dans toutes les sous-populations mémoires, tandis que l'expression des facteurs anti-apoptotiques et de survie comme Bcl-2, APRIL et BAFF-R, étaient diminués. Ces deux tendances étaient particulièrement accentuées dans les sous-groupes des cellules mémoires TEM et TTEM. A noter que malgré le fait que leur expression était également diminuée dans les autres cellules mémoires, le facteur de survie IL-7Ra, était sélectivement surexprimé dans la sous-population de cellules TcM et l'expression d'IL-15Ra était sélectivement augmentée dans les TEM. Dans les cellules CD4+, le taux d'expression des gènes analysés était plus variable entre les sujets étudiés que dans les cellules CD8+, ne permettant pas de définir un profil d'expression spécifique. L'expression du gène de survie BAFF par contre, a été significativement augmentée dans toutes les sous-populations mémoire CD4+. Il en va de même pour l'expression d' APRIL et de BAFF-R, bien que dans moindre degré. A remarquer que l'expression du facteur anti-apoptotique Fast a été observée uniquement dans la souspopulation des TTEM. Discussion et Conclusions: Cette étude montre une nette différence entre les cellules CD8+ et CD4+, en ce qui concerne les profils d'expression des gènes impliqués dans la survie et l'apoptose des cellules T mémoires. Ceci pourrait impliquer une régulation cellulaire homéostatique distincte dans ces deux compartiments de cellules T mémoires. Dans les cellules CD8+ l'expression d'un nombre de gènes impliqués dans la survie et la protection de l'apoptose semblerait être diminuée dans les populations TEM et TTEM en comparaison à celle des sous-populations naïves et TEM, tandis que l'expression des gènes pro-apoptotiques semblerait être augmentée. Comme ceci paraît être plus accentué dans les TTEM, cela pourrait indiquer une plus grande disposition à l'apopotose dans les populations CCR7- (effectrices) et une perte de survie parallèlement à l'acquisition de capacités effectrices. Ceci parlerait en faveur d'un modèle de différentiation linéaire dans les cellules CD8+. De plus, l'augmentation sélective de l'expression d'IL-7Ra observée dans le sous-groupe de cellules mémoires TEM, et d'IL-15Ra dans celui des TEM, pourrait indiquer un moyen de sélection pour des réponses immunitaires mémoires à long terme par une réponse distincte à ces cytokines. Dans les cellules CD4+ par contre, aucun profil d'expression n'a pu être déterminé; les résultats suggèrent même une résistance relative à l'apoptose de la part des cellules mémoires. Ceci pourrait favoriser l'existence d'un modèle de différentiation plus flexible avec des possibilités d'interaction multiples. Ainsi, la surexpression sélective de BAFF, APRIL et BAFF-R dans les sous-populations individuelles des cellules mémoires pourrait être un indice de l'interaction de ces sous-groupes avec des cellules B. ABSTRACT Introduction: Based on their surface expression of the CD45 isoform and of the CCR7 chemokine receptor, memory T cells have been divided into the following three subsets: central memory (TAM), effector memory (TEM) and terminal effector memory (ITEM). Distinct functional roles and different proliferative and regenerative capacities have been attributed to each one of these subpopulations. The molecular mechanisms underlying these differences; however, remain poorly understood. Materials and Methods: According to their expression of CD4, CD8, CD45RA and CCR7, human peripheral blood mononuclear cells were sorted by flow-cytometry into CD4+ or CD8+ naïve, TAM, TEM and ITEM subsets. Using real-time PCR, the expression of 14 genes known to be involved in apoptotis, survival or proliferation of T cells was quantified separately in each individual subset, relative to an endogenous reference gene. The RNA equivalent of 450 T cells was used for each gene and subset. The target gene panel included the survival genes BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα and IL-7Rα, the anti-apoptotic genes Bcl2, Bcl-xL and FLIP, the pro-apoptotic genes Bad, Bax and Fast, as well as the antiproliferative gene Tob. Using the comparative CT-method, the expression of the target genes in the three memory T cell subsets of both CD4+ and CD8+ T cell populations was compared to their expression in the naïve T cells. Results: In CD8+ cells, the pro-apoptotic factors Bax and Fast were found to be upregulated in all memory T cell subsets, whereas the survival and anti-apoptotic factors Bcl-2, APRIL and BAFF-R were downregulated. These tendencies were most accentuated in TEM and TTEM subsets. Even though the survival factor IL-7Rα was also downregulated in these subsets, interestingly, it was selectively upregulated in the CD8+ TAM subset. Similarly, IL-15Rαexpression was shown to be selectively upregulated in the CD8+ TEM subset. In CD4+ cells, the expression levels of the analyzed genes showed a greater inter-individual variability than in CD8+ cells, thus suggesting the absence of any particular expression pattern for CD4+ memory T cells. However, the survival factor BAFF was found to be significantly upregulated in all CD4+ memory T cell subsets, as was also the expression of APRIL and BAFF-R, although to a lesser extent. Furthermore, it was noted that the pro-apoptotic gene Fast was only expressed in the TTEM CD4+ subset. Discussion and Conclusions: Genes involved in apoptosis and survival in human memory T cells have been shown to be expressed differently in CD8+ cells as compared to CD4+ cells, suggesting a distinct regulation of cell homeostasis in these two memory T cell compartments. The present study suggests that, in CD8+ T cells, the expression of various survival and antiapoptotic genes is downregulated in TEM and TTEM subsets, while the expression of proapoptotic genes is upregulated in comparison to the naïve and the TAM populations. These characteristics, potentially translating to a greater susceptibility to apoptosis in the CCR7- (effector) memory populations, are accentuated in the TTEM population, suggesting a loss of survival in parallel to the acquisition of effector capacities. This speaks in favour of a linear differentiation model in CD8+ T memory cells. Moreover, the observed selectively increased expression of IL-7Rα in CD8+ TAM cells - as that of IL-15Rα in CD8+ TEM cells -suggest that differential responsiveness to cytokines could confer a selection bias for distinct long-term memory cell responses. Relative to the results for CD8+ T cells, those for CD4+ T cells seem to indicate a certain resistance of the memory subsets to apoptosis, suggesting the possibility of a more flexible differentiation model with multiple checkpoints and potential interaction of CD4+ memory cells with other cells. Thus, the selective upregulation of BAFF, APRIL and BAFF-R in individual memory subsets could imply an interaction of these subsets with B cells.

Pollen storages in nests of bees of the genera Partamona, Scaura and Trigona (Hymenoptera, Apidae)

Bees and angiosperms established a mutualistic relationship along the evolutionary time. The aim of this study is to contribute for the understanding of this relation analyzing pollen stored by stingless bees colonies distributed along the Rio Negro. Fourteen species of Meliponini from the genera Partamona, Scaura, and Trigona were studied with regard to the content of pollen pots. The pollen material was removed from the pollen pots, homogenized, and prepared according to the usual acetolysis technique. The overlap of the trophic niche and the grouping of species by similarity of niches was calculated. The identification revealed 78 pollen types belonging to 36 families, being 37 types attractive and 16 considered as promoters of a temporary specialization event. With the results, it was possible to indicate a list of important plants for meliponiculture in the Amazon.

Harnessing epithelial stem cell potency

Increase in potency of adult stem/progenitor cells holds great expectations for regenerative medicine; reprogramming is achieved by manipulating the genome or indirectly by manipulating the microenvironment. However, the genetic approach, which can result in lineage conversion up to ground pluripotent embryonic state, will certainly face strict regulatory constraints and consequently translation to the clinic may be difficult. Manipulating stem cell fate without altering the genome of adult stem cells is a promising alternative. My laboratory has demonstrated that non hairy squamous epithelia e.g. the cornea, the oral cavity, the oesophagus, the vagina, contain clonogenic stem cells that can respond to skin morphogenetic signals and form epidermis, cycling hair follicles and sebaceous glands. This capacity is maintained in serial transplantation, crosses primary germ line boundaries and is intrinsic to the stem cells, as cells which have never been exposed to cell culture behave in a similar fashion. Even more surprising, the thymus contains a population of clonogenic epithelial cells of endodermal origin that maintain a thymic identity in culture and have the capacity to incorporate into a thymic network, but can acquire the functionality of bona fide multipotent stem cells of the skin when exposed to proper developmental signals. Thymic epithelial cells exposed to a skin microenvironment exhibit a down-regulation or silencing of transcription factors important for thymic function. Hence, it is possible to reveal unsuspected potency and even to robustly reprogram stem cells by solely manipulating the microenvironment.

D-serine increases adult hippocampal neurogenesis.

Adult hippocampal neurogenesis results in the continuous formation of new neurons and is a process of brain plasticity involved in learning and memory. The neurogenic niche regulates the stem cell proliferation and the differentiation and survival of new neurons and a major contributor to the neurogenic niche are astrocytes. Among the molecules secreted by astrocytes, D-serine is an important gliotransmitter and is a co-agonist of the glutamate, N-methyl-D-aspartate (NMDA) receptor. D-serine has been shown to enhance the proliferation of neural stem cells in vitro, but its effect on adult neurogenesis in vivo is unknown. Here, we tested the effect of exogenous administration of D-serine on adult neurogenesis in the mouse dentate gyrus. We found that 1 week of treatment with D-serine increased cell proliferation in vivo and in vitro and increased the density of neural stem cells and transit amplifying progenitors. Furthermore, D-serine increased the survival of newborn neurons. Together, these results indicate that D-serine treatment resulted in the improvement of several steps of adult neurogenesis in vivo.

Forecasting the effects of global warming on biodiversity

The demand for accurate forecasting of the effects of global warming on biodiversity is growing, but current methods for forecasting have limitations. in this article, we compare and discuss the different uses of four forecasting methods: (1) models that consider species individually, (2) niche-theory models that group species by habitat (more specifically, by environmental conditions under which a species can persist or does persist), (3) general circulation models and coupled ocean-atmosphere-biosphere models, and (4) specics-area curve models that consider all species or large aggregates of species. After outlining the different uses and limitations of these methods, we make eight primary suggestions for improving forecasts. We find that greater use of the fossil record and of modern genetic studies would improve forecasting methods. We note a Quaternary conundrum: While current empirical and theoretical ecological results suggest that many species could be at risk from global warming, during the recent ice ages surprisingly few species became extinct. The potential resolution of this conundrum gives insights into the requirements for more accurate and reliable forecasting. Our eight suggestions also point to constructive synergies in the solution to the different problems.

Dung beetle assemblages (Coleoptera, Scarabaeinae) in Atlantic forest fragments in southern Brazil

Dung beetle assemblages (Coleoptera, Scarabaeinae) in Atlantic forest fragments in southern Brazil. The beetles of the subfamily Scarabaeinae are important organisms that participate in the cycle of decomposition, especially in tropical ecosystems. Most species feed on feces (dung) or carcasses (carrion) and are associated with animals that produce their food resources. Dung beetles are divided into three functional groups: rollers, tunnelers and dwellers. This present work aims to study the diversity of dung beetle communities inhabiting fragments of the Atlantic Forest, with the purpose of describing the ecology of the species in southern Brazil. This study was conducted in the region of Campos Novos, in Santa Catarina, where twenty sites of Atlantic forest fragments were sampled. Samplings of dung beetles were conducted using 200 pitfall traps, of which 100 were baited with human feces and another 100 with carrion. Size and environmental complexity were also measured for each forest fragment. A total of 1,502 dung beetles, belonging to six tribes, 12 genera and 33 species, were collected. Results of the Levin's index of niche breadth indicated that 11 species were categorized as being coprophagous, ten as generalists, and two as necrophagous. Most species are tunnelers (19), nine of rollers and four of dwellers. The great diversity of Scarabaeinae in the region of Campos Novos, including several rare species, adds important data to the Scarabaeinae fauna in the central-western region of Santa Catarina. It may also help choosing priority areas for conservation in the region, where human impact, with large areas of monoculture, increasingly threatens the fragments of Mixed Ombrophilous Forest.

Genetic and environmental effects on the covariation betweencolour polymorphism and a life history trait

Variation in coloration with a strong underlying genetic basis is frequently found within animal populations but little is known about its function. Covariation between colour polymorphism and life-history traits can arise because morphs perform differently among environments or because they possess alternative alleles coding for key life-history traits. To test these two hypotheses, we studied a population of tawny owls Strix aluco, a bird displaying red, brown and grey morphs. We assessed the colour morph of breeding females, swapped eggs or hatchlings between pairs of nests, and examined how body condition in 3-week-old nestlings covaries with coloration of foster and genetic mothers. Redder foster and genetic mothers produced young in better condition. Because in two other years we observed that greyish females produced offspring in better condition than those of red females, the present study suggests that colour polymorphism signals genetic and phenotypic adaptations to cope with a fluctuating environment.