The impact of p53 and p73 on aneuploidy and cancer

Initiation, progression and evasion are sequential steps in cancer formation, with autonomous cell proliferation as a final outcome. Genetic or epigenetic alterations of key regulatory genes of the cell cycle are frequently associated with these phenomena. Recently, chromosomal instability, a long-supposed driving force of tumorigenesis, was associated with dysregulation of mitotic genes, providing advantages to tumor cells. Numerous molecules thus provide a key link in the chain of relationships between chromosomal instability and cancer. Here, we discuss emerging evidence revealing that two p53 family members, p53 and p73, might be key regulatory genes at the heart of the relationship between chromosomal instability and cancer. We argue that the role of members of the p53 family as tumor suppressor proteins, their impact on the control of cellular ploidy, and their newly emerging connection with mitotic checkpoint regulatory genes support the suggestion that p73 and p53 could be two of the missing links among chromosomal instability, the mitotic checkpoint and cancer.     

Antagonism between Cry1Ac1 and Cyt1A1 toxins of bacillus thuringiensis

Most strains of the insecticidal bacterium Bacillus thuringiensis have a combination of different protoxins in their parasporal crystals. Some of the combinations clearly interact synergistically, like the toxins present in B. thuringiensis subsp. israelensis. In this paper we describe a novel joint activity of toxins from different strains of B. thuringiensis. In vitro bioassays in which we used pure, trypsin-activated Cry1Ac1 proteins from B. thuringiensis subsp. kurstaki, Cyt1A1 from B. thuringiensis subsp. israelensis, and Trichoplusia ni BTI-Tn5B1-4 cells revealed contrasting susceptibility characteristics. The 50% lethal concentrations (LC50s) were estimated to be 4,967 of Cry1Ac1 per ml of medium and 11.69 ng of Cyt1A1 per ml of medium. When mixtures of these toxins in different proportions were assayed, eight different LC50s were obtained. All of these LC50s were significantly higher than the expected LC50s of the mixtures. In addition, a series of bioassays were performed with late first-instar larvae of the cabbage looper and pure Cry1Ac1 and Cyt1A1 crystals, as well as two different combinations of the two toxins. The estimated mean LC50 of Cry1Ac1 was 2.46 ng/cm2 of diet, while Cyt1A1 crystals exhibited no toxicity, even at very high concentrations. The estimated mean LC50s of Cry1Ac1 crystals were 15.69 and 19.05 ng per cm2 of diet when these crystals were mixed with 100 and 1,000 ng of Cyt1A1 crystals per cm2 of diet, respectively. These results indicate that there is clear antagonism between the two toxins both in vitro and in vivo. Other joint-action analyses corroborated these results. Although this is the second report of antagonism between B. thuringiensis toxins, our evidence is the first evidence of antagonism between toxins from different subspecies of B. thuringiensis (B. thuringiensis subsp. kurstaki and B. thuringiensis subsp. israelensis) detected both in vivo and in vitro. Some possible explanations for this relationship are discussed.     

Varix of the vortex ampulla: a dynamic phenomenon

A vortex varix consists of a bulging of the vortex ampulla and overlying retina. This dynamic retinal finding can change with the patient's direction of gaze. The clinician can often visualize a red, elevated lesion that appears and disappears thus, making the diagnosis confusing. An overview of vortex varices, methods of diagnosis and differential diagnoses will be discussed.     

Evolution of Trypanosoma cruzi: clarifying hybridisations,mitochondrial introgressions and phylogenetic relationships between major lineages

Several different models of Trypanosoma cruzi evolution have been proposed. These models suggest that scarce events of genetic exchange occurred during the evolutionary history of this parasite. In addition, the debate has focused on the existence of one or two hybridisation events during the evolution of T. cruzi lineages. Here, we reviewed the literature and analysed available sequence data to clarify the phylogenetic relationships among these different lineages. We observed that TcI, TcIII and TcIV form a monophyletic group and that TcIII and TcIV are not, as previously suggested, TcI-TcII hybrids. Particularly, TcI and TcIII are sister groups that diverged around the same time that a widely distributed TcIV split into two clades (TcIV_S and TcIV_N). In addition, we collected evidence that TcIII received TcIV_S kDNA by introgression on several occasions. Different demographic hypotheses (surfing and asymmetrical introgression) may explain the origin and expansion of the TcIII group. Considering these hypotheses, genetic exchange should have been relatively frequent between TcIII and TcIV_S in the geographic area in which their distributions overlapped. In addition, our results support the hypothesis that two independent hybridisation events gave rise to TcV and TcVI. Consequently, TcIV_S kDNA was first transferred to TcIII and later to TcV and TcVI in TcII/TcIII hybridisation events.     

When does gene flow facilitate evolutionary rescue?

Experimental and theoretical studies have highlighted the impact of gene flow on the probability of evolutionary rescue in structured habitats. Mathematical modeling and simulations of evolutionary rescue in spatially or otherwise structured populations showed that intermediate migration rates can often maximize the probability of rescue in gradually or abruptly deteriorating habitats. These theoretical results corroborate the positive effect of gene flow on evolutionary rescue that has been identified in experimental yeast populations. The observations that gene flow can facilitate adaptation are in seeming conflict with traditional population genetics results that show that gene flow usually hampers (local) adaptation. Identifying conditions for when gene flow facilitates survival chances of populations rather than reducing them remains a key unresolved theoretical question. We here present a simple analytically tractable model for evolutionary rescue in a two-deme model with gene flow. Our main result is a simple condition for when migration facilitates evolutionary rescue, as opposed as no migration. We further investigate the roles of asymmetries in gene flow and/or carrying capacities, and the effects of density regulation and local growth rates on evolutionary rescue.     

How Often Do They Have Sex? A Comparative Analysis of the Population Structure of Seven Eukaryotic Microbial Pathogens

The model of predominant clonal evolution (PCE) proposed for micropathogens does not state that genetic exchange is totally absent, but rather, that it is too rare to break the prevalent PCE pattern. However, the actual impact of this “residual” genetic exchange should be evaluated. Multilocus Sequence Typing (MLST) is an excellent tool to explore the problem. Here, we compared online available MLST datasets for seven eukaryotic microbial pathogens: Trypanosoma cruzi, the Fusarium solani complex, Aspergillus fumigatus, Blastocystis subtype 3, the Leishmania donovani complex, Candida albicans and Candida glabrata. We first analyzed phylogenetic relationships among genotypes within each dataset. Then, we examined different measures of branch support and incongruence among loci as signs of genetic structure and levels of past recombination. The analyses allow us to identify three types of genetic structure. The first was characterized by trees with well-supported branches and low levels of incongruence suggesting well-structured populations and PCE. This was the case for the T. cruzi and F. solani datasets. The second genetic structure, represented by Blastocystis spp., A. fumigatus and the L. donovani complex datasets, showed trees with weakly-supported branches but low levels of incongruence among loci, whereby genetic structuration was not clearly defined by MLST. Finally, trees showing weakly-supported branches and high levels of incongruence among loci were observed for Candida species, suggesting that genetic exchange has a higher evolutionary impact in these mainly clonal yeast species. Furthermore, simulations showed that MLST may fail to show right clustering in population datasets even in the absence of genetic exchange. In conclusion, these results make it possible to infer variable impacts of genetic exchange in populations of predominantly clonal micro-pathogens. Moreover, our results reveal different problems of MLST to determine the genetic structure in these organisms that should be considered.     

Selective gray matter staining of human brain slices: optimized use of cadaver materials

We report a novel staining technique for human brain slices that distinguishes clearly gray from white matter. Previously described techniques using either Prussian blue (Berlin blue) or phthalocyanine dyes usually have included a hot phenol pretreatment to prevent white matter staining. The technique we describe here does not require hot phenol pretreatment and allows the use of brains stored for postmortem periods of one to two years prior to staining. Our technique involves staining with copper(II) phthalocyanine-tetrasulfonic acid tetrasodium salt 1% in water for 2 h followed by acetic acid treatment; this produces excellent blue staining of gray matter with little white matter staining. The stained brain slices are excellent for teaching human brain anatomy and/or pathology, or for research purposes.