Sperry versus Hebb: topographic mapping in Isl2/EphA3 mutant mice

BACKGROUND: In wild-type mice, axons of retinal ganglion cells establish topographically precise projection to the superior colliculus of the midbrain. This means that axons of neighboring retinal ganglion cells project to the proximal locations in the target. The precision of topographic projection is a result of combined effects of molecular labels, such as Eph receptors and ephrins, and correlated neural activity. In the Isl2/EphA3 mutant mice the expression levels of molecular labels are changed. As a result the topographic projection is rewired so that the neighborhood relationships between retinal cell axons are disrupted. RESULTS: Here we study the computational model for retinocollicular connectivity formation that combines the effects of molecular labels and correlated neural activity. We argue that the effects of correlated activity presenting themselves in the form of Hebbian learning rules can facilitate the restoration of the topographic connectivity even when the molecular labels carry conflicting instructions. This occurs because the correlations in electric activity carry information about retinal cells' origin that is independent on molecular labels. We argue therefore that partial restoration of the topographic property of the retinocollicular projection observed in Isl2/EphA3 heterozygous knockin mice may be explained by the effects of correlated neural activity. We address the maps observed in Isl2/EphA3 knockin/EphA4 knockout mice in which the levels of retinal labels are uniformly reduced. These maps can be explained by either the saturation of EphA receptor mapping leading to the relative signaling model or by the reverse signaling conveyed by ephrin-As expressed by retinal axons. CONCLUSION: According to our model, experiments in Isl2/EphA3 knock-in mice test the interactions between effects of molecular labels and correlated activity during the development of neural connectivity. Correlated activity can partially restore topographic order even when molecular labels carry conflicting information

What have proteomics taught us about Leishmania development?

Leishmania are obligatory intracellular parasitic protozoa that cycle between sand fly mid-gut and phagolysosomes of mammalian macrophages. They have developed genetically programmed changes in gene and protein expression that enable rapid optimization of cell function according to vector and host environments. During the last two decades, host-free systems that mimic intra-lysosomal environments have been devised in which promastigotes differentiate into amastigotes axenically. These cultures have facilitated detailed investigation of the molecular mechanisms underlying Leishmania development inside its host. Axenic promastigotes and amastigotes have been subjected to transcriptome and proteomic analyses. Development had appeared somewhat variable but was revealed by proteomics to be strictly coordinated and regulated. Here we summarize the current understanding of Leishmania promastigote to amastigote differentiation, highlighting the data generated by proteomics

Crossover from percolation to diffusion

A problem of the crossover from percolation to diffusion transport is considered. A general scaling theory is proposed. It introduces phenomenologically four critical exponents which are connected by two equations. One exponent is completely new. It describes the increase of the diffusion below percolation threshold. As an example, an exact solution of one dimensional lattice problem is given. In this case the new exponent $q=2$.Comment: 10 pages, 1 figur

On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

PhosTryp: a phosphorylation site predictor specific for parasitic protozoa of the family trypanosomatidae

<p>Abstract</p> <p>Background</p> <p>Protein phosphorylation modulates protein function in organisms at all levels of complexity. Parasites of the <it>Leishmania </it>genus undergo various developmental transitions in their life cycle triggered by changes in the environment. The molecular mechanisms that these organisms use to process and integrate these external cues are largely unknown. However <it>Leishmania </it>lacks transcription factors, therefore most regulatory processes may occur at a post-translational level and phosphorylation has recently been demonstrated to be an important player in this process. Experimental identification of phosphorylation sites is a time-consuming task. Moreover some sites could be missed due to the highly dynamic nature of this process or to difficulties in phospho-peptide enrichment.</p> <p>Results</p> <p>Here we present PhosTryp, a phosphorylation site predictor specific for trypansomatids. This method uses an SVM-based approach and has been trained with recent <it>Leishmania </it>phosphosproteomics data. PhosTryp achieved a 17% improvement in prediction performance compared with Netphos, a non organism-specific predictor. The analysis of the peptides correctly predicted by our method but missed by Netphos demonstrates that PhosTryp captures <it>Leishmania</it>-specific phosphorylation features. More specifically our results show that <it>Leishmania </it>kinases have sequence specificities which are different from their counterparts in higher eukaryotes. Consequently we were able to propose two possible <it>Leishmania</it>-specific phosphorylation motifs.</p> <p>We further demonstrate that this improvement in performance extends to the related trypanosomatids <it>Trypanosoma brucei </it>and <it>Trypanosoma cruzi</it>. Finally, in order to maximize the usefulness of PhosTryp, we trained a predictor combining all the peptides from <it>L. infantum, T. brucei and T. cruzi</it>.</p> <p>Conclusions</p> <p>Our work demonstrates that training on organism-specific data results in an improvement that extends to related species. PhosTryp is freely available at <url>http://phostryp.bio.uniroma2.it</url></p

Analysis of undiagnosed tuberculosis-related deaths identified at post-mortem among HIV-infected patients in Russia: a descriptive study

<p>Abstract</p> <p>Background</p> <p>Tuberculosis remains a serious public health threat and economic burden in Russia with escalating rates of drug resistance against a background of growing HIV-epidemic. Samara Oblast is one of the regions of the Russian Federation where more than 1% of the population is affected by the HIV-epidemic; almost half of the cases are concentrated in the largely-industrial city of Togliatti with a population of 800 000.</p> <p>Methods</p> <p>We conducted a retrospective analysis of errors leading to death of HIV-positive patients in general health care hospitals in Togliatti, Russia, in 2008. All (n = 29) cases when tuberculosis was established at autopsy as a cause of death were included.</p> <p>Results</p> <p>Median length of hospital stay was 20 days; in 11 cases the death occurred within the first 24 hours of admission. All cases were known to be HIV-positive prior to admission, however HAART was not initiated for any case, and no relevant tests to assess severity of immunosupression were performed despite their availability. No appropriate diagnostic algorithms were applied to confirm tuberculosis. Major gaps were identified in the work of hospital and consulting physicians including insufficient records keeping. In almost all patients earlier regular HIV-relevant tests were not performed due to poor compliance of patients, many of whom abused alcohol and drugs.</p> <p>Conclusions</p> <p>We conclude that introduction of prompt and accurate diagnostics tests, adequate treatment protocols and intensive training of physicians in management of AIDS and TB is vital. This should include reviewing standards of care for HIV-positive individuals with accompanying social problems.</p

EphA3 Expressed in the Chicken Tectum Stimulates Nasal Retinal Ganglion Cell Axon Growth and Is Required for Retinotectal Topographic Map Formation

BACKGROUND: Retinotopic projection onto the tectum/colliculus constitutes the most studied model of topographic mapping and Eph receptors and their ligands, the ephrins, are the best characterized molecular system involved in this process. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. However, there are conflicting data regarding the nature of the second force that guides nasal axons to invade and branch only in the caudal tectum/colliculus. The predominant model postulates that this second force is produced by a decreasing rostro-caudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. However, as optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule. METHODOLOGY/PRINCIPAL FINDINGS: By using chicken retinal cultures we showed that EphA3 ectodomain stimulates nasal RGC axon growth in a concentration dependent way. Moreover, we showed that nasal axons choose growing on EphA3-expressing cells and that EphA3 diminishes the density of interstitial filopodia in nasal RGC axons. Accordingly, in vivo EphA3 ectodomain misexpression directs nasal optic fibers toward the caudal tectum preventing their branching in the rostral tectum. CONCLUSIONS: We demonstrated in vitro and in vivo that EphA3 ectodomain (which is expressed in a decreasing rostro-caudal gradient in the tectum) is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum. Furthermore, the ability of EphA3 of stimulating axon growth allows understanding how optic fibers invade the tectum growing throughout this molecular gradient. Therefore, opposing tectal gradients of repellent ephrin-As and of axon growth stimulating EphA3 complement each other to map optic fibers along the rostro-caudal tectal axis