Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode. © 2014 Agassandian et al

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action. © 2010 Macmillan Publishers Limited. All rights reserved

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Universal Geometric Graphs

We introduce and study the problem of constructing geometric graphs that have few vertices and edges and that are universal for planar graphs or for some sub-class of planar graphs; a geometric graph is \emph{universal} for a class $\mathcal H$ of planar graphs if it contains an embedding, i.e., a crossing-free drawing, of every graph in $\mathcal H$. Our main result is that there exists a geometric graph with $n$ vertices and $O(n \log n)$ edges that is universal for $n$-vertex forests; this extends to the geometric setting a well-known graph-theoretic result by Chung and Graham, which states that there exists an $n$-vertex graph with $O(n \log n)$ edges that contains every $n$-vertex forest as a subgraph. Our $O(n \log n)$ bound on the number of edges cannot be improved, even if more than $n$ vertices are allowed. We also prove that, for every positive integer $h$, every $n$-vertex convex geometric graph that is universal for $n$-vertex outerplanar graphs has a near-quadratic number of edges, namely $\Omega_h(n^{2-1/h})$; this almost matches the trivial $O(n^2)$ upper bound given by the $n$-vertex complete convex geometric graph. Finally, we prove that there exists an $n$-vertex convex geometric graph with $n$ vertices and $O(n \log n)$ edges that is universal for $n$-vertex caterpillars.Comment: 20 pages, 8 figures; a 12-page extended abstracts of this paper will appear in the Proceedings of the 46th Workshop on Graph-Theoretic Concepts in Computer Science (WG 2020

On cycle transversals and their connected variants in the absence of a small linear forest.

A graph is H-free if it contains no induced subgraph isomorphic to H. We prove new complexity results for the two classical cycle transversal problems Feedback Vertex Set and Odd Cycle Transversal by showing that they can be solved in polynomial time for (sP1+P3) -free graphs for every integer s≥1 . We show the same result for the variants Connected Feedback Vertex Set and Connected Odd Cycle Transversal. For the latter two problems we also prove that they are polynomial-time solvable for cographs; this was known already for Feedback Vertex Set and Odd Cycle Transversal

Neural antecedents of self-initiated actions in secondary motor cortex

The neural origins of spontaneous or self-initiated actions are not well understood and their interpretation is controversial. To address these issues, we used a task in which rats decide when to abort waiting for a delayed tone. We recorded neurons in the secondary motor cortex (M2) and interpreted our findings in light of an integration-to-bound decision model. A first population of M2 neurons ramped to a constant threshold at rates proportional to waiting time, strongly resembling integrator output. A second population, which we propose provide input to the integrator, fired in sequences and showed trial-to-trial rate fluctuations correlated with waiting times. An integration model fit to these data also quantitatively predicted the observed inter-neuronal correlations. Together, these results reinforce the generality of the integration-to-bound model of decision-making. These models identify the initial intention to act as the moment of threshold crossing while explaining how antecedent subthreshold neural activity can influence an action without implying a decision.info:eu-repo/semantics/publishedVersio

Hidden Sylvatic Foci of the Main Vector of Chagas Disease Triatoma infestans: Threats to the Vector Elimination Campaign?

Triatoma infestans, a highly domesticated species and historically the main vector of Trypanosoma cruzi, is the target of an insecticide-based elimination program in the southern cone countries of South America since 1991. Only limited success has been achieved in the Gran Chaco region due to repeated reinfestations. We conducted full-coverage spraying of pyrethroid insecticides of all houses in a well-defined rural area in northwestern Argentina, followed by intense monitoring of house reinfestation and searches for triatomine bugs in sylvatic habitats during the next two years, to establish the putative sources of new bug colonies. We found low-density sylvatic foci of T. infestans in trees located within the species' flight range from the nearest infested house detected before control interventions. Using multiple methods (fine-resolution satellite imagery, geographic information systems, spatial statistics, genetic markers and wing geometric morphometry), we corroborated the species identity of the sylvatic bugs as T. infestans and found they were indistinguishable from or closely related to local domestic or peridomestic bug populations. Two sylvatic foci were spatially associated to the nearest peridomestic bug populations found before interventions. Sylvatic habitats harbor hidden foci of T. infestans that may represent a threat to vector suppression attempts

Co-expression of nuclear and cytoplasmic HMGB1 is inversely associated with infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer

<p>Abstract</p> <p>Background</p> <p>The intratumoral infiltration of T cells, especially memory T cells, is associated with a favorable prognosis in early colorectal cancers. However, the mechanism underlying this process remains elusive. This study examined whether high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is involved in the infiltration of T cells and disease progression in locally advanced colon cancer.</p> <p>Methods</p> <p>Seventy-two cases of pathologically-confirmed specimens were obtained from patients with stage IIIB (T3N1M0) colon cancer who underwent radical resection between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University. The density of tumor-infiltrating lymphocytes (TILs) within the tumor tissue and the expression of HMGB1 in the cancer cells were examined via immunohistochemical analysis. The phenotype of CD45RO+ cells was confirmed using a flow cytometric assay. The association between HMGB1 expression, the density of TILs, and the 5-year survival rate were analyzed.</p> <p>Results</p> <p>The density of CD45RO+ T cells within the tumor was independently prognostic, although a higher density of CD3+ T cells was also associated with a favorable prognosis. More importantly, the expression of HMGB1 was observed in both the nucleus and the cytoplasm (co-expression pattern) in a subset of colon cancer tissues, whereas nuclear-only expression of HMGB1 (nuclear expression pattern) existed in most of the cancer tissues and normal mucosa. The co-expression pattern of HMGB1 in colon cancer cells was inversely associated with the infiltration of both CD3+ and CD45RO+ T cells and 5-year survival rates.</p> <p>Conclusions</p> <p>This study revealed that the co-expression of HMGB1 is inversely associated with the infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer, indicating that the distribution patterns of HMGB1 might contribute to the progression of colon cancer via modulation of the local immune response.</p

Phylogenomics and the rise of the angiosperms

Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods1,2. A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome3,4. Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins5–7. However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes8. This 15-fold increase in genus-level sampling relative to comparable nuclear studies9 provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade