Improved Implementation of Point Location in General Two-Dimensional Subdivisions

We present a major revamp of the point-location data structure for general two-dimensional subdivisions via randomized incremental construction, implemented in CGAL, the Computational Geometry Algorithms Library. We can now guarantee that the constructed directed acyclic graph G is of linear size and provides logarithmic query time. Via the construction of the Voronoi diagram for a given point set S of size n, this also enables nearest-neighbor queries in guaranteed O(log n) time. Another major innovation is the support of general unbounded subdivisions as well as subdivisions of two-dimensional parametric surfaces such as spheres, tori, cylinders. The implementation is exact, complete, and general, i.e., it can also handle non-linear subdivisions. Like the previous version, the data structure supports modifications of the subdivision, such as insertions and deletions of edges, after the initial preprocessing. A major challenge is to retain the expected O(n log n) preprocessing time while providing the above (deterministic) space and query-time guarantees. We describe an efficient preprocessing algorithm, which explicitly verifies the length L of the longest query path in O(n log n) time. However, instead of using L, our implementation is based on the depth D of G. Although we prove that the worst case ratio of D and L is Theta(n/log n), we conjecture, based on our experimental results, that this solution achieves expected O(n log n) preprocessing time.Comment: 21 page

Endovascular therapy versus no endovascular therapy in patients receiving best medical management for acute isolated occlusion of the posterior cerebral artery : A systematic review and meta-analysis

Background and purpose Endovascular therapy (EVT) is increasingly reported for treatment of isolated posterior cerebral artery (PCA) occlusions although its clinical benefit remains uncertain. This study-level meta-analysis investigated the functional outcomes and safety of EVT and best medical management (BMM) compared to BMM alone for treatment of PCA occlusion stroke. Methods We conducted a literature search in PubMed, Web of Science and Embase for studies in patients with isolated PCA occlusion stroke treated with EVT + BMM or BMM including intravenous thrombolysis. There were no randomized trials and all studies were retrospective. The primary outcome was modified Rankin Scale score of 0-2 at 3 months, while safety outcomes included mortality rate and incidence of symptomatic intracranial hemorrhage (sICH). Results Twelve studies with a total of 679 patients were included in the meta-analysis: 338 patients with EVT + BMM and 341 patients receiving BMM alone. Good functional outcome at 3 months was achieved in 58.0% (95% confidence interval [CI] 43.83-70.95) of patients receiving EVT + BMM and 48.1% (95% CI 40.35-55.92) of patients who received BMM alone, with respective mortality rates of 12.6% (95% CI 7.30-20.93) and 12.3% (95% CI 8.64-17.33). sICH occurred in 4.2% (95% CI 2.47-7.03) of patients treated with EVT + BMM and 3.2% (95% CI 1.75-5.92) of patients treated with BMM alone. Comparative analyses were performed on studies that included both treatments and these demonstrated no significant differences. Conclusions Our results demonstrate that EVT represents a safe treatment for patients with isolated PCA occlusion stroke. There were no differences in clinical or safety outcomes between treatments, supporting randomization of future patients into distal vessel occlusion trials.Peer reviewe

Motion Planning via Manifold Samples

We present a general and modular algorithmic framework for path planning of robots. Our framework combines geometric methods for exact and complete analysis of low-dimensional configuration spaces, together with practical, considerably simpler sampling-based approaches that are appropriate for higher dimensions. In order to facilitate the transfer of advanced geometric algorithms into practical use, we suggest taking samples that are entire low-dimensional manifolds of the configuration space that capture the connectivity of the configuration space much better than isolated point samples. Geometric algorithms for analysis of low-dimensional manifolds then provide powerful primitive operations. The modular design of the framework enables independent optimization of each modular component. Indeed, we have developed, implemented and optimized a primitive operation for complete and exact combinatorial analysis of a certain set of manifolds, using arrangements of curves of rational functions and concepts of generic programming. This in turn enabled us to implement our framework for the concrete case of a polygonal robot translating and rotating amidst polygonal obstacles. We demonstrate that the integration of several carefully engineered components leads to significant speedup over the popular PRM sampling-based algorithm, which represents the more simplistic approach that is prevalent in practice. We foresee possible extensions of our framework to solving high-dimensional problems beyond motion planning.Comment: 18 page

Dendritic cell-mediated vaccination relies on interleukin-4 receptor signaling to avoid tissue damage after Leishmania major infection of BALB/c mice

Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is involved in the redirection of the immune response towards a type 1 profile, we were interested in further exploring the role of IL-4. Thus, wild-type (wt) BALB/c mice or DC-specific IL-4 receptor alpha (IL-4Rα)-deficient (CD11ccreIL-4Rα−/lox) BALB/c mice were given either wt or IL-4Rα-deficient LmAg-loaded bone marrow-derived DC exposed or not to CpG ODN prior to inoculation of 2×105 stationary-phase L. major promastigotes into the BALB/c footpad. The results provide evidence that IL4/IL-4Rα-mediated signaling in the vaccinating DC is required to prevent tissue damage at the site of L. major inoculation, as properly conditioned wt DC but not IL-4Rα-deficient DC were able to confer resistance. Furthermore, uncontrolled L. major population size expansion was observed in the footpad and the footpad draining lymph nodes of CD11ccreIL-4Rα−/lox mice immunized with CpG ODN-exposed LmAg-loaded IL-4Rα-deficient DC, indicating the influence of IL-4Rα-mediated signaling in host DC to control parasite replication. In addition, no footpad damage occurred in BALB/c mice that were systemically immunized with LmAg-loaded wt DC doubly exposed to CpG ODN and recombinant IL-4. We discuss these findings and suggest that the IL4/IL4Rα signaling pathway could be a key pathway to trigger when designing vaccines aimed to prevent damaging processes in tissues hosting intracellular microorganisms

p53 Plays a Role in Mesenchymal Differentiation Programs, in a Cell Fate Dependent Manner

Background: The tumor suppressor p53 is an important regulator that controls various cellular networks, including cell differentiation. Interestingly, some studies suggest that p53 facilitates cell differentiation, whereas others claim that it suppresses differentiation. Therefore, it is critical to evaluate whether this inconsistency represents an authentic differential p53 activity manifested in the various differentiation programs. Methodology/Principal Findings: To clarify this important issue, we conducted a comparative study of several mesenchymal differentiation programs. The effects of p53 knockdown or enhanced activity were analyzed in mouse and human mesenchymal cells, representing various stages of several differentiation programs. We found that p53 downregulated the expression of master differentiation-inducing transcription factors, thereby inhibiting osteogenic, adipogenic and smooth muscle differentiation of multiple mesenchymal cell types. In contrast, p53 is essential for skeletal muscle differentiation and osteogenic re-programming of skeletal muscle committed cells. Conclusions: These comparative studies suggest that, depending on the specific cell type and the specific differentiatio

The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation

N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation

Identification of a Novel Chromosomal Passenger Complex and Its Unique Localization during Cytokinesis in Trypanosoma brucei

Aurora B kinase is a key component of the chromosomal passenger complex (CPC), which regulates chromosome segregation and cytokinesis. An ortholog of Aurora B was characterized in Trypanosoma brucei (TbAUK1), but other conserved components of the complex have not been found. Here we identified four novel TbAUK1 associated proteins by tandem affinity purification and mass spectrometry. Among these four proteins, TbKIN-A and TbKIN-B are novel kinesin homologs, whereas TbCPC1 and TbCPC2 are hypothetical proteins without any sequence similarity to those known CPC components from yeasts and metazoans. RNAi-mediated silencing of each of the four genes led to loss of spindle assembly, chromosome segregation and cytokinesis. TbKIN-A localizes to the mitotic spindle and TbKIN-B to the spindle midzone during mitosis, whereas TbCPC1, TbCPC2 and TbAUK1 display the dynamic localization pattern of a CPC. After mitosis, the CPC disappears from the central spindle and re-localizes at a dorsal mid-point of the mother cell, where the anterior tip of the daughter cell is tethered, to start cell division toward the posterior end, indicating a most unusual CPC-initiated cytokinesis in a eukaryote