Grey matter alterations co-localize with functional abnormalities in developmental dyslexia : an ALE meta-analysis

The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions

Natural killer cells in experimental and human leishmaniasis

Infections with parasites of the genus Leishmania lead to a rapid, but transient activation of natural killer (NK) cells. In mice activation of NK cells requires a toll-like-receptor 9-dependent stimulation of dendritic cells (DC) which is followed by the production of IL-12. Although NK cells appear to be non-essential for the ultimate control of cutaneous and visceral leishmaniasis (VL) and can exhibit immunosuppressive functions, they form an important source of interferon (IFN)-γ, which elicits antileishmanial activity in macrophages and helps to pave a protective T helper cell response. In contrast, the cytotoxic activity of NK cells is dispensable, because Leishmania-infected myeloid cells are largely resistant to NK-mediated lysis. In human cutaneous and VL, the functional importance of NK cells is suggested by reports that demonstrate (1) a direct activation or inhibition of NK cells by Leishmania promastigotes, (2) the suppression of NK cell numbers or activity during chronic, non-healing infections, and (3) the recovery of NK cell activity following treatment. This review aims to provide an integrated view on the migration, activation, inhibition, function, and therapeutic modulation of NK cells in experimental and human leishmaniasis

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats

Leishmaniasis is an intracellular protozoan infection that can lead to cutaneous, mucocutaneous, visceral or systemic manifestations depending on the parasite species and virulence and on the host immune response. It is endemic in countries of Europe (Mediterranean basin), Asia, Africa, Central and South America, but autochthonous cases begin to emerge outside classical disease areas. CD4+ T helper cells, interferon γ, dendritic cells and macrophages are the key components of antileishmanial defence. Leishmaniasis is an important differential diagnosis in patients with chronic lesions of the skin or mucous membranes or with fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, histocytosis, haemophagocytic syndrome or glomerulonephritis. Organ transplant recipients and patients with autoimmune syndromes are at particular risk of developing visceral leishmaniasis following immunosuppressive therapy (eg, with steroids, methotrexate, ciclosporin or tumour necrosis factor-neutralising biological agents). Diagnosis and adequate treatment of leishmaniasis requires the combined use of culture, microscopic and nucleic acid amplication methods and species identification by sequencing and other molecular techniques. Standard regimens for the treatment of visceral leishmaniasis are intravenous liposomal amphotericin B (3 mg/kg body weight for 10 days) or oral miltefosine (150 mg/day for 28 days)

Edge length dynamics on graphs with applications to pp-adic AdS/CFT

We formulate a Euclidean theory of edge length dynamics based on a notion of Ricci curvature on graphs with variable edge lengths. In order to write an explicit form for the discrete analog of the Einstein-Hilbert action, we require that the graph should either be a tree or that all its cycles should be sufficiently long. The infinite regular tree with all edge lengths equal is an example of a graph with constant negative curvature, providing a connection with $p$-adic AdS/CFT, where such a tree takes the place of anti-de Sitter space. We compute simple correlators of the operator holographically dual to edge length fluctuations. This operator has dimension equal to the dimension of the boundary, and it has some features in common with the stress tensor.Comment: 42 pages, 6 figure

Tumor necrosis factor-α\alpha in combination with interferon-γ\gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BLl6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$) which is known to be a potent maerophage M$\Phi$ stimulator in other parasitic diseases. In the present study we investigated whether TNF-$\alpha$ activates M$\Phi$ for killing of L. major parasites. In the absence of interferon-y (IFN-$\gamma$) or lipopolysaccharide, TNF-$\alpha$ (0.025-25000 U/ml) failed to activate peritoneal exudate M$\Phi$ from BALB/c mice for killling of L. major amastigotes. In the presence of suboptimal doses of IFN-$\gamma$ (5 or 10 Vlml), however, TNF-$\alpha$ mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-$\gamma$ alone. Tbe combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conelude that the presence of IFN-$\gamma$ is crucial for TNF-$\alpha$-mediated killing of L. major parasites by M$\Phi$. Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-$\gamma$ and a predominance of interleukin 4 rather than the result of an excess amount of TNF-$\alpha$

The Case for Polymorphic Registers in Dataflow Computing

Heterogeneous systems are becoming increasingly popular, delivering high performance through hardware specialization. However, sequential data accesses may have a negative impact on performance. Data parallel solutions such as Polymorphic Register Files (PRFs) can potentially accelerate applications by facilitating high-speed, parallel access to performance-critical data. This article shows how PRFs can be integrated into dataflow computational platforms. Our semi-automatic, compiler-based methodology generates customized PRFs and modifies the computational kernels to efficiently exploit them. We use a separable 2D convolution case study to evaluate the impact of memory latency and bandwidth on performance compared to a state-of-the-art NVIDIA Tesla C2050 GPU. We improve the throughput up to 56.17X and show that the PRF-augmented system outperforms the GPU for 9×9 or larger mask sizes, even in bandwidth-constrained systems

Function of Macrophage and Parasite Phosphatases in Leishmaniasis

The kinetoplastid protozoan parasites belonging to the genus Leishmania are the causative agents of different clinical forms of leishmaniasis, a vector-borne infectious disease with worldwide prevalence. The protective host immune response against Leishmania parasites relies on myeloid cells such as dendritic cells and macrophages in which upon stimulation by cytokines (e.g., interferon-γ) a complex network of signaling pathways is switched on leading to strong antimicrobial activities directed against the intracellular parasite stage. The regulation of these pathways classically depends on post-translational modifications of proteins, with phosphorylation events playing a cardinal role. Leishmania parasites deactivate their phagocytic host cells by inducing specific mammalian phosphatases that are capable to impede signaling. On the other hand, there is now also evidence that Leishmania spp. themselves express phosphatases that might target host cell molecules and thereby facilitate the intracellular survival of the parasite. This review will present an overview on the modulation of host phosphatases by Leishmania parasites as well as on the known families of Leishmania phosphatases and their possible function as virulence factors. A more detailed understanding of the role of phosphatases in Leishmania–host cell interactions might open new avenues for the treatment of non-healing, progressive forms of leishmaniasis