Dissociation between Mature Phenotype and Impaired Transmigration in Dendritic Cells from Heparanase-Deficient Mice

To reach the lymphatics, migrating dendritic cells (DCs) need to interact with the extracellular matrix (ECM). Heparanase, a mammalian endo-β-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and ECM. The role of heparanase in the physiology of bone marrow-derived DCs was studied in mutant heparanase knock-out (Hpse-KO) mice. Immature DCs from Hpse-KO mice exhibited a more mature phenotype; however their transmigration was significantly delayed, but not completely abolished, most probably due to the observed upregulation of MMP-14 and CCR7. Despite their mature phenotype, uptake of beads was comparable and uptake of apoptotic cells was more efficient in DCs from Hpse-KO mice. Heparanase is an important enzyme for DC transmigration. Together with CCR7 and its ligands, and probably MMP-14, heparanase controls DC trafficking

The Shift from Local to Global Visual Processing in 6-Year-Old Children Is Associated with Grey Matter Loss

International audienceBackground: A real-world visual scene consists of local elements (e.g. trees) that are arranged coherently into a global configuration (e.g. a forest). Children show psychological evolution from a preference for local visual information to an adult-like preference for global visual information, with the transition in visual preference occurring around 6 years of age. The brain regions involved in this shift in visual preference have not been described. Methods and Results: We used voxel-based morphometry (VBM) to study children during this developmental window to investigate changes in gray matter that underlie the shift from a bias for local to global visual information. Six-year-old children were assigned to groups according to their judgment on a global/local task. The first group included children who still presented with local visual processing biases, and the second group included children who showed global visual processing biases. VBM results indicated that compared to children with local visual processing biases, children with global visual processing biases had a loss of gray matter in the right occipital and parietal visuospatial areas. Conclusions: These anatomical findings are in agreement with previous findings in children with neurodevelopmental disorders and represent the first structural identification of brain regions that allow healthy children to develop a global perception of the visual world

Differentiation and Glucocorticoid Regulated Apopto-Phagocytic Gene Expression Patterns in Human Macrophages. Role of Mertk in Enhanced Phagocytosis

The daily clearance of physiologically dying cells is performed safely mainly by cells in the mononuclear phagocyte system. They can recognize and engulf dying cells utilizing several cooperative mechanisms. In our study we show that the expression of a broad range of apopto-phagocytic genes is strongly up-regulated during differentiation of human monocytes to macrophages with different donor variability. The glucocorticoid dexamethasone has a profound effect on this process by selectively up-regulating six genes and down-regulating several others. The key role of the up-regulated mer tyrosine kinase (Mertk) in dexamethasone induced enhancement of phagocytosis could be demonstrated in human monocyte derived macrophages by gene silencing as well as blocking antibodies, and also in a monocyte-macrophage like cell line. However, the additional role of other glucocorticoid induced elements must be also considered since the presence of autologous serum during phagocytosis could almost completely compensate for the blocked function of Mertk

Cetaceans in the Mediterranean Sea. Encounter rate, dominant species, and diversity hotspots

We investigated the presence and diversity of cetaceans in the Mediterranean Sea, analysing the data collected by 32 different research units, over a period of 15 years (2004–2018), and shared on the common web-GIS platform named Intercet. We used the encounter rate, the species prevalence, and the Shannon diversity index as parameters for data analysis. The results show that cetacean diversity, in the context of the Mediterranean basin, is generally quite low when compared with the eastern Atlantic, as few species, namely the striped dolphin, the bottlenose dolphin, the fin whale, and the sperm whale, dominate over all the others. However, some areas, such as the Alboran Sea or the north-western Mediterranean Sea, which includes the Pelagos Sanctuary (the Specially Protected Area of Mediterranean Interest located in the northern portion of the western basin), show higher levels of diversity and should be considered hotspots to be preserved. Primary production and seabed profile seem to be the two main drivers influencing the presence and distribution of cetaceans, with the highest levels of diversity observed in areas characterized by high levels of primary production and high bathymetric variability and gradient. This collective work underlines the importance of data sharing to deepen our knowledge on marine fauna at the scale of the whole Mediterranean Sea and encourages greater efforts in the networking process, also to accomplish the requirements of the Marine Strategy Framework Directive, with particular reference to Descriptor 1: biological diversity is maintained

Attentional Set-Shifting Deficit in Parkinson’s Disease Is Associated with Prefrontal Dysfunction: An FDG-PET Study

The attentional set-shifting deficit that has been observed in Parkinson’s disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients

Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic Neurons

The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss.These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease

Common and distinct neural regions for the guidance of selection by visuoverbal information held in memory: converging evidence from fMRI and rTMS.

Recent research indicates that working memory (WM) and attention interact, with attention automatically biased to stimuli that match the contents of WM. Though there is behavioral evidence for verbal guidance (written words) as well as guidance by more visual cues in WM, we have limited understanding of how these two representational formats influence the guidance of visual selection at a neural level. Here, we present converging evidence from functional MRI and transcranial magnetic stimulation (TMS), which indicates that both common and distinct neural regions mediate the influence of visuoverbal representations on WM. Colored shapes, but not words, in WM activated the superior frontal gyrus (SFG) and recognition memory areas in the temporal lobe when the contents of WM matched a stimulus in a subsequent search display. rTMS to the SFG disrupted WM effects from colored shapes. The lateral occipital cortex, however, tended to be more activated with written word cues, and rTMS to the lateral occipital complex tended to disrupt effects from written words more than from colored shapes in WM. There was also evidence for cue validity effects from colored shapes and written stimuli operating through different subthalamic nuclei. We discuss the evidence for understanding the neural systems mediating attention effects from WM