Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advanced Parkinson's disease. Non‐invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN‐DBS in control and parkinsonian (6‐hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN‐DBS has duration‐dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition.

     

An unsuccessful attempt to elicit orientation responses to linearly polarized light in hatchling loggerhead sea turtles (Caretta caretta)

Sea turtles undertake long migrations in the open ocean, during which they rely at least partly on magnetic cues for navigation. In principle, sensitivity to polarized light might be an additional sensory capability that aids navigation. Furthermore, polarization sensitivity has been linked to ultraviolet (UV) light perception which is present in sea turtles. Here, we tested the ability of hatchling loggerheads (Caretta caretta) to maintain a swimming direction in the presence of broad-spectrum polarized light. At the start of each trial, hatchling turtles, with their magnetic sense temporarily impaired by magnets, successfully established a steady course towards a light-emitting diode (LED) light source while the polarized light field was present. When the LED was removed, however, hatchlings failed to maintain a steady swimming direction, even though the polarized light field remained. Our results have failed to provide evidence for polarized light perception in young sea turtles and suggest that alternative cues guide the initial migration offshore.     

Proteomic pathway analysis reveals inflammation increases myeloid-derived suppressor cell resistance to apoptosis

Myeloid-derived suppressor cells (MDSC) accumulate in patients and animals with cancer where they mediate systemic immune suppression and obstruct immune-based cancer therapies. We have previously demonstrated that inflammation, which frequently accompanies tumor onset and progression, increases the rate of accumulation and the suppressive potency of MDSC. To determine how inflammation enhances MDSC levels and activity we used mass spectrometry to identify proteins produced by MDSC induced in highly inflammatory settings. Proteomic pathway analysis identified the Fas pathway and caspase network proteins, leading us to hypothesize that inflammation enhances MDSC accumulation by increasing MDSC resistance to Fas-mediated apoptosis. The MS findings were validated and extended by biological studies. Using activated caspase 3 and caspase 8 as indicators of apoptosis, flow cytometry, confocal microscopy, and Western blot analyses demonstrated that inflammation-induced MDSC treated with a Fas agonist contain lower levels of activated caspases, suggesting that inflammation enhances resistance to Fas-mediated apoptosis. Resistance to Fas-mediated apoptosis was confirmed by viability studies of MDSC treated with a Fas agonist. These results suggest that an inflammatory environment, which is frequently present in tumor-bearing individuals, protects MDSC against extrinsic-induced apoptosis resulting in MDSC with a longer in vivo half-life, and may explain why MDSC accumulate more rapidly and to higher levels in inflammatory settings.     

Proteolytic cleavage of covalently linked cell wall proteins by Candida albicans Sap9 and Sap10

The cell wall of the human-pathogenic fungus Candida albicans is a robust but also dynamic structure which mediates adaptation to changing environmental conditions during infection. Sap9 and Sap10 are cell surface-associated proteases which function in C. albicans cell wall integrity and interaction with human epithelial cells and neutrophils. In this study, we have analyzed the enzymatic properties of Sap9 and Sap10 and investigated whether these proteases cleave proteins on the fungal cell surface. We show that Sap9 and Sap10, in contrast to other aspartic proteases, exhibit a near-neutral pH optimum of proteolytic activity and prefer the processing of peptides containing basic or dibasic residues. However, both proteases also cleaved at nonbasic sites, and not all tested peptides with dibasic residues were processed. By digesting isolated cell walls with Sap9 or Sap10, we identified the covalently linked cell wall proteins (CWPs) Cht2, Ywp1, Als2, Rhd3, Rbt5, Ecm33, and Pga4 as in vitro protease substrates. Proteolytic cleavage of the chitinase Cht2 and the glucan-cross-linking protein Pir1 by Sap9 was verified using hemagglutinin (HA) epitope-tagged versions of both proteins. Deletion of the SAP9 and SAP10 genes resulted in a reduction of cell-associated chitinase activity similar to that upon deletion of CHT2, suggesting a direct influence of Sap9 and Sap10 on Cht2 function. In contrast, cell surface changes elicited by SAP9 and SAP10 deletion had no major impact on the phagocytosis and killing of C. albicans by human macrophages. We propose that Sap9 and Sap10 influence distinct cell wall functions by proteolytic cleavage of covalently linked cell wall proteins.     

Akt phosphorylates Sec24: new clues into the regulation of ER-to-Golgi trafficking

Regulation of protein transport within the early secretory pathway is a relatively unexplored area. Here, we propose a new player in the control of protein transport from the endoplasmic reticulum (ER) to the Golgi. Akt is an important signaling kinase whose functioning is perturbed in diseases such as cancer and diabetes. We discovered that Akt phosphorylates Sec24, an essential coat protein II (COPII) component involved in mediating cargo selection for ER-to-Golgi trafficking. We discuss how this finding may provide new insights into the regulation of protein transport.     

Abundance of introduced species at home predicts abundance away in herbaceous communities

Many ecosystems worldwide are dominated by introduced plant species, leading to loss of biodiversity and ecosystem function. A common but rarely tested assumption is that these plants are more abundant in introduced vs. native communities, because ecological or evolutionary-based shifts in populations underlie invasion success. Here, data for 26 herbaceous species at 39 sites, within eight countries, revealed that species abundances were similar at native (home) and introduced (away) sites - grass species were generally abundant home and away, while forbs were low in abundance, but more abundant at home. Sites with six or more of these species had similar community abundance hierarchies, suggesting that suites of introduced species are assembling similarly on different continents. Overall, we found that substantial changes to populations are not necessarily a pre-condition for invasion success and that increases in species abundance are unusual. Instead, abundance at home predicts abundance away, a potentially useful additional criterion for biosecurity programmes.     

Endothelial basement membrane limits tip cell formation by inducing Dll4/Notch signalling in vivo

How individual components of the vascular basement membrane influence endothelial cell behaviour remains unclear. Here we show that laminin α4 (Lama4) regulates tip cell numbers and vascular density by inducing endothelial Dll4/Notch signalling in vivo. Lama4 deficiency leads to reduced Dll4 expression, excessive filopodia and tip cell formation in the mouse retina, phenocopying the effects of Dll4/Notch inhibition. Lama4-mediated Dll4 expression requires a combination of integrins in vitro and integrin β1 in vivo. We conclude that appropriate laminin/integrin-induced signalling is necessary to induce physiologically functional levels of Dll4 expression and regulate branching frequency during sprouting angiogenesis in vivo.     

Absence of isolation by distance patterns at the regional scale in the fungal plant pathogen Leptosphaeria maculans

Outcomes of host-pathogen coevolution are influenced by migration rates of the interacting species. Reduced gene flow with increasing spatial distance between populations leads to spatial genetic structure, as predicted by the isolation by distance (IBD) model. In wind-dispersed plant-pathogenic fungi, a significant spatial genetic structure is theoretically expected if local spore dispersal is more frequent than long-distance dispersal, but this remains to be documented by empirical data. For 29 populations of the oilseed rape fungus Leptosphaeria maculans sampled from two French regions, genetic structure was determined using eight minisatellite markers. Gene diversity (H = 0.62-0.70) and haplotypic richness (R = 0.96-1) were high in all populations. No linkage disequilibrium was detected between loci, suggesting the prevalence of panmictic sexual reproduction. Analysis of molecular variance showed that > 97% of genetic diversity was observed within populations. Genetic differentiation was low among populations (F(st) < 0.05). Although direct methods previously revealed short-distance dispersal for L. maculans, our findings of no correlation between genetic and geographic distances among populations illustrate that the IBD model does not account for dispersal of the fungus at the spatial scale we examined. These results indicate high gene flow among French populations of L. maculans, suggesting high dispersal rates and/or large effective population sizes, two characteristics giving the pathogen high evolutionary potential against the deployment of resistant oilseed rape cultivars.