The Endo-Lysosomal System of Brain Endothelial Cells Is Influenced by Astrocytes In Vitro

Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes. We used primary porcine BEC in monoculture and in co-culture with primary rat astrocytes. The presence of astrocytes changed the intraendothelial vesicular network and significantly impacted vesicular number, morphology, and distribution. Additionally, gene set enrichment analysis revealedthat 60 genes associated with vesicular trafficking showed altered expression in co-cultured BEC. Cytosolic proteins involved in subcellular trafficking were investigated to mark transport routes, such as RAB25 for transcytosis. Strikingly, the adaptor protein called AP1-1B, important for basolateral sorting in epithelial cells, was not expressed in BEC. Altogether, our data pin-point unique features of BEC trafficking network, essentially mapping the endo-lysosomal system of in vitro BBB models. Consequently, our findings constitute a valuable basis for planning the optimal route across the BBB when advancing drug delivery to the brain.Peer reviewe

Game fence presence and permeability influences the local movement and distribution of South African mammals

Fences are utilized throughout the world to restrict the movements of wildlife, protecting them from threats and reducing human-wildlife conflict. In South Africa the number of privately-owned fenced game reserves has greatly increased in recent years, but little is known about how fencing affects the distribution and movements of target and non-target mammals. We surveyed 2m either side of the complete fence line of a recently established commercial game reserve in South Africa, identifying signs of animal presence (spoor, scat, foraging or other field signs) while also recording damage (holes) to the fence. Every 250m we carried out 100m perpendicular transects either side of the fence, recording vegetation cover and height at 10m intervals along the transect. We found that livestock (largely cattle) were excluded from the reserve. However, 12% of records of large animal species were recorded outside of the fence line. These species had been introduced to the reserve, strongly suggesting that they had crossed the boundary into the surrounding farmland. Sixteen naturally present wild species were found on both sides of the fence, but we found more evidence of their presence inside the reserve. Observational evidence suggests that they were regularly crossing the boundary, particularly where the fence was damaged, with hole size affecting species recorded. We also found evidence that the construction of the fence had led to a difference in vegetation structure with plant diversity and percentage of non-woody plant cover significantly higher inside the fence. While fencing was highly effective at preventing movement of livestock, introduced and wild animals were able to cross the boundary, via holes in the fence. This work shows that the efficacy of the most common approach to preventing animal movement around protected areas depends on the species being considered and fence condition

The recent intellectual structure of geography

An active learning project in an introductory graduate course used multidimensional scaling of the name index in Geography in America at the Dawn of the 21st Century, by Gary Gaile and Cort Willmott, to reveal some features of the discipline\u27s recent intellectual structure relevant to the relationship between human and physical geography. Previous analyses, dating to the 1980s, used citation indices or Association of American Geographers spe- cialty-group rosters to conclude that either the regional or the methods and environmental subdisciplines bridge human and physical geography. The name index has advantages over those databases, and its analysis reveals that the minimal connectivity that occurs between human and physical geography has recently operated more through environmental than through either methods or regional subdisciplines

Kelp carbon sink potential decreases with warming due to accelerating decomposition

Cycling of organic carbon in the ocean has the potential to mitigate or exacerbate global climate change, but major questions remain about the environmental controls on organic carbon flux in the coastal zone. Here, we used a field experiment distributed across 28° of latitude, and the entire range of 2 dominant kelp species in the northern hemisphere, to measure decomposition rates of kelp detritus on the seafloor in relation to local environmental factors. Detritus decomposition in both species were strongly related to ocean temperature and initial carbon content, with higher rates of biomass loss at lower latitudes with warmer temperatures. Our experiment showed slow overall decomposition and turnover of kelp detritus and modeling of coastal residence times at our study sites revealed that a significant portion of this production can remain intact long enough to reach deep marine sinks. The results suggest that decomposition of these kelp species could accelerate with ocean warming and that low-latitude kelp forests could experience the greatest increase in remineralization with a 9% to 42% reduced potential for transport to long-term ocean sinks under short-term (RCP4.5) and long-term (RCP8.5) warming scenarios. However, slow decomposition at high latitudes, where kelp abundance is predicted to expand, indicates potential for increasing kelp-carbon sinks in cooler (northern) regions. Our findings reveal an important latitudinal gradient in coastal ecosystem function that provides an improved capacity to predict the implications of ocean warming on carbon cycling. Broad-scale patterns in organic carbon decomposition revealed here can be used to identify hotspots of carbon sequestration potential and resolve relationships between carbon cycling processes and ocean climate at a global scale.publishedVersio

Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries

Jimmy Swaggart's Secular Confession

This is the author's accepted manuscript. The published version is available from http://dx.doi.org/10.1080/02773940902766748 .Following the exposure of televangelist Jimmy Swaggart’s illicit rendezvous with a New Orleans prostitute, the Assemblies of God simultaneously orchestrated a massive attempt to silence those who would discuss the tryst and arranged the most widely publicized confession in American history theretofore. The coincidence of a “silence campaign” with the vast distribution of a public confession invites us to reconsider the nature of the public confession. For what place has a public confession, the discourse of disclosure par excellence, in a silence campaign? This question is best answered, I argue, if we understand public confession not as a stable a-historical form, but as a practice that is informed by multiple, competing traditions. I argue that by situating Swaggart’s performance in a philosophically modern and secular tradition of public confession we can understand both its complicity in a silence campaign and, more generally, the political logic of the modern public confession

Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder

Adolescents with conduct and substance problems ("Antisocial Substance Disorder" (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders