The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

Neuroinflammation is a complex integration of the responses of all cells present within the CNS, including the neurons, macroglia, microglia and the infiltrating leukocytes. The initiating insult, environmental factors, genetic background and age/past experiences all combine to modulate the integrated response of this complex neuroinflammatory circuit. Here, we explore how these factors interact to lead to either neuroprotective versus neurotoxic inflammatory responses. We specifically focus on microglia and astrocytic regulation of autoreactive T cell responses.     

Barnacle reproductive hotspots linked to nearshore ocean conditions

Coastal marine ecosystems provide important ecosystem services to human populations worldwide. Understanding the contexts in which a species has markedly higher reproductive output is vital for effective management and conservation of these valuable and highly impacted systems. We documented reproductive hotspots along the Oregon coast for an ecologically significant marine invertebrate, the intertidal barnacle Balanus glandula. Greater larval production in both natural and experimental populations was associated with higher primary productivity in the adjacent nearshore ocean, providing strong evidence for bottom-up forcing. Mean cumulative larval production per 100 cm2 in natural barnacle populations in the region of higher primary productivity was almost 5x that of populations in the less productive region. Mean estimated larval production per individual in experimental populations in the region of higher primary productivity was >2x that of populations in the region of lower productivity, and mean larval production per 100 cm2 was >120x greater in the region of higher productivity. Our results highlight the importance of spatial heterogeneity in reproduction and other ecological processes in the marine environment and provide a mechanistic basis for evaluating the relative contributions of different sites when designing marine reserves and other protected areas. Our findings also advance the understanding of the role of bottom-up influences on population and community dynamics and contribute data for the next generation of models of marine community dynamics.     

SAR11 lipid renovation in response to phosphate starvation

Phytoplankton inhabiting oligotrophic ocean gyres actively reduce their phosphorus demand by replacing polar membrane phospholipids with those lacking phosphorus. Although the synthesis of nonphosphorus lipids is well documented in some heterotrophic bacterial lineages, phosphorus-free lipid synthesis in oligotrophic marine chemoheterotrophs has not been directly demonstrated, implying they are disadvantaged in phosphate-deplete ecosystems, relative to phytoplankton. Here, we show the SAR11 clade chemoheterotroph Pelagibacter sp. str. HTCC7211 renovates membrane lipids when phosphate starved by replacing a portion of its phospholipids with monoglucosyl- and glucuronosyl-diacylglycerols and by synthesizing new ornithine lipids. Lipid profiles of cells grown with excess phosphate consisted entirely of phospholipids. Conversely, up to 40% of the total lipids were converted to nonphosphorus lipids when cells were starved for phosphate, or when growing on methylphosphonate. Cells sequentially limited by phosphate and methylphosphonate transformed >75% of their lipids to phosphorus-free analogs. During phosphate starvation, a four-gene cluster was significantly up-regulated that likely encodes the enzymes responsible for lipid renovation. These genes were found in Pelagibacterales strains isolated from a phosphate-deficient ocean gyre, but not in other strains from coastal environments, suggesting alternate lipid synthesis is a specific adaptation to phosphate scarcity. Similar gene clusters are found in the genomes of other marine α-proteobacteria, implying lipid renovation is a common strategy used by heterotrophic cells to reduce their requirement for phosphorus in oligotrophic habitats.Microbes primarily assimilate phosphorus (P) in its +5 valence state (phosphate; P_i), which comprises ∼3% of total cellular mass as a structural constituent of nucleic acids and phospholipids, and is intimately involved in energy metabolism and some transport functions (via ATP hydrolysis) (1). In oligotrophic ocean gyres, P_i concentrations are extremely low (0.2–1.0 nM in the Sargasso Sea; ref. 2) and the availability of P_i can limit bacterial and primary production (2–5). Microbes inhabiting these low P_i environments have evolved numerous strategies to maintain growth and enhance their competitiveness for trace amounts of P_i. These mechanisms are commonly induced by P_i starvation and include one or more of the following: (i) expression of high affinity P_i transporters (6); (ii) reduction of cellular P_i quotas (7, 8); (iii) utilization of alternate phosphorus sources (9, 10); and (iv) polyphosphate storage and breakdown (11, 12). Such strategies facilitate survival in the face of P_i insufficiency.Polar membrane lipids are a substantial cellular sink for phosphate in bacteria. Structural lipids consist of glycerol esterified to hydrophobic fatty acid chains (diacylglycerol) and a hydrophilic polar head group, which commonly contains P_i (phospholipids). When grown with sufficient P_i, phospholipids in Gram-negative marine bacteria frequently include phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and diphosphatidylglycerol (13). However, when P_i is low or limiting, many microbes replace phospholipids with those that lack phosphorus (14–16). Nonphosphorus polar head groups are structurally diverse and include sulfoquinovose (sulfolipids) (17), various monosaccharides and disaccharides (glycolipids; reviewed in ref. 18), ornithine, or other amino acids (reviewed in ref. 19). When P_i stressed, the marine cyanobacteria Prochlorococcus and Synechococcus reduce their P_i demand by 0.5–8.6 attomoles P per cell by substituting phosphorus-containing lipids with sulfolipids; depending on the strain, this reduction equates to 10–86% of the P bound in their nucleic acids (7). There is indirect evidence natural populations of marine chemoheterotrophic bacteria also use nonphosphorus lipids in response to P_i deprivation. Bacterioplankton collected in the Sargasso Sea had greater concentrations of nonphosphorus lipids than those from adjacent regions of the North Atlantic where P_i was relatively abundant (20).Oligotrophic bacteria belonging to the SAR11 clade (Pelagibacterales) of α-proteobacteria are numerically dominant chemoheterotrophs in marine euphotic zones worldwide (21). Pelagibacterales cells are small (volume of 0.01 μm³; ref. 22) and contain streamlined genomes (23, 24). The reduced cell and genome size likely stem from natural selection to reduce the overhead cost of replication in oligotrophic ocean gyres where P and N may periodically limit growth (25, 26). Despite their abundance in low P_i environments, it remains unknown whether Pelagibacterales synthesize phosphorus-free lipids to reduce their P quota. The genome of Pelagibacter ubique str. HTCC1062 lacks genes predicted to encode proteins used in sulfolipid, betaine, or ornithine lipid biosynthesis, suggesting this strain is unable to modulate lipid composition in response to P_i availability (7, 8). Previous laboratory experiments partially supported this prediction by showing that P. ubique lacks nonphosphorus lipids when grown under P_i replete conditions; however, lipids from P_i limited cells were not examined in that research (7). Relative to P. ubique, a Sargasso Sea isolate, Pelagibacter sp. str. HTCC7211 (str. HTCC7211) contains extended genetic inventory associated with P_i acquisition, storage, and metabolism (10). When P_i limited, str. HTCC7211 induces a suite of these genes, including both inorganic (pstSCAB) and organophosphate (phnCDEE₂) ABC transporters and the C–P lyase complex (phnGHIJKLNM), required for phosphonate degradation (10). Laboratory experiments have distinctly linked the expression of these genes to the utilization of both phosphate esters and phosphonates (including methylphosphonate; MPn) (10). This finding indicates organophosphate utilization is one strategy str. HTCC7211 employs to evade P_i growth limitation.While examining gene expression profiles of P_i starved str. HTCC7211 cultures, we observed the unexpected up-regulation of a four gene cluster proximal to the collection of P uptake genes on the str. HTCC7211 chromosome. Two of the genes were annotated as “putative hemolysins,” one as a “glycosyltransferase,” and a “metallophosphatase.” Comparative genomic examination of these genes led us to hypothesize that the four genes might be involved in the restructuring of lipid polar head groups and the synthesis of nonphosphorus lipids. Herein, we present the results of laboratory experiments designed to test the potential for synthesis of nonphosphorus lipids in response to P_i stress by Pelagibacter.     

Longitudinal Patterns of Predominant Asthma Disease Activity in Pediatric Patients Enrolled in an Asthma-Specific Disease Management Program

To determine if patterns of predominant asthma disease activity are more closely related than baseline asthma severity to measures of morbidity (acute asthma attack, emergency room visit/hospitalization, missed school days, and/or steroid burst). Retrospective analysis was performed for inner-city Los Angeles asthmatic children (3 to 18 years of age) during their first year of enrollment in an asthma-specific disease management program. All measures of morbidity were more closely related to patterns of predominant disease activity than baseline severity. We conclude that patterns of predominant disease activity are a more significant predictor of asthma morbidity than is baseline severity.     

Versatile effects of sildenafil: recent pharmacological applications

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfunction, sildenafil also provides a prolonged benefit in various other diseases. Sildenafil has been shown to have a potential therapeutic efficacy for disorders related to the central nervous system and pulmonary system. In the central nervous system, it exerts its neuroprotective effects in multiple sclerosis and has a significant memory enhancing action. Sildenafil also significantly enhances neurogenesis. Several lines of evidence indicate that targeting PDE5 with sildenafil offers novel strategies in the treatment of age-related memory impairment. Guanylate cyclase/cGMP/protein kinase G pathway or glutamate/nitric oxide/cGMP pathway appears to mediate memory enhancing effects. Some of the positive cognitive features of sildenafil therapy are likely attributable to the mechanisms reviewed here. Sildenafil has been shown to reduce pulmonary hypertension and alleviate pain in animals and humans. The present review primarily focuses on the various pharmacological effects of sildenafil with regard to its influence on the nervous and pulmonary system.     

Factors contributing to relapse in rigidly fixed mandibular setbacks

The incidence of, and factors accounting for, relapse in 25 subjects who underwent mandibular setbacks via a bilateral sagittal split osteotomy with rigid fixation were studied. Fourteen had single-jaw operations, and the remaining 11 had concomitant maxillary procedures. Cephalometric radiographs were reviewed preoperatively, immediately postoperatively, and 6 months to 3 years after surgery. Relapse was defined as forward movement of pogonion during the postoperative period. No difference in the movement of the mandible in one- or two-jaw cases was noted. Even with excellent occlusal results, there was a tendency for the mandible (chin point) to rotate forward. In the one-jaw cases 43.7% relapse was noted, whereas 53.4% was seen in the two-jaw cases. A regression analysis showed that the magnitude of setback was the single factor that significantly predicted relapse in one-jaw cases, whereas alteration of the proximal segment accounted for relapse in two-jaw procedures. These results seem interrelated when considering alterations in the spatial arrangement of the muscular tissues and their attachments.     

Performance of seven blood glucose testing systems at high altitude

Consumers and health care professionals expect blood glucose monitoring systems to consistently generate results that are close to actual blood glucose levels. Numerous environmental, physiologic, and operational factors can affect system performance, yielding results that are inaccurate or unpredictable. This study examined the effect of one factor--high altitude--on the performance of seven blood glucose monitoring systems. One of the systems overestimated blood glucose results; the other six systems underestimated blood glucose values (more than the expected variance). The findings of this study support previous reports of altered blood glucose monitoring system performance at high altitude. Diabetes educators can use this information when counseling consumers who reside or who plan to visit locations at high altitude.