Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal

Background

Characteristic symptoms of malaria include recurrent fever attacks and neurodegeneration, signs that are also found in patients with a hyperactive Nalp3 inflammasome. Plasmodium species produce a crystal called hemozoin that is generated by detoxification of heme after hemoglobin degradation in infected red blood cells. Thus, we hypothesized that hemozoin could activate the Nalp3 inflammasome, due to its particulate nature reminiscent of other inflammasome-activating agents.

Methodology/Principal Findings

We found that hemozoin acts as a proinflammatory danger signal that activates the Nalp3 inflammasome, causing the release of IL-1β. Similar to other Nalp3-activating particles, hemozoin activity is blocked by inhibiting phagocytosis, K⁺ efflux and NADPH oxidase. In vivo, intraperitoneal injection of hemozoin results in acute peritonitis, which is impaired in Nalp3-, caspase-1- and IL-1R-deficient mice. Likewise, the pathogenesis of cerebral malaria is dampened in Nalp3-deficient mice infected with Plasmodium berghei sporozoites, while parasitemia remains unchanged.

Significance/Conclusions

The potent pro-inflammatory effect of hemozoin through inflammasome activation may possibly be implicated in plasmodium-associated pathologies such as cerebral malaria.     

Interaction of alcohols with serum LDL An infrared study

The interaction of low molecular weight alcohols with low density lipoprotein (LDL) has been studied using amide I band-fitting, thermal profiling and two-dimensional infrared correlation spectroscopy (2D-IR). At 0.3 M alcohol, no changes in secondary structure are observed. In the presence of 1 M alcohol, ethanol and propanol decreases protein denaturation temperature and produces changes in the amide I thermal profiles of protein components and in the lipid bands. The 2D-IR synchronous map corresponding to protein or lipid component at 20-37 degrees C suggests differences in the presence of propanol. The asynchronous map corresponding to the lipid component indicates changes in bandwidth, compatible with a more fluid environment. In the 37-80 degrees C temperature range the thermal profile is different in the presence of propanol, both for the lipid and protein components. The results presented show that when alcohols affect the protein component, the lipid spectrum also varies pointing to an effect on the lipid-protein interaction.     

Development and characterization of stable sediment-free anaerobic bacterial enrichment cultures that dechlorinate aroclor 1260

We have developed sediment-free anaerobic enrichment cultures that dechlorinate a broad spectrum of highly chlorinated polychlorinated biphenyls (PCBs). The cultures were developed from Aroclor 1260-contaminated sediment from the Housatonic River in Lenox, MA. Sediment slurries were primed with 2,6-dibromobiphenyl to stimulate Process N dechlorination (primarily meta dechlorination), and sediment was gradually removed by successive transfers (10%) to minimal medium. The cultures grow on pyruvate, butyrate, or acetate plus H(2). Gas chromatography-electron capture detector analysis demonstrated that the cultures extensively dechlorinate 50 to 500 mug/ml of Aroclor 1260 at 22 to 24 degrees C by Dechlorination Process N. Triplicate cultures of the eighth transfer without sediment dechlorinated 76% of the hexa- through nonachlorobiphenyls in Aroclor 1260 (250 mug/ml) to tri- through pentachlorobiphenyls in 110 days. At least 64 PCB congeners, all of which are chlorinated on both rings and 47 of which have six or more chlorines, were substrates for this dechlorination. To characterize the bacterial diversity in the enrichments, we used eubacterial primers to amplify and clone 16S rRNA genes from DNA extracted from cultures grown on acetate plus H(2). Restriction fragment length polymorphism analysis of 107 clones demonstrated the presence of Thauera-like Betaproteobacteria, Geobacter-like Deltaproteobacteria, Pseudomonas species, various Clostridiales, Bacteroidetes, Dehalococcoides of the Chloroflexi group, and unclassified Eubacteria. Our development of highly enriched, robust, stable, sediment-free cultures that extensively dechlorinate a highly chlorinated commercial PCB mixture is a major and unprecedented breakthrough in the field. It will enable intensive study of the organisms and genes responsible for a major PCB dechlorination process that occurs in the environment and could also lead to effective remediation applications.     

Basal Endothelial Nitric Oxide Release Is Preserved in Overweight and Obese Adults

Objective: Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans. Research Methods and Procedures: Seventy sedentary adults were studied: 32 normal weight (BMI <25 kg/m²), 24 overweight (BMI ≥ 25 < 30 kg/m²), and 14 obese (BMI ≥ 30 kg/m²). Forearm blood flow (FBF) responses to intra‐arterial infusions of N^g‐monomethyl‐l ‐arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release. Results: N^g‐monomethyl‐l ‐arginine elicited significant reductions in FBF in the normal weight (from 4.1 ± 0.2 to 2.7 ± 0.2 mL/100 mL tissue/min), overweight (4.1 ± 0.1 to 2.8 ± 0.2 mL/100 mL tissue/min), and obese (3.9 ± 0.3 to 2.7 ± 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (～30%) was similar among the groups. Discussion: These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults.     

Long Term Effects of Social Deprivation during Early Adulthood in the Mongolian Gerbil (Meriones unguiculatus)

The influence of isolation on ♂-♀♀ relationships was investigated. Animals isolated between 90 and 200 days of age showed more agonistic behaviour in paired encounters than controls. This difference disappeared when the animals had been housed with a cagemate. A secondary isolation late in life resulted in a more rapid onset of agonistic behaviour in the early isolates than in the controls. Thus it is concluded that the early isolation had a lasting influence, which only became evident after renewed isolation treatment.     

Importance of visual cues of conspecifics and predators during the habitat selection of coral reef fish larvae

The study investigated visual recognition of conspecifics and predators by settlement-stage coral reef fish larvae in a set of three experiments using a dual-choice aquarium (Moorea Island). Experiments 1 and 2 were conducted under artificial light conditions. Experiment 3 was conducted under natural light during new and full moon nights. In experiment 1, five out of six species preferred conspecifics rather than heterospecifics (Acanthurus triostegus, Chromis viridis, Ostorhinchus angustatus, Stegastes fasciolatus, Valenciaenna strigata). In experiment 2, three out of six species were repulsed by predators (Mulloidichtys flavolineatus, O. angustatus, V. strigata). In experiment 3 (conducted on one species), A. triostegus was attracted to conspecifics during bright nights, but did not show such behavior during dark nights. Our study raises the question of trade-off for fish larvae to settle during the night with high light intensities to favor the visual recognition of conspecifics and predators, or during darker nights to reduce reef predation.     

Developmental stage on day-5 and fragmentation rate on day-3 can influence the implantation potential of top-quality blastocysts in IVF cycles with single embryo transfer

Background  

In IVF-ICSI cycles with single embryo transfer (SET), embryo selection for transfer is of crucial importance. The present study aimed to define which embryo parameters might be related to the implantation potential of advanced blastocysts.     

Oxygen activation and defence against oxygen toxicity in a psychrophilic bacteroidaceae

When suddenly exposed to air the growth of the obligate anaerobic bacterium of the bacteroidaceae type, strain B6, continues for a few hours before coming to a complete stop. When air is shut off soon after growth has ceased, the organism is able to reestablish anaerobic conditions due to an ability to reduce O₂, and resumes normal growth after another few hours. The O₂ reducing ability of the organism is due to the presence in the cells of a particlebound NADH oxidase, a soluble NADPH oxidase and a soluble pyruvate oxidase. The two pyridine nucleotide oxidase reduce O₂ to H₂O₂, the pyruvate oxidase reduces O₂ to H₂O. Catalase and peroxidase were not detected in anaerobically grown cells. Kinetic studies with cell-free extracts showed that the pyruvate oxidase had a considerably greater affinity (smaller K _m) for O₂ and capacity (higher V _max) for O₂ reduction than the two other oxidases. It is postulated that the pyruvate oxidase acts as a scavenger for O₂, leading to the non-toxic reduction product H₂O, and thus functions as a defense mechanism against oxygen toxicity when the organism is exposed to aerobic condition.Abbreviations PY peptone-yeast extract - PYG PY-glucose - PN pyridine nucleotide - PNH reduced PN - CCCP carbonylcyanide m-chlorophenylhydrazone - DNP 2.4-dinitrophenol     

Differential expression of NLRP3 among hematopoietic cells

Although the importance of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in health and disease is well appreciated, a precise characterization of NLRP3 expression is yet undetermined. To this purpose, we generated a knock-in mouse in which the Nlrp3 coding sequence was substituted for the GFP (enhanced GFP [egfp]) gene. In this way, the expression of eGFP is driven by the endogenous regulatory elements of the Nlrp3 gene. In this study, we show that eGFP expression indeed mirrors that of NLRP3. Interestingly, splenic neutrophils, macrophages, and, in particular, monocytes and conventional dendritic cells showed robust eGFP fluorescence, whereas lymphoid subsets, eosinophils, and plasmacytoid dendritic cells showed negligible eGFP levels. NLRP3 expression was highly inducible in macrophages, both by MyD88- and Trif-dependent pathways. In vivo, when mice were challenged with diverse inflammatory stimuli, differences in both the number of eGFP-expressing cells and fluorescence intensity were observed in the draining lymph node. Thus, NLRP3 levels at the site of adaptive response initiation are controlled by recruitment of NLRP3-expressing cells and by NLRP3 induction.