TNFα induced by DNA-sensing in macrophage compromises retinal pigment epithelial (RPE) barrier function.

Increasing evidence suggests that chronic inflammation plays an important role in the pathogenesis of age-related macular degeneration (AMD); however, the precise pathogenic stressors and sensors, and their impact on disease progression remain unclear. Several studies have demonstrated that type I interferon (IFN) response is activated in the retinal pigment epithelium (RPE) of AMD patients. Previously, we demonstrated that human RPE cells can initiate RNA-mediated type I IFN responses through RIG-I, yet are unable to directly sense and respond to DNA. In this study, we utilized a co-culture system combining primary human macrophage and iPS-derived RPE to study how each cell type responds to nucleic acids challenges and their effect on RPE barrier function in a homotypic and heterotypic manner. We find that DNA-induced macrophage activation induces an IFN response in the RPE, and compromises RPE barrier function via tight-junction remodeling. Investigation of the secreted cytokines responsible for RPE dysfunction following DNA-induced macrophages activation indicates that neutralization of macrophage-secreted TNFα, but not IFNß, is sufficient to rescue RPE morphology and barrier function. Our data reveals a novel mechanism of intercellular communication by which DNA induces RPE dysfunction via macrophage-secreted TNFa, highlighting the complexity and potential pathological relevance of RPE and macrophage interactions.

Hydrothermal enrichment of lithium in intracaldera illite-bearing claystones.

Developing a sustainable supply chain for the global proliferation of lithium ion batteries in electric vehicles and grid storage necessitates the extraction of lithium resources that minimize local environmental impacts. Volcano sedimentary lithium resources have the potential to meet this requirement, as they tend to be shallow, high-tonnage deposits with low waste:ore strip ratios. Illite-bearing Miocene lacustrine sediments within the southern portion of McDermitt caldera (USA) at Thacker Pass contain extremely high lithium grades (up to ~1 weight % of Li), more than double the whole-rock concentration of lithium in smectite-rich claystones in the caldera and other known claystone lithium resources globally (<0.4 weight % of Li). Illite concentrations measured in situ range from ~1.3 to 2.4 weight % of Li within fluorine-rich illitic claystones. The unique lithium enrichment of illite at Thacker Pass resulted from secondary lithium- and fluorine-bearing hydrothermal alteration of primary neoformed smectite-bearing sediments, a phenomenon not previously identified.

Genetic Control of Collective Behavior in Zebrafish.

Many animals, including humans, have evolved to live and move in groups. In humans, disrupted social interactions are a fundamental feature of many psychiatric disorders. However, we know little about how genes regulate social behavior. Zebrafish may serve as a powerful model to explore this question. By comparing the behavior of wild-type fish with 90 mutant lines, we show that mutations of genes associated with human psychiatric disorders can alter the collective behavior of adult zebrafish. We identify three categories of behavioral variation across mutants: "scattered," in which fish show reduced cohesion; "coordinated," in which fish swim more in aligned schools; and "huddled," in which fish form dense but disordered groups. Changes in individual interaction rules can explain these differences. This work demonstrates how emergent patterns in animal groups can be altered by genetic changes in individuals and establishes a framework for understanding the fundamentals of social information processing.

αKlotho Regulates Age-Associated Vascular Calcification and Lifespan in Zebrafish.

The hormone αKlotho regulates lifespan in mice, as knockouts die early of what appears to be accelerated aging due to hyperphosphatemia and soft tissue calcification. In contrast, the overexpression of αKlotho increases lifespan. Given the severe mouse phenotype, we generated zebrafish mutants for αklotho as well as its binding partner fibroblast growth factor-23 (fgf23). Both mutations cause shortened lifespan in zebrafish, with abrupt onset of behavioral and degenerative physical changes at around 5 months of age. There is a calcification of vessels throughout the body, most dramatically in the outflow tract of the heart, the bulbus arteriosus (BA). This calcification is associated with an ectopic activation of osteoclast differentiation pathways. These findings suggest that the gradual loss of αKlotho found in normal aging might give rise to ectopic calcification.

Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine.

Dopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3-/- fish hover near the tank bottom, with a repetitive digging-like behavior. slc6a3-/- fish manifest pruning and cellular loss of particular tyrosine hydroxylase-immunoreactive neurons in the midbrain. Clozapine, an effective therapeutic for treatment-resistant schizophrenia, rescues the abnormal behavior of slc6a3-/- fish. Clozapine also reverses the abnormalities in the A8 region of the mutant midbrain. By RNA sequencing analysis, clozapine increases the expression of erythropoietin pathway genes. Transgenic over-expression of erythropoietin in neurons of slc6a3-/- fish partially rescues the mutant behavior, suggesting a potential mechanistic basis for clozapine's efficacy.

Lithium enrichment in intracontinental rhyolite magmas leads to Li deposits in caldera basins.

The omnipresence of lithium-ion batteries in mobile electronics, and hybrid and electric vehicles necessitates discovery of new lithium resources to meet rising demand and to diversify the global lithium supply chain. Here we demonstrate that lake sediments preserved within intracontinental rhyolitic calderas formed on eruption and weathering of lithium-enriched magmas have the potential to host large lithium clay deposits. We compare lithium concentrations of magmas formed in a variety of tectonic settings using in situ trace-element measurements of quartz-hosted melt inclusions to demonstrate that moderate to extreme lithium enrichment occurs in magmas that incorporate felsic continental crust. Cenozoic calderas in western North America and in other intracontinental settings that generated such magmas are promising new targets for lithium exploration because lithium leached from the eruptive products by meteoric and hydrothermal fluids becomes concentrated in clays within caldera lake sediments to potentially economically extractable levels.Lithium is increasingly being utilized for modern technology in the form of lithium-ion batteries. Here, using in situ measurements of quartz-hosted melt inclusions, the authors demonstrate that preserved lake sediments within rhyolitic calderas have the potential to host large lithium-rich clay deposits.

Post-supereruption recovery at Toba Caldera.

Large calderas, or supervolcanoes, are sites of the most catastrophic and hazardous events on Earth, yet the temporal details of post-supereruption activity, or resurgence, remain largely unknown, limiting our ability to understand how supervolcanoes work and address their hazards. Toba Caldera, Indonesia, caused the greatest volcanic catastrophe of the last 100 kyr, climactically erupting ∼74 ka. Since the supereruption, Toba has been in a state of resurgence but its magmatic and uplift history has remained unclear. Here we reveal that new 14C, zircon U-Th crystallization and (U-Th)/He ages show resurgence commenced at 69.7±4.5 ka and continued until at least ∼2.7 ka, progressing westward across the caldera, as reflected by post-caldera effusive lava eruptions and uplifted lake sediment. The major stratovolcano north of Toba, Sinabung, shows strong geochemical kinship with Toba, and zircons from recent eruption products suggest Toba's climactic magma reservoir extends beneath Sinabung and is being tapped during eruptions.

Effects of night work, sleep loss and time on task on simulated threat detection performance.

STUDY OBJECTIVES: To investigate the effects of night work and sleep loss on a simulated luggage screening task (SLST) that mimicked the x-ray system used by airport luggage screeners. DESIGN: We developed more than 5,800 unique simulated x-ray images of luggage organized into 31 stimulus sets of 200 bags each. 25% of each set contained either a gun or a knife with low or high target difficulty. The 200-bag stimuli sets were then run on software that simulates an x-ray screening system (SLST). Signal detection analysis was used to obtain measures of hit rate (HR), false alarm rate (FAR), threat detection accuracy (A'), and response bias (B"(D)). SETTING: Experimental laboratory study PARTICIPANTS: 24 healthy nonprofessional volunteers (13 women, mean age +/- SD = 29.9 +/- 6.5 years). INTERVENTIONS: Subjects performed the SLST every 2 h during a 5-day period that included a 35 h period of wakefulness that extended to night work and then another day work period after the night without sleep. RESULTS: Threat detection accuracy A' decreased significantly (P < 0.001) while FAR increased significantly (P < 0.001) during night work, while both A' (P = 0.001) and HR decreased (P = 0.008) during day work following sleep loss. There were prominent time-on-task effects on response bias B"(D) (P= 0.002) and response latency (P = 0.004), but accuracy A' was unaffected. Both HR and FAR increased significantly with increasing study duration (both P < 0.001), while response latency decreased significantly (P <0.001). CONCLUSIONS: This study provides the first systematic evidence that night work and sleep loss adversely affect the accuracy of detecting complex real world objects among high levels of background clutter. If the results can be replicated in professional screeners and real work environments, fatigue in luggage screening personnel may pose a threat for air traffic safety unless countermeasures for fatigue are deployed.