Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

<p>Abstract</p> <p>Purpose</p> <p>Microglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.</p> <p>Methods</p> <p>Mouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative <it>in vivo </it>analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.</p> <p>Results</p> <p>Our results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated <it>in vitro </it>(1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. <it>In vivo </it>activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.</p> <p>Conclusion</p> <p>Our findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.</p

A Hybrid Multi-objective Genetic Algorithm for Bi-objective Time Window Assignment Vehicle Routing Problem

Providing a satisfying delivery service is an important way to maintain the customers’ loyalty and further expand profits for manufacturers and logistics providers. Considering customers’ preferences for time windows, a bi-objective time window assignment vehicle routing problem has been introduced to maximize the total customers’ satisfaction level for assigned time windows and minimize the expected delivery cost. The paper designs a hybrid multi-objective genetic algorithm for the problem that incorporates modified stochastic nearest neighbour and insertion-based local search. Computational results show the positive effect of the hybridization and satisfactory performance of the metaheuristics. Moreover, the impacts of three characteristics are analysed including customer distribution, the number of preferred time windows per customer and customers’ preference type for time windows. Finally, one of its extended problems, the bi-objective time window assignment vehicle routing problem with time-dependent travel times has been primarily studied.</p

Comparative venom gland transcriptome analysis of the scorpion Lychas mucronatus reveals intraspecific toxic gene diversity and new venomous components

<p>Abstract</p> <p>Background</p> <p><it>Lychas mucronatus </it>is one scorpion species widely distributed in Southeast Asia and southern China. Anything is hardly known about its venom components, despite the fact that it can often cause human accidents. In this work, we performed a venomous gland transcriptome analysis by constructing and screening the venom gland cDNA library of the scorpion <it>Lychas mucronatus </it>from Yunnan province and compared it with the previous results of Hainan-sourced <it>Lychas mucronatus</it>.</p> <p>Results</p> <p>A total of sixteen known types of venom peptides and proteins are obtained from the venom gland cDNA library of Yunnan-sourced <it>Lychas mucronatus</it>, which greatly increase the number of currently reported scorpion venom peptides. Interestingly, we also identified nineteen atypical types of venom molecules seldom reported in scorpion species. Surprisingly, the comparative transcriptome analysis of Yunnan-sourced <it>Lychas mucronatus </it>and Hainan-sourced <it>Lychas mucronatus </it>indicated that enormous diversity and vastly abundant difference could be found in venom peptides and proteins between populations of the scorpion <it>Lychas mucronatus </it>from different geographical regions.</p> <p>Conclusions</p> <p>This work characterizes a large number of venom molecules never identified in scorpion species. This result provides a comparative analysis of venom transcriptomes of the scorpion <it>Lychas mucronatus </it>from different geographical regions, which thoroughly reveals the fact that the venom peptides and proteins of the same scorpion species from different geographical regions are highly diversified and scorpion evolves to adapt a new environment by altering the primary structure and abundance of venom peptides and proteins.</p

Expecting Floods: Firm Entry, Employment, and Aggregate Implications

Flood events and flood risk have been increasing in the past few decades and have important consequences on the economy. Using county-level and ZIP-code-level data during 1998–2018 from the U.S., we document that (1) increased flood risk has large negative impacts on firm entry, employment and output in the long run; (2) flood events reduce output in the short run while their impact on firm entry and employment is limited. Motivated by these findings, we construct a spatial equilibrium model to characterize how flood risk shapes firms’ location choices and workers’ employment, which we use to estimate the aggregate impact of increased flood risk on the economy. We find that flood risk reduced U.S. aggregate output by 0.52 percent in 2018, 80% of which stemmed from expectation effects and 20% from direct damages. We also apply our model to studying the distributional consequences and forecasting the impact of future changes in flood risk. Our results highlight the importance of considering the adjustment of firms and workers in response to risk in evaluating the consequences of natural disasters

7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration.

Age-related macular degeneration (AMD) has been associated with both accumulation of lipid and lipid oxidative products, as well as increased neuroinflammatory changes and microglial activation in the outer retina. However, the relationships between these factors are incompletely understood. 7-Ketocholesterol (7KCh) is a cholesterol oxidation product localized to the outer retina with prominent pro-inflammatory effects. To explore the potential relationship between 7KCh and microglial activation, we localized 7KCh and microglia to the outer retina of aged mice and investigated 7KCh effects on retinal microglia in both in vitro and in vivo systems. We found that retinal microglia demonstrated a prominent chemotropism to 7KCh and readily internalized 7KCh. Sublethal concentrations of 7KCh resulted in microglial activation and polarization to a pro-inflammatory M1 state via NLRP3 inflammasome activation. Microglia exposed to 7KCh reduced expression of neurotrophic growth factors but increased expression of angiogenic factors, transitioning to a more neurotoxic and pro-angiogenic phenotype. Finally, subretinal transplantation of 7KCh-exposed microglia promoted choroidal neovascularization (CNV) relative to control microglia in a Matrigel-CNV model. The interaction of retinal microglia with 7KCh in the aged retina may thus underlie how outer retinal lipid accumulation in intermediate AMD results in neuroinflammation that ultimately drives progression towards advanced AMD

Microglia in the Mouse Retina Alter the Structure and Function of Retinal Pigmented Epithelial Cells: A Potential Cellular Interaction Relevant to AMD

BACKGROUND:Age-related macular degeneration (AMD) is a leading cause of legal blindness in the elderly in the industrialized word. While the immune system in the retina is likely to be important in AMD pathogenesis, the cell biology underlying the disease is incompletely understood. Clinical and basic science studies have implicated alterations in the retinal pigment epithelium (RPE) layer as a locus of early change. Also, retinal microglia, the resident immune cells of the retina, have been observed to translocate from their normal position in the inner retina to accumulate in the subretinal space close to the RPE layer in AMD eyes and in animal models of AMD. METHODOLOGY/PRINCIPAL FINDINGS:In this study, we examined the effects of retinal microglia on RPE cells using 1) an in vitro model where activated retinal microglia are co-cultured with primary RPE cells, and 2) an in vivo mouse model where retinal microglia are transplanted into the subretinal space. We found that retinal microglia induced in RPE cells 1) changes in RPE structure and distribution, 2) increased expression and secretion of pro-inflammatory, chemotactic, and pro-angiogenic molecules, and 3) increased extent of in vivo choroidal neovascularization in the subretinal space. CONCLUSIONS/SIGNIFICANCE:These findings share similarities with important pathological features found in AMD and suggest the relevance of microglia-RPE interactions in AMD pathogenesis. We speculate that the migration of retinal microglia into the subretinal space in early stages of the disease induces significant changes in RPE cells that perpetuate further microglial accumulation, increase inflammation in the outer retina, and fosters an environment conducive for the formation of neovascular changes responsible for much of vision loss in advanced AMD

Novel Ionic Liquid with Both Lewis and Brønsted Acid Sites for Michael Addition

Ionic liquid with both Lewis and Brønsted acid sites has been synthesized and its catalytic activities for Michael addition were carefully studied. The novel ionic liquid was stable to water and could be used in aqueous solution. The molar ratio of the Lewis and Brønsted acid sites could be adjusted to match different reactions. The results showed that the novel ionic liquid was very efficient for Michael addition with good to excellent yields within several min. Operational simplicity, high stability to water and air, small amount used, low cost of the catalyst used, high yields, chemoselectivity, applicability to large-scale reactions and reusability are the key features of this methodology, which indicated that this novel ionic liquid also holds great potential for environmentally friendly processes