AAA ATPases regulate membrane association of yeast oxysterol binding proteins and sterol metabolism

The yeast genome encodes seven oxysterol binding protein homologs, Osh1p-Osh7p, which have been implicated in regulating intracellular lipid and vesicular transport. Here, we show that both Osh6p and Osh7p interact with Vps4p, a member of the AAA (ATPases associated with a variety of cellular activities) family. The coiled-coil domain of Osh7p was found to interact with Vps4p in a yeast two-hybrid screen and the interaction between Osh7p and Vps4p appears to be regulated by ergosterol. Deletion of VPS4 induced a dramatic increase in the membrane-associated pools of Osh6p and Osh7p and also caused a decrease in sterol esterification, which was suppressed by overexpression of OSH7. Lastly, overexpression of the coiled-coil domain of Osh7p (Osh7pCC) resulted in a multivesicular body sorting defect, suggesting a dominant negative role of Osh7pCC possibly through inhibiting Vps4p function. Our data suggest that a common mechanism may exist for AAA proteins to regulate the membrane association of yeast OSBP proteins and that these two protein families may function together to control subcellular lipid transport.     

Icam-1 participates in the entry of west nile virus into the central nervous system

Determining how West Nile virus crosses the blood-brain barrier is critical to understanding the pathogenesis of encephalitis. Here, we show that ICAM-1(-/-) mice are more resistant than control animals to lethal West Nile encephalitis. ICAM-1(-/-) mice have a lower viral load, reduced leukocyte infiltration, and diminished neuronal damage in the brain compared to control animals. This is associated with decreased blood-brain barrier leakage after viral infection. These data suggest that ICAM-1 plays an important role in West Nile virus neuroinvasion and that targeting ICAM-1 signaling may help control viral encephalitis.     

Matrix metalloproteinase 9 facilitates West Nile virus entry into the brain

West Nile virus (WNV) is the most-common cause of mosquito-borne encephalitis in the United States. Invasion of the brain by WNV is influenced by viral and host factors, and the molecular mechanism underlying disruption of the blood-brain barrier is likely multifactorial. Here we show that matrix metalloproteinase 9 (MMP9) is involved in WNV entry into the brain by enhancing blood-brain barrier permeability. Murine MMP9 expression was induced in the circulation shortly after WNV infection, and the protein levels remained high even when viremia subsided. In the murine brain, MMP9 expression and its enzymatic activity were upregulated and MMP9 was shown to partly localize to the blood vessels. Interestingly, we also found that cerebrospinal fluid from patients suffering from WNV contained increased MMP9 levels. The peripheral viremia and expression of host cytokines were not altered in MMP9(-/-) mice; however, these animals were protected from lethal WNV challenge. The resistance of MMP9(-/-) mice to WNV infection correlated with an intact blood-brain barrier since immunoglobulin G, Evans blue leakage into brain, and type IV collagen degradation were markedly reduced in the MMP9(-/-) mice compared with their levels in controls. Consistent with this, the brain viral loads, selected inflammatory cytokines, and leukocyte infiltrates were significantly reduced in the MMP9(-/-) mice compared to their levels in wild-type mice. These data suggest that MMP9 plays a role in mediating WNV entry into the central nervous system and that strategies to interrupt this process may influence the course of West Nile encephalitis.     

Complement-Related Proteins Control the Flavivirus Infection of Aedes aegypti by Inducing Antimicrobial Peptides

The complement system functions during the early phase of infection and directly mediates pathogen elimination. The recent identification of complement-like factors in arthropods indicates that this system shares common ancestry in vertebrates and invertebrates as an immune defense mechanism. Thioester (TE)-containing proteins (TEPs), which show high similarity to mammalian complement C3, are thought to play a key role in innate immunity in arthropods. Herein, we report that a viral recognition cascade composed of two complement-related proteins limits the flaviviral infection of Aedes aegypti. An A. aegypti macroglobulin complement-related factor (AaMCR), belonging to the insect TEP family, is a crucial effector in opposing the flaviviral infection of A. aegypti. However, AaMCR does not directly interact with DENV, and its antiviral effect requires an A. aegypti homologue of scavenger receptor-C (AaSR-C), which interacts with DENV and AaMCR simultaneously in vitro and in vivo. Furthermore, recognition of DENV by the AaSR-C/AaMCR axis regulates the expression of antimicrobial peptides (AMPs), which exerts potent anti-DENV activity. Our results both demonstrate the existence of a viral recognition pathway that controls the flaviviral infection by inducing AMPs and offer insights into a previously unappreciated antiviral function of the complement-like system in arthropods.     

Lipases secreted by a gut bacterium inhibit arbovirus transmission in mosquitoes

Arboviruses are etiological agents of various severe human diseases that place a tremendous burden on global public health and the economy; compounding this issue is the fact that effective prophylactics and therapeutics are lacking for most arboviruses. Herein, we identified 2 bacterial lipases secreted by a Chromobacterium bacterium isolated from Aedes aegypti midgut, Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with broad-spectrum virucidal activity against mosquito-borne viruses, such as dengue virus (DENV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), yellow fever virus (YFV) and Sindbis virus (SINV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation in the lipase motif of CbAE-1 fully abrogated the virucidal ability. Furthermore, CbAEs also exert lipase-dependent entomopathogenic activity in mosquitoes. The anti-arboviral and entomopathogenic properties of CbAEs render them potential candidates for the development of novel transmission control strategies against vector-borne diseases.     

海口市生态用地变化与安全格局构建

城市化过程中,城市生态用地变化与安全格局构建对于城市生态系统健康、城市居民生活质量和城市可持续发展有着重要意义,生态用地的变化直接影响生态安全格局变化,生态用地安全格局又对生态用地的规划有指导作用。基于GIS技术,对海口市1991年至2016年生态用地的时空变化过程进行研究,进而分析生态用地演变。选取高度、坡度、水资源安全作为生态安全影响单因子,并分级赋值,构建综合生态用地分布格局。以底线型生态用地为源,基于最小累计阻力模型(MCR),以阻力阈值作为分级边界,划分不同安全水平的生态用地区域,进而确定源间生态廊道、辐射道与战略点,构建生态用地安全格局。分析结果表明:1991年至2016年,海口市三类生态用地变化最大,其中林地减少13.33%,园地增加9.136%,坑塘水面增加3.71%。南渡江以西生态用地从以林地为主转为园地与建设用地为主,其余地区变化较少。生态用地安全变化区域集中在海口市西部与东部,其中西部高安全水平区减少,整体安全水平急剧恶化,东部高安全水平区略有提升。故需要制定和实施合理的生态用地保护政策,对生态用地格局进行优化调整,以期构建区域内生态环境协调发展的可行方案。     

Galanin and its receptors: a novel strategy for appetite control and obesity therapy

The rapid increase in the prevalence of overweight and obesity is becoming an important health problem. Overweight and obesity may cause several metabolic complications, including type 2 diabetes mellitus, hyperlipidemia, high cholesterol, coronary artery disease as well as hypertension. Prevention and treatment of obesity will benefit the treatment of these related diseases. Current strategies for treatment of obesity are not adequately effective and are frequently companied with many side effects. Thus, new ways to treat obesity are urgently needed. Galanin is undoubtedly involved in the regulation of food intake and body weight. The aim of this review is to provide up-to-date knowledge concerning the roles of central and peripheral galanin as well as its receptors in the regulation of metabolism, obesity and appetite. We also highlight the mechanisms of galanin and its receptors in experimental obesity, trying to establish a novel anti-obesity strategy.     

An in vivo transfection approach elucidates a role for Aedes aegypti thioester-containing proteins in flaviviral infection

Mosquitoes transmit pathogens that cause infectious diseases of global importance. Techniques to easily introduce genes into mosquitoes, however, limit investigations of the interaction between microbes and their arthropod vectors. We now show that a cationic liposome significantly enhances delivery and expression of plasmid DNA in Aedes aegypti and Anopheles gambiae mosquitoes. We then introduced the genes for Ae. aegypti thioester-containing proteins (AeTEPs), which are involved in the control of flaviviral infection, into mosquitoes using this technique. In vivo transfection of AeTEP-1 into Ae. aegypti significantly reduced dengue virus infection, suggesting that the approach can further our understanding of pathogen-mosquito interactions.