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11.
Ebola virus entry requires the cholesterol transporter Niemann-Pick C1   总被引:1,自引:0,他引:1  
Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.  相似文献   
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Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.  相似文献   
14.
Red giants are evolved stars that have exhausted the supply of hydrogen in their cores and instead burn hydrogen in a surrounding shell. Once a red giant is sufficiently evolved, the helium in the core also undergoes fusion. Outstanding issues in our understanding of red giants include uncertainties in the amount of mass lost at the surface before helium ignition and the amount of internal mixing from rotation and other processes. Progress is hampered by our inability to distinguish between red giants burning helium in the core and those still only burning hydrogen in a shell. Asteroseismology offers a way forward, being a powerful tool for probing the internal structures of stars using their natural oscillation frequencies. Here we report observations of gravity-mode period spacings in red giants that permit a distinction between evolutionary stages to be made. We use high-precision photometry obtained by the Kepler spacecraft over more than a year to measure oscillations in several hundred red giants. We find many stars whose dipole modes show sequences with approximately regular period spacings. These stars fall into two clear groups, allowing us to distinguish unambiguously between hydrogen-shell-burning stars (period spacing mostly ~ 50 seconds) and those that are also burning helium (period spacing ~ 100 to 300 seconds).  相似文献   
15.
Sosulski DL  Bloom ML  Cutforth T  Axel R  Datta SR 《Nature》2011,472(7342):213-216
Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. Here we investigate how this ordered representation is transformed in higher olfactory centres in mice. We have developed a tracing strategy to define the neural circuits that convey information from individual glomeruli in the olfactory bulb to the piriform cortex and the cortical amygdala. The spatial order in the bulb is discarded in the piriform cortex; axons from individual glomeruli project diffusely to the piriform without apparent spatial preference. In the cortical amygdala, we observe broad patches of projections that are spatially stereotyped for individual glomeruli. These projections to the amygdala are overlapping and afford the opportunity for spatially localized integration of information from multiple glomeruli. The identification of a distributive pattern of projections to the piriform and stereotyped projections to the amygdala provides an anatomical context for the generation of learned and innate behaviours.  相似文献   
16.
Wu H  D'Alessio AC  Ito S  Xia K  Wang Z  Cui K  Zhao K  Sun YE  Zhang Y 《Nature》2011,473(7347):389-393
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A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut–brain interaction, inflammatory bowel diseases, and colorectal cancer.

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19.
Acromyrmex balzani is a grass-cutting ant species frequently found in Cerrado areas. However, little is known about the architecture of the polydomous nests of this ant. Fifteen A. balzani nests located in a cerrado region in Botucatu, São Paulo, Brazil, were studied. The polydomous nests were studied in three ways. First, we investigated the architecture in nests moulded with cement and without moulding. Second, we performed an aggressiveness test among workers in different subnests and nests. Third, we excavated the nest and collected the colony to measure the population, verifying the existence or not of a queen in all nests. A cement mould was made of seven nests to permit better visualization of internal structures such as chambers and tunnels. Eight nests were excavated without moulding and white neutral talc was used to highlight the parts of the nests. After excavation, the depth and dimensions (length, width and height) of the chambers were measured. The results showed that the nests had a single entrance hole whose structure consisted of straw and other plant residues in winter. Mounds of loose soil, if present, were found 6–48 cm from the hole. The number of chambers containing fungus ranged from one to five, with the first being found a few centimetres beneath the ground surface (4 cm) and the last up to a maximum depth of 160 cm. The length of the tunnels ranged from 12 to 28 cm. These tunnels were built in a vertical or inclined position, leading to the chambers. No waste chambers were found, with the waste being deposited externally. Additionally, the polydomous nests contained one to eight subnests. In the aggressiveness test, when concolonial workers were confronted, no aggressiveness was observed. In contrast, when allocolonial workers were confronted, there was a high incidence of aggression among them. Excavation of polydomous nests showed only one queen for each polydomous nest, i.e. subnests with a single queen. Our study contributes to a better understanding of the so far unknown nest architecture of the polydomous grass-cutting ant A. balzani.  相似文献   
20.
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.  相似文献   
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