An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection

Herpes simplex virus 2 (HSV-2) infection causes significant morbidity and is an important cofactor for the transmission of HIV infection. A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.     

Chicken welfare is influenced more by housing conditions than by stocking density

Intensive broiler (meat) chicken production now exceeds 800 million birds each year in the United Kingdom and 2 x 10(10) birds worldwide, but it attracts accusations of poor welfare. The European Union is currently adopting standards for broilers aimed at a chief welfare concern--namely, overcrowding--by limiting maximum 'stocking density' (bird weight per unit area). It is not clear, however, whether this will genuinely improve bird welfare because evidence is contradictory. Here we report on broiler welfare in relation to the European Union proposals through a large-scale study (2.7 million birds) with the unprecedented cooperation of ten major broiler producers in an experimental manipulation of stocking density under a range of commercial conditions. Producer companies stocked birds to five different final densities, but otherwise followed company practice, which we recorded in addition to temperature, humidity, litter and air quality. We assessed welfare through mortality, physiology, behaviour and health, with an emphasis on leg health and walking ability. Our results show that differences among producers in the environment that they provide for chickens have more impact on welfare than has stocking density itself.     

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses, may be a feature shared by the virulent influenza viruses.     

NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats

Acidic amino acids, such as glutamate and aspartate, are thought to be excitatory transmitters in the cerebral neocortex and hippocampus. Receptors for these amino acids can be classified into at least three types on the basis of their agonists. Quisqualate-preferring receptors and kainate-preferring receptors are implicated in the mediation of synaptic transmission in many regions including the hippocampus and visual cortex, whereas N-methyl-D-aspartate (NMDA)-preferring receptors are thought to be involved in modulating synaptic efficacy, for example in longterm potentiation, a form of synaptic plasticity in the hippocampus. In the visual cortex of the cat and monkey, it is well established that synaptic plasticity, estimated by susceptibility of binocular responsiveness of cortical neurons to monocular visual deprivation, disappears after the 'critical' period of postnatal development. Here we report that during the critical period in young kittens, a selective NMDA-receptor antagonist blocks visual responses of cortical neurons much more effectively than it does in the adult cat. This suggests that NMDA receptors may be involved in establishing synaptic plasticity in the kitten visual cortex.     

The condensing vacuole of exocrine cells is more acidic than the mature secretory vesicle

A number of intracellular, membrane-bound compartments in both the endocytic and exocytic pathways of eukaryotic cells have an acidic internal pH. In endocrine cells, the mature secretory vesicle has an acidic pH; secretory vesicles isolated from exocrine cells, however, appear to have a neutral pH. Recently we have used a newly developed immunocytochemical technique to map low-pH compartments in insulin-secreting islet cells with the electron microscope and find that during the maturation of the secretory vesicle there is a progressive acidification of these vesicles that begins as soon as the trans Golgi condensing vacuoles form. Now we have used this technique to examine two exocrine cells: the pancreatic acinar cell and the parotid serous cell. In both cell types, the trans Golgi condensing vacuoles are acidic and accumulate the low-pH probe to the same extent as condensing vacuoles of insulin-secreting islet cells. Unlike insulin-secreting cells, however, maturation of the granules is accompanied by a return of luminal pH to near neutrality. Therefore, although the pH of storage granules in exocrine and endocrine cells is different, the pH of the condensing vacuoles in both cells is acidic.     

分子轨道理论能够说明O2+比O2更稳定吗

根据MOT，讨论了O2和O2^＋键级、键能的大小，指出：并不能根据键能的大小判断它们的热力学相对稳定性．因为它们没有可比性。     

Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection

Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that antiviral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the amino-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for antiviral therapy.     

The expression of morphine-induced behavioral sensitization depends more on treatment regimen and environmental novelty than on conditioned drug effects

Both conditioned responses (CRs) and sensitized behaviors induced by addictive drugs are considered to reflect drug-seeking motivation. Based on an excitatory conditioning model of behavioral sensitization, this work hypothesizes that conditioned locomotor activity and locomotor sensitization concomitantly occur using different drug treatment regimens. In the present study, conditioned locomotor activity and sensitized locomotion and stereotypy are assessed with pretreatment of two doses of morphine in a familiar or novel environment. When rats are trained with morphine (3 or 5 mg/kg) in an environment to which the animals are habituated, a CR but not contextual sensitization is induced when tested after 1 week of abstinence. When rats receive the 5 mg/kg dose of morphine immediately after placement into a novel environment, the same results are obtained, but when the drug dose is decreased to 3 mg/kg, both the CR and contextual sensitization are observed. Therefore, the sensitized behaviors, rather than the CR produced by morphine pretreatment, appear to be dependent on the drug treatment regimen and environmental novelty, suggesting that different mechanisms may be involved in the expression of the CR and contextual sensitization.