A bacterial dynamin-like protein

Dynamins form a superfamily of large mechano-chemical GTPases that includes the classical dynamins and dynamin-like proteins (DLPs). They are found throughout the Eukarya, functioning in core cellular processes such as endocytosis and organelle division. Many bacteria are predicted by sequence to possess large GTPases with the same multidomain architecture that is found in DLPs. Mechanistic dissection of dynamin family members has been impeded by a lack of high-resolution structural data currently restricted to the GTPase and pleckstrin homology domains, and the dynamin-related human guanylate-binding protein. Here we present the crystal structure of a cyanobacterial DLP in both nucleotide-free and GDP-associated conformation. The bacterial DLP shows dynamin-like qualities, such as helical self-assembly and tubulation of a lipid bilayer. In vivo, it localizes to the membrane in a manner reminiscent of FZL, a chloroplast-specific dynamin-related protein with which it shares sequence similarity. Our results provide structural and mechanistic insight that may be relevant across the dynamin superfamily. Concurrently, we show compelling similarity between a cyanobacterial and chloroplast DLP that, given the endosymbiotic ancestry of chloroplasts, questions the evolutionary origins of dynamins.     

Spider toxins activate the capsaicin receptor to produce inflammatory pain

Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the pain pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit pain and inflammation.     

Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans

Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.     

Geochemistry: how well can Pb isotopes date core formation?

Timescale and the physics of planetary core formation are essential constraints for models of Earth's accretion and early differentiation. Wood and Halliday use the apparent mismatch in core-formation dates determined from tungsten (W) and lead (Pb) chrono-meters to argue for a two-stage core formation, involving an early phase of metal segregation followed by a protracted episode of sulphide melt addition. However, we show here that crust-;mantle Pb isotope systematics do not require diachronous core formation. Our observations indicate that very early (< or = 35 Myr) core formation and planet accretion remain the most plausible scenario.     

大学数学课堂教学中学生心理因素的分析

论述了随着教学改革的不断深入,在大学数学课堂教学中分析学生心理因素的重要性,应用模糊数学中二元对比排序法对其不同时刻的心理因素活动建立了动态轨迹,并用模糊熵分析各因素的重要程度,以此优化数学课堂教学.     

Light-avoidance-mediating photoreceptors tile the Drosophila larval body wall

Photoreceptors for visual perception, phototaxis or light avoidance are typically clustered in eyes or related structures such as the Bolwig organ of Drosophila larvae. Unexpectedly, we found that the class IV dendritic arborization neurons of Drosophila melanogaster larvae respond to ultraviolet, violet and blue light, and are major mediators of light avoidance, particularly at high intensities. These class IV dendritic arborization neurons, which are present in every body segment, have dendrites tiling the larval body wall nearly completely without redundancy. Dendritic illumination activates class IV dendritic arborization neurons. These novel photoreceptors use phototransduction machinery distinct from other photoreceptors in Drosophila and enable larvae to sense light exposure over their entire bodies and move out of danger.     

RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.     

Prenatal and early life home environment exposure in relation to preschool children’s asthma, allergic rhinitis and eczema in Taiyuan, China

Prenatal and early life home environment might be related to children’s asthma or allergic diseases later in life.A cross-sectional epidemiological study was designed and a questionnaire survey was performed in 3700 preschool children in urban areas in Taiyuan,Shanxi Province,China.Questions on children’s asthma and allergic diseases from the International Study on Asthma and Allergies in Childhood(ISAAC)were integrated with questions on home environment from the Swedish Dampness in Buildings and Health(DBH)study,appropriately modified for Chinese life habits.By multivariate regression analyses controlling for age,gender,heredity,location in urban/suburban or rural areas,environmental tobacco smoke(ETS)and breastfeeding,we found that home new furniture(HNF)before birth(referring to 1 year before pregnancy and during pregnancy)was positively associated with wheezing ever(odds ratio(OR)1.23 with 95%CI of 1.03–1.48)and wheezing last 12 months(1.24,1.00–1.54),allergic rhinitis(AR)(1.26,1.06–1.51),and eczema(1.42,1.01–1.99).HNF between 0–1 years old was also positively associated with wheezing last 12 months.Home new decoration(HND)during 0–1 years old was positively associated with AR symptoms and eczema symptoms,more in the last 12 months.Stronger positive associations were found for signs of home mold and dampness with almost all children’s asthmatic and allergic symptoms(OR ranging from 1.23–1.85,P<0.05).By mutual adjustment between HNF before children’s birth and home mold or dampness,all the significance remained unchanged.Prenatal HNF and home mold or dampness was independently associated with children’s asthmatic and allergic diseases later in life.