Search

Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.

Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.

Sequencing of bacterial and archaeal genomes has revolutionized our understanding of the many roles played by microorganisms. There are now nearly 1,000 completed bacterial and archaeal genomes available, most of which were chosen for sequencing on the basis of their physiology. As a result, the perspective provided by the currently available genomes is limited by a highly biased phylogenetic distribution. To explore the value added by choosing microbial genomes for sequencing on the basis of their evolutionary relationships, we have sequenced and analysed the genomes of 56 culturable species of Bacteria and Archaea selected to maximize phylogenetic coverage. Analysis of these genomes demonstrated pronounced benefits (compared to an equivalent set of genomes randomly selected from the existing database) in diverse areas including the reconstruction of phylogenetic history, the discovery of new protein families and biological properties, and the prediction of functions for known genes from other organisms. Our results strongly support the need for systematic phylogenomic efforts to compile a phylogeny-driven Genomic Encyclopedia of Bacteria and Archaea in order to derive maximum knowledge from existing microbial genome data as well as from genome sequences to come. © 2009 Macmillan Publishers Limited. All rights reserved.

After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion (1,2). Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes (3) also initiate remodelling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion--driven by lymphocyte influx and proliferation--that is the critical hallmark of adaptive immunity., Lymph nodes are meeting places for T lymphocytes and antigen-presenting dendritic cells (1,2). T-cell-dendritic-cell interactions are supported by FRCs (4,5), a complex interconnected network that produces and ensheathes extracellular matrix [...]

Speciation generally involves a three-step process--range expansion, range fragmentation and the development of reproductive isolation between spatially separated populations (1,2). Speciation relies on cycling through these three steps and each may limit the rate at which new species form (1,3). We estimate phylogenetic relationships among all Himalayan songbirds to ask whether the development of reproductive isolation and ecological competition, both factors that limit range expansions (4), set an ultimate limit on speciation. Based on a phylogeny for all 358 species distributed along the eastern elevational gradient, here we show that body size and shape differences evolved early in the radiation, with the elevational band occupied by a species evolving later. These results are consistent with competition for niche space limiting species accumulation (5). Even the elevation dimension seems to be approaching ecological saturation, because the closest relatives both inside the assemblage and elsewhere in the Himalayas are on average separated by more than five million years, which is longer than it generally takes for reproductive isolation to be completed (2,3,6); also, elevational distributions are well explained by resource availability, notably the abundance of arthropods, and not by differences in diversification rates in different elevational zones. Our results imply that speciation rate is ultimately set by niche filling (that is, ecological competition for resources), rather than by the rate of acquisition of reproductive isolation., Range expansions are a critical step in the speciation cycle: without them, allopatric and parapatric forms would have ranges of ever decreasing size, unlikely to be further fragmented by barriers [...]

The most unique feature of Earth is the existence of life, and the most extraordinary feature of life is its diversity. Approximately 9 million types of plants, animals, protists and fungi inhabit the Earth. So, too, do 7 billion people. Two decades ago, at the first Earth Summit, the vast majority of the world's nations declared that human actions were dismantling the Earth's ecosystems, eliminating genes, species and biological traits at an alarming rate. This observation led to the question of how such loss of biological diversity will alter the functioning of ecosystems and their ability to provide society with the goods and services needed to prosper., In the past 20 years remarkable progress has been made towards understanding how the loss of biodiversity affects the functioning of ecosystems and thus affects society. Soon after the 1992 [...]

Evidence is mounting that extinctions are altering key processes important to the productivity and sustainability of Earth's ecosystems (1-4). Further species loss will accelerate change in ecosystem processes (5-8), but it is unclear how these effects compare to the direct effects of other forms of environmental change that are both driving diversity loss and altering ecosystem function. Here we use a suite of meta-analyses of published data to show that the effects of species loss on productivity and decomposition--two processes important in all ecosystems--are of comparable magnitude to the effects of many other global environmental changes. In experiments, intermediate levels of species loss (21-40%) reduced plant production by 5-10%, comparable to previously documented effects of ultraviolet radiation and climate warming. Higher levels of extinction (41-60%) had effects rivalling those of ozone, acidification, elevated C[O.sub.2] and nutrient pollution. At intermediate levels, species loss generally had equal or greater effects on decomposition than did elevated C[O.sub.2] and nitrogen addition. The identity of species lost also had a large effect on changes in productivity and decomposition, generating a wide range of plausible outcomes for extinction. Despite the need for more studies on interactive effects of diversity loss and environmental changes, our analyses clearly show that the ecosystem consequences of local species loss are as quantitatively significant as the direct effects of several global change stressors that have mobilized major international concern and remediation efforts (9)., A variety of global changes are driving rates of species extinction that greatly outpace background rates in the fossil record (10,11). If these trends continue, projections suggest that within (240) [...]

Gradual inflation of magma chambers often precedes eruptions at highly active volcanoes. During such eruptions, rapid deflation occurs as magma flows out and pressure is reduced (1-3). Less is known about the deformation style at moderately active volcanoes, such as Eyjafjallajokull, Iceland, where an explosive summit eruption of trachyandesite beginning on 14 April 2010 caused exceptional disruption to air traffic, closing airspace over much of Europe for days. This eruption was preceded by an effusive flank eruption of basalt from 20 March to 12 April 2010. The 2010 eruptions are the culmination of 18 years of intermittent volcanic unrest (4-9). Here we show that deformation associated with the eruptions was unusual because it did not relate to pressure changes within a single magma chamber. Deformation was rapid before the first eruption (>5 mm per day after 4 March), but negligible during it. Lack of distinct co-eruptive deflation indicates that the net volume of magma drained from shallow depth during this eruption was small; rather, magma flowed from considerable depth. Before the eruption, a ~0.05 [km.sup.3] magmatic intrusion grew over a period of three months, in a temporally and spatially complex manner, as revealed by GPS (Global Positioning System) geodetic measurements and interferometric analysis of satellite radar images. The second eruption occurred within the ice-capped caldera of the volcano, with explosivity amplified by magma-ice interaction. Gradual contraction of a source, distinct from the pre-eruptive inflation sources, is evident from geodetic data. Eyjafjallajokull's behaviour can be attributed to its off-rift setting with a 'cold' subsurface structure and limited magma at shallow depth, as may be typical for moderately active volcanoes. Clear signs of volcanic unrest signals over years to weeks may indicate reawakening of such volcanoes, whereas immediate short-term eruption precursors may be subtle and difficult to detect., Volcanic processes leading to eruptions can be investigated by monitoring a variety of phenomena, including increased earthquake activity and uplift of volcanoes due to magma accumulation, as well as variations [...]

The epithelial cells that line the intestine have been found to sense tight attachment of bacteria, and to respond by producing proteins that shape the effector functions of the immune [...]

Author(s): Helen Davies [1, 2]; Graham R. Bignell [1, 2]; Charles Cox [1, 2]; Philip Stephens [1, 2]; Sarah Edkins [1]; Sheila Clegg [1]; Jon Teague [1]; Hayley Woffendin [1]; [...]

Author(s): Athanasios Theologis (corresponding author) [1, 2]; Joseph R. Ecker (corresponding author) [1, 3, 4]; Curtis J. Palm [5]; Nancy A. Federspiel [4, 5]; Samir Kaul [6]; Owen White [6]; [...]

Author(s): F. Stuart Chapin III (corresponding author) [1]; Erika S. Zavaleta [2]; Valerie T. Eviner [4]; Rosamond L. Naylor [3]; Peter M. Vitousek [2]; Heather L. Reynolds [5]; David U. [...]

Viruses of different subtypes in the major group of human immunodeficiency virus type 1 show considerable genetic diversity. HIV-1 sequences pre-dating the recognition of AIDS could be essential in defining the time of origin of the virus in humans. Viral sequences from a 1959 African plasma sample, previously found to be HIV-1 seropositive, were amplified and characterized. Multiple phylogenetic analyses authenticate the case as the earliest known HIV-1 infection.

The tumour-suppressor gene, patched (Ptc), is a receptor for the protein Sonic hedgehog (Shh). Shh binds to cells expressing Ptc with high affinity. Ptc, Shh and a vertebrate homologue of the Drosophila protein Smoothened (vSmo) form a physical protein complex. vSmo coexpresses with vPtc in a number of tissues. However, it fails to bind Shh directly. vPtc is a legend-binding component, and vSMo is a signalling component that is linked to Ptc. Genetic mutations causing unstability of Ptc protein are associated with basal cell carcinoma.

The use of additional, exogenous platelet-activating factor (PAF) acetylhydrolase may be an effective therapy for acute inflammation. The sequence of human plasma PAF acetylhydrolase possesses a Gly-Xaa-Ser-Xaa-Gly motif, as confirmed from molecular cloning. The substrate specific PAF acetylhydrolase causes lipoprotein association of the native enzyme. The vascular leakage in pleurisy and paw oedema is decreased by the PAF acetylhydrolase.

An experimental study of autocrine Wingless (Wg) signalling in Drosophila embryos using zeste-white3 (zw3) and patched mutant backgrounds showed that there are differences between Wg signalling to adjoining cells and direct Wg autoregulation. The difference is due to the greater significance of fused, smoothened and cubitus interruptus genes in the Wg expression than zw3 and armadillo. The lack of gooseberry participation also differentiates Wg autoregulation early and late in the signalling.

Various agents are responsible for initiating apoptosis and expression of the tumor suppressor p53 gene may also be a factor. Short-term thymocyte cultures from mice were used to study the role of p53 expression in apoptosis of cells from the thymus cortex. Introduction of ionizing radiation, glucocorticoid methylprednisolone, etoposide or calcium induced apoptosis in wild type thymocytes. On the other hand, radiation or etoposide did not induce apoptosis in homozygous null p53 thymocytes. Results showed that p53 was a factor in apoptosis when induced by agents causing DNA-strand breakage.

Research using mice with mutant T-cell antigen receptor (TCR) genes shows that rearrangement or expression of the TCR-beta gene is necessary and sufficient for differentiation of CD4-CD8-thymocytes into the CD4+CD8+ form and for expanding the pool of thymocytes. Expression of the TCR-alpha gene is irrelevant to these processes. Furthermore, the TCR-alpha and TCR-beta mutation does not hinder development of gamma and delta T-cells.

A new mouse model for cystic fibrosis (CF) has been devised that should be useful in trials of potential treatments for this deadly autosomal recessive disorder. The new model was produced through mutagenesis or the genetic disruption of the CF transmembrane conductance regulator gene in murine embryonic stem cells. The detection of the characteristic CF pathophysiology in the mice such as abnormal chloride ion transport verified the similarity of the model to human CF.

RB-1, a gene the mutation of which has been linked to retinoblastoma, produces different homozygous and heterozygous effects when inactivated in mouse embryos. Heterozygous mice survive to term and exhibit neither physical abnormalities nor the growth of retinoblastoma tumors. On the other hand, homozygous mouse embryos die before birth and exhibit an array of neural and hematopoietic abnormalities.