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Disseminated infections with the fungal species Cryptococcus neoformans or, less frequently, C. gattii, are a leading cause of mortality in immunocompromised individuals. Central to the virulence of both species is an elaborate polysaccharide capsule that consists predominantly of glucuronoxylomannan (GXM). Due to its abundance, GXM is an ideal target for host antibodies, and several monoclonal antibodies (mAbs) have previously been derived using purified GXM or whole capsular preparations as antigen. In addition to their application in the diagnosis of cryptococcosis, anti-GXM mAbs are invaluable tools for studying capsule structure. In this study, we report the production and characterisation of a novel anti-GXM mAb, Crp127, that unexpectedly reveals a role for GXM remodelling during the process of fungal Titanisation. We show that Crp127 recognises a GXM epitope in an O-acetylation dependent, but xylosylation-independent, manner. The epitope is differentially expressed by the four main serotypes of Cryptococcus neoformans and gattii, is heterogeneously expressed within clonal populations of C. gattii serotype B strains and is typically confined to the central region of the enlarged capsule. Uniquely, however, this epitope redistributes to the capsular surface in Titan cells, a recently recognised subset of giant fungal cells that are produced in the host lung and are critical for successful infection. Crp127 therefore highlights hitherto unexpected features of cryptococcal morphological change and may hold significant therapeutic potential in differentially identifying cryptococcal strains and subtypes. Cryptococcus neoformans and Cryptococcus gattii are the etiological agents of cryptococcosis, an invasive fungal infection responsible for approximately 200,000 deaths each year and 15% of AIDS-related deaths annually. Whilst the main virulence factor for both species is a highly variable polysaccharide capsule, formation of Titan cells also underlies the pathogenesis of C. neoformans. Previous studies have shown that capsule composition differs between yeast and Titan cells, however no clear distinctions in the expression or localisation of specific capsular epitopes have been made. In this study, we characterise a novel monoclonal antibody (mAb) specific to a capsular epitope that is differentially distributed throughout the capsules produced by yeast and Titan cells. Whilst this epitope is found within the midzone of yeast capsules, the presentation of this epitope on the surface of Titan cell capsules may represent a way in which these cell types are perceived differently by the immune system.

Abstract Opportunistic infections by environmental fungi are a growing clinical problem, driven by an increasing population of people with immunocompromising conditions. Spores of the Mucorales order are ubiquitious in the environment but can also cause acute invasive infections in humans through germination and evasion of the mammalian host immune system. How they achieve this, and the evolutionary drivers underlying the acquisition of virulence mechanisms, are poorly understood. Here we show that a clinical isolate of Rhizopus microsporus contains a Ralstonia pickettii bacterial endosymbiont required for virulence in both zebrafish and mice, and that this endosymbiosis enables secretion of factors that potently suppress growth of the soil amoeba Dictyostelium discoideum, as well as their ability to engulf and kill other microbes. As amoebae are natural environmental predators of both bacteria and fungi, we propose this tri-kingdom interaction contributes to establishing the endosymbiosis, and acquisition of anti-phagocyte activity. Importantly, we show this activity also protects fungal spores from phagocytosis and clearance by human macrophages, and endosymbiont removal renders the fungal spores avirulent in vivo. Together, these findings describe a novel role for a bacterial endosymbiont in Rhizopus microsporus pathogenesis in animals, and suggest a mechanism of virulence acquisition through environmental interactions with amoebae. In brief How environmental fungi evolved the mechanisms that enable them to cause opportunistic infections in humans is unclear. Here, we identify a novel tri-kingdom interaction, whereby a bacterial endosymbiont, living within a clinical isolate of the ubiquitous environmental fungus Rhizopus microsporus, causes the generation of a secreted activity that blocks the growth and predatory activity of amoebae. We suggest this provides a new evolutionary driver for the establishment of bacterial/fungal endosymbiosis and demonstrate this is critical for fungal pathogenicity in vivo. Competing Interest Statement The authors have declared no competing interest. Footnotes * Revised to reflect reviewer feedback

The synthesis is reported of some analogues of 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP,3) an intermediate in the Shikimate pathway, and of some analogues of 3-deoxy- -D-arabino-heptulosonic acid 2,7-diphosphate (167), the intermediacy the existence of which is proposed in this thesis in a new alternative mechanism for the enzymic reaction catalysed by DAHP synthase. 2-Deoxy- - and - -D-arabino-hexopyranosyl-phosphonic acids (169) and (168) were synthesised in high yield from 2-deoxy-D-glucose (69). Acetylation of (69) in acetic anhydride and pyridine gave 1,3,4,6-tetra-O-acetyl-2-deoxy- , -D-arabino-hexopyranose (23 , ) which was then treated with trimethyl phosphite and trimethylsilyl triflate to give dimethyl (3,4,6-tri-O-acetyl-2-deoxy- - and - -D-arabino-hexopyranosyl)-phosphonates (180) and (181). These were deprotected with trimethylsilyl bromide followed by sodium methoxide in methanol to give the phosphonic acids (169) and (168). A stereospecific synthesis to give a protected form of (169) was also carried out. Tri-O-benzyl-D-glucal (80) was treated with hydrogen chloride gas in toluene followed by lithio tributylstannylate to give specifically tributyl (3,4,6-tri-O-benzyl-2-deoxy- -D-arabino-hexopyranosyl)stannane (204). Transmetallation with butyllithium followed by reaction with diethyl chlorophosphate then gave diethyl (3,4,6-tri-O-benzyl-2-deoxy- -D-arabino-hexopyranosyl)-phosphonate (208). As an alternative 3,4,6-tri-O-t-butyldiphenylsilyl-D-glucal (228) was synthesised from D-glucal (176) and was treated with t-butyllithium followed by diethyl chlorophosphate to give diethyl (tri-O-t-butyldiphenylsilyl-2-deoxy-D-arabino-hex-1-enopyranosyl)-phosphonate (229). An attempt to hydrogenate this specifically to give a protected -phosphonate was unsuccessful. (DX179064)

Newsday reporter Patrick Owens' articles [\"Disability Nightmare Isn't Over,\" July 23 and \"Disability Policy Shift Termed Sham,\" July 24] has again brought to light the problems that will be caused by the Reagan administration's continued attack on the Social Security Disability program.

To provide an effective substrate for cognitive processes, functional brain networks should be able to reorganize and coordinate on a sub-second temporal scale. We used magnetoencephalography recordings of spontaneous activity to characterize whole-brain functional connectivity dynamics at high temporal resolution. Using a novel approach that identifies the points in time at which unique patterns of activity recur, we reveal transient (100–200 ms) brain states with spatial topographies similar to those of well-known resting state networks. By assessing temporal changes in the occurrence of these states, we demonstrate that within-network functional connectivity is underpinned by coordinated neuronal dynamics that fluctuate much more rapidly than has previously been shown. We further evaluate cross-network interactions, and show that anticorrelation between the default mode network and parietal regions of the dorsal attention network is consistent with an inability of the system to transition directly between two transient brain states. When subjects lie motionless inside scanners without any particular task to perform, their brains show stereotyped patterns of activity across regions known as resting state networks. Each network consists of areas with a common function, such as the ‘motor’ network or the ‘visual’ network. The role of resting state networks is unclear, but these spontaneous activity patterns are altered in disorders including autism, schizophrenia, and Alzheimer’s disease. One puzzling feature of resting state networks is that they seem to last for relatively long times. However, the majority of studies into resting state networks have used fMRI brain scans, in which changes in the level of oxygen in the blood are used as a proxy for the activity of a given brain region. Since changes in blood oxygen occur relatively slowly, the ability of fMRI to detect rapid changes in activity is limited: it is thus possible that the long-lived nature of resting state networks is an artefact of the use of fMRI. Now, Baker et al. have used a different type of brain scan known as an MEG scan to show that the activity of resting state networks is shorter lived than previously thought. MEG scanners measure changes in the magnetic fields generated by electrical currents in the brain, which means that they can detect alterations in brain activity much more rapidly than fMRI. MEG recordings from the brains of nine healthy subjects revealed that individual resting state networks were typically stable for only 100 ms to 200 ms. Moreover, transitions between different networks did not occur randomly; instead, certain networks were much more likely to become active after others. The work of Baker et al. suggests that the resting brain is constantly changing between different patterns of activity, which enables it to respond quickly to any given situation.

Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS.

David Steven Boote, 32, was found hanging by bed sheets in his cell at Blakenhurst Prison near Redditch, at 10.45pm last night. He was pronounced dead at the town's Alexandra Hospital shortly after midnight.

David Steven Boote, 32, was found hanging by bed sheets in his cell at Blakenhurst Prison, near Redditch, at 10.45 last night. He was pronounced dead at the town's Alexandra Hospital shortly after midnight. Boote had been remanded in custody on a charge of murdering 25year-old Natalie Bowcott at her home in Arrow Walk, Walker's Heath. Miss Bowcott's body was discovered on Sunday, June 1, by a neighbour who alerted police shortly before midnight.

Three cattle and 150 sheep were due to be destroyed after the Ministry of Agriculture declared Windy Bank Farm, in Astwood Lane, Astwood Bank, Redditch, infected by virus. Two other nearby farms were also suspected of being infected, it added. A Ministry of Agriculture spokesman said: 'Vets are presently at a farm at Astwood Bank and foot and mouth has been confirmed. Mr Nick Fraser, spokesman for Bromsgrove and Redditch NFU, which covers the affected area, said: 'This news is just devastating and catastrophic for the immediate area as there are many members who manage family-based livestock farms.'

A few years ago we heard about [Charles Wang] buying up the properties and heard different things about his intentions for Oyster Bay. To this day, the only things I can see happening are high cost of living and congestion. Abraham Poznanski has said, \"We would like to get as much housing into the downtown area as possible.\" He seems to think that this would pump money into the local economy. But I wonder if Poznanski ever rode through the streets of Oyster Bay and saw the dozens of houses for sale and the vacant store buildings. We need to get more businesses into town that people want and need. You can only go to so many delis and nail salons. Unfortunately, the current U.S. policy on global warming is one of indifference at a time when our country's production of greenhouse-gas pollution from burning oil, coal and gasoline is increasing. But in coming weeks, U.S. senators will have a chance to vote for decisive action on global warming in the McCain-Lieberman Climate Stewardship Act. Last October, the reasonable and responsible measure secured 43 votes in the Senate, surprising the pundits and building momentum for the upcoming vote on global warming. The Metropolitan Transportation Authority, New York City Transit, Long Island Rail Road, Long Island Bus, Metro-North Commuter Railroad, Staten Island Rapid Transit, New Jersey Transit, Port Authority of New York and New Jersey, Connecticut Department of Transportation, New York City Department of Transportation, and Staten Island Ferry, along with many other services supported by Nassau, Suffolk, Westchester, Rockland and Putnam counties and the City of Long Beach and Town of Huntington, all provide such options. There are many private bus and ferry operators, including New York Waterways, Command Bus Lines in Brooklyn, New York Bus and Liberty Lines Express in the Bronx, along with Green Bus Lines, Jamaica Buses of Queens, Queens Surface and Triboro Coach in Queens and many smaller suburban operators.