Blue Waters, Green Bottoms: Benthic Filamentous Algal Blooms Are an Emerging Threat to Clear Lakes Worldwide.

Nearshore (littoral) habitats of clear lakes with high water quality are increasingly experiencing unexplained proliferations of filamentous algae that grow on submerged surfaces. These filamentous algal blooms (FABs) are sometimes associated with nutrient pollution in groundwater, but complex changes in climate, nutrient transport, lake hydrodynamics, and food web structure may also facilitate this emerging threat to clear lakes. A coordinated effort among members of the public, managers, and scientists is needed to document the occurrence of FABs, to standardize methods for measuring their severity, to adapt existing data collection networks to include nearshore habitats, and to mitigate and reverse this profound structural change in lake ecosystems. Current models of lake eutrophication do not explain this littoral greening. However, a cohesive response to it is essential for protecting some of the world's most valued lakes and the flora, fauna, and ecosystem services they sustain.

Metabonomics uncovers a reversible proatherogenic lipid profile during infliximab therapy of inflammatory bowel disease.

BACKGROUND: One-third of inflammatory bowel disease (IBD) patients show no response to infliximab (IFX) induction therapy, and approximately half of patients responding become unresponsive over time. Thus, identification of potential treatment response biomarkers are of great clinical significance. This study employs spectroscopy-based metabolic profiling of serum from patients with IBD treated with IFX and healthy subjects (1) to substantiate the use of spectroscopy as a semi-invasive diagnostic tool, (2) to identify potential biomarkers of treatment response and (3) to characterise the metabolic changes during management of patients with tumour necrosis factor-α inhibitors. METHODS: Successive serum samples collected during IFX induction treatment (weeks 0, 2, 6 and 14) from 87 IBD patients and 37 controls were analysed by 1H nuclear magnetic resonance (NMR) spectroscopy. Data were analysed with principal components analysis and orthogonal projection to latent structures discriminant analysis using SIMCA-P+ v12 and MATLAB. RESULTS: Metabolic profiles were significantly different between active ulcerative colitis and controls, active Crohn's disease and controls, and quiescent Crohn's disease and controls. Metabolites holding differential power belonged primarily to lipids and phospholipids with proatherogenic characteristics and metabolites in the pyruvate metabolism, suggestive of an intense inflammation-driven energy demand. IBD patients not responding to IFX were identified as a potentially distinct group based on their metabolic profile, although no applicable response biomarkers could be singled out in the current setting. CONCLUSION: 1H NMR spectroscopy of serum samples is a powerful semi-invasive diagnostic tool in flaring IBD. With its use, we provide unique insights into the metabolic changes taking place during induction treatment with IFX. Of distinct clinical relevance is the identification of a reversible proatherogenic lipid profile in IBD patients with active disease, which partially explains the increased risk of cardiovascular disease associated with IBD.

Assignment of the orphan nuclear receptor Nurr1 by NMR.

The orphan nuclear receptor Nurr1 has been implicated in a number of conditions including Parkinson's disease and Schizophrenia. As such, it is of interest to study its interactions with other proteins, possibly mediated by small molecules, considering possible use as a drug target. We produced (2)H, (15)N, (13)C labelled-Nurr1 to generate the backbone amide NH, carbonyl C', C(alpha) and C(beta) assignments. About 84.0% of residues could be assigned. Most of the 37 missing assignments fall in 3 regions of the protein. Two of these surround a putative ligand-binding region of Nurr1, suggesting that this region of the protein is flexible, despite the ligand-binding pocket being filled with hydrophobic side-chains from residues surrounding the ligand binding pocket.

Interaction of human complement with Sbi, a staphylococcal immunoglobulin-binding protein: indications of a novel mechanism of complement evasion by Staphylococcus aureus.

Staphylococcal immunoglobulin-binding protein, Sbi, is a 436-residue protein produced by many strains of Staphylococcus aureus. It was previously characterized as being cell surface-associated and having binding capacity for human IgG and beta(2)-glycoprotein I. Here we show using small angle x-ray scattering that the proposed extracellular region of Sbi (Sbi-E) is an elongated molecule consisting of four globular domains, two immunoglobulin-binding domains (I and II) and two novel domains (III and IV). We further show that together domains III and IV (Sbi-III-IV), as well as domain IV on its own (Sbi-IV), bind complement component C3 via contacts involving both the C3dg fragment and the C3a anaphylatoxin domain. Preincubation of human serum with either Sbi-E or Sbi-III-IV is inhibitory to all complement pathways, whereas domain IV specifically inhibits the alternative pathway. Monitoring C3 activation in serum incubated with Sbi fragments reveals that Sbi-E and Sbi-III-IV both activate the alternative pathway, leading to consumption of C3. By contrast, inhibition of this pathway by Sbi-IV does not involve C3 consumption. The observation that Sbi-E activates the alternative pathway is counterintuitive to intact Sbi being cell wall-associated, as recruiting complement to the surface of S. aureus would be deleterious to the bacterium. Upon re-examination of this issue, we found that Sbi was not associated with the cell wall fraction, but rather was found in the growth medium, consistent with it being an excreted protein. As such, our data suggest that Sbi helps mediate bacterial evasion of complement via a novel mechanism, namely futile fluid-phase consumption.

S. aureus IgG-binding proteins SpA and Sbi: host specificity and mechanisms of immune complex formation.

The evasion of the host immune response is central to the pathogenicity of Staphylococcus aureus, and is facilitated by the ability of the cell wall-associated protein A (SpA) to bind immunoglobulin G Fc fragments, thereby impeding phacocytosis and classical pathway complement fixation. SpA also acts as a B-cell superantigen through interactions with the heavy-chain variable part of Fab fragments, and sequesters immunoglobulins by forming large insoluble immune complexes with human IgG. Here we show that the formation of insoluble immune complexes is mediated by the binding of (VH3+) Fab fragments in addition to Fc, and that SpA forms soluble complexes with IgG Fc fragments. We compared these results with those for Sbi, a second staphylococcal immunoglobulin-binding protein, and note that this protein requires only the Fc fragment for precipitation with human IgG. Homology models of immunoglobulin-binding domains of SpA and Sbi in complex with Fc reveal the molecular basis of the Fab-independent formation of insoluble complexes by Sbi. Finally, we compared the sequences of the spa and sbi genes from human strains to those infecting a range of animal hosts to determine whether Sbi and SpA have acquired specificity for host IgG. We note remarkable sequence conservation within the IgG-binding domains of these genes, consistent with a lack of host specificity. The Fab-independent binding of IgG by Sbi could have significant clinical implications. The use of SpA in immunoadsorption therapy can cause severe side-effects, thought to be mediated by Fc gamma R recognition and complement fixation. The formation of insoluble immune complexes with Sbi occurs only via Fc binding and free Fc regions are unlikely to be available for Fc gamma R recognition and complement fixation.

Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene.

Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5-10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (Rp1) of human RP1. In Rp1(-/-) mice, the number of rod photoreceptors decreased progressively over a period of 1 year, whereas that of cone photoreceptors did not change for at least 10 months. Light and electron microscopic analysis revealed that outer segments of Rp1(-/-) rods and cones were morphologically abnormal and became progressively shorter in length. Before photoreceptor cell death, rhodopsin was mislocalized in inner segments and cell bodies of Rp1(-/-) rods. Rod ERG amplitudes of Rp1(-/-) mice were significantly smaller than those of Rp1(+/+) mice over a period of 12 months, whereas those of Rp1(+/-) mice were intermediate. The decreases in cone ERG amplitudes were slower and less severe than those in rods. These findings demonstrate that Rp1 is required for normal morphogenesis of photoreceptor outer segments and also may play a role in rhodopsin transport to the outer segments. The phenotype of Rp1 mutant mice resembles the human RP1 disease. Thus, these mice provide a useful model for studies of RP1 function, disease pathology, and therapeutic interventions.