Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.
We report a method for large-scale absolute protein expression measurements (APEX) and apply it to estimate the relative contributions of transcriptional- and translational-level gene regulation in the yeast and Escherichia coli proteomes. APEX relies upon correcting each protein's mass spectrometry sampling depth (observed peptide count) by learned probabilities for identifying the peptides. APEX abundances agree with measurements from controls, western blotting, flow cytometry and two-dimensional gels, as well as known correlations with mRNA abundances and codon bias, providing absolute protein concentrations across approximately three to four orders of magnitude. Using APEX, we demonstrate that 73% of the variance in yeast protein abundance (47% in E. coli) is explained by mRNA abundance, with the number of proteins per mRNA log-normally distributed about approximately 5,600 ( approximately 540 in E. coli) protein molecules/mRNA. Therefore, levels of both eukaryotic and prokaryotic proteins are set per mRNA molecule and independently of overall protein concentration, with >70% of yeast gene expression regulation occurring through mRNA-directed mechanisms.
Glioblastoma (GBM) is among the most aggressive of human cancers. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined. Here we demonstrate that a subpopulation of endothelial cells within glioblastomas harbour the same somatic mutations identified within tumour cells, such as amplification of EGFR and chromosome 7. We additionally demonstrate that the stem-cell-like CD133(+) fraction includes a subset of vascular endothelial-cadherin (CD144)-expressing cells that show characteristics of endothelial progenitors capable of maturation into endothelial cells. Extensive in vitro and in vivo lineage analyses, including single cell clonal studies, further show that a subpopulation of the CD133(+) stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate CD133(+)/CD144(+) progenitor cell. The findings are supported by genetic studies of specific exons selected from The Cancer Genome Atlas, quantitative FISH and comparative genomic hybridization data that demonstrate identical genomic profiles in the CD133(+) tumour cells, their endothelial progenitor derivatives and mature endothelium. Exposure to the clinical anti-angiogenesis agent bevacizumab or to a γ-secretase inhibitor as well as knockdown shRNA studies demonstrate that blocking VEGF or silencing VEGFR2 inhibits the maturation of tumour endothelial progenitors into endothelium but not the differentiation of CD133(+) cells into endothelial progenitors, whereas γ-secretase inhibition or NOTCH1 silencing blocks the transition into endothelial progenitors. These data may provide new perspectives on the mechanisms of failure of anti-angiogenesis inhibitors currently in use. The lineage plasticity and capacity to generate tumour vasculature of the putative cancer stem cells within glioblastoma are novel findings that provide new insight into the biology of gliomas and the definition of cancer stemness, as well as the mechanisms of tumour neo-angiogenesis.
Adipocytes hold the body's major energy reserve as triacylglycerols packaged in large lipid droplets. Perilipins, the most abundant proteins on these lipid droplets, play a critical role in facilitating both triacylglycerol storage and hydrolysis. The stimulation of lipolysis by ␤-adrenergic agonists triggers rapid phosphorylation of perilipin and translocation of hormone-sensitive lipase to the surfaces of lipid droplets and more gradual fragmentation and dispersion of micro-lipid droplets. Because few lipid droplet-associated proteins have been identified in adipocytes, we isolated lipid droplets from basal and lipolytically stimulated 3T3-L1 adipocytes and identified the component proteins by mass spectrometry. Structural proteins identified in both preparations include perilipin, S3-12, vimentin, and TIP47; in contrast, adipophilin, caveolin-1, and tubulin selectively localized to droplets in lipolytically stimulated cells. Lipid metabolic enzymes identified in both preparations include hormone-sensitive lipase, lanosterol synthase, NAD(P)-dependent steroid dehydrogenase-like protein, acyl-CoA synthetase, long chain family member (ACSL) 1, and CGI-58. 17-␤-Hydroxysteroid dehydrogenase, type 7, was identified only in basal preparations, whereas ACSL3 and 4 and two short-chain reductase/dehydrogenases were identified on droplets from lipolytically stimulated cells. Additionally, both preparations contained FSP27, ribophorin I, EHD2, diaphorase I, and ancient ubiquitous protein. Basal preparations contained CGI-49, whereas lipid droplets from lipolytically stimulated cells contained several Rab GTPases and tumor protein D54. A close association of mitochondria with lipid droplets was suggested by the identification of pyruvate carboxylase, prohibitin, and a subunit of ATP synthase in the preparations. Thus, adipocyte lipid droplets contain specific structural proteins as well as lipid metabolic enzymes; the structural reorganization of lipid droplets in response to the hormonal stimulation of lipolysis is accompanied by increases in the relative mass of several proteins and the recruitment of additional proteins.In vertebrate animals the most abundant energy reserve is stored as triacylglycerol in the lipid droplets of adipocytes. These lipid droplets can be as large as 100 m and are composed of a core of triacylglycerol surrounded by a phospholipid and cholesterol monolayer into which numerous proteins are embedded. Most other types of cells contain tiny lipid droplets that store primarily cholesterol esters and serve as a reservoir of cholesterol for the synthesis and maintenance of membranes; steroidogenic cells of the adrenal cortex, testes, and ovaries use stored cholesterol additionally as a source of substrate for steroid hormone synthesis. Little is known about the mechanisms that control the flux of neutral lipids into and out of lipid droplets in any type of cell, but it is clear that the processes that control lipid traffic in adipocytes are central to the regulation of whole body energy metabolism.T...
The discovery of photoinduced water splitting on TiO 2 electrodes  has prompted extensive research on TiO 2 and other semiconductor materials, which have been widely adopted as potential substances for solar energy conversion and environmental purification. Most work has focused on improving the efficiency of energy conversion [2±5] or photocatalytic reactions. [6±12] Little research has been reported to clarify the effect of light on the properties of TiO 2 surfaces. Very recently, we found that UV illumination of TiO 2 materials can generate surfaces that display 0 contact angle for both water and oily liquids.  Following this finding, intensive research has been performed to explicate the mechanism of this unique amphiphilic surface character. In this communication, we report the details of the photoconvertible surface wettability. The formation of a microstructured composite between hydrophilic and oleophilic phases, which results from the photogenerated Ti 3+ defects at definite sites, is considered to account for this unique feature.The observation of the amphiphilic surfaces was initiated by the contact angle measurements of TiO 2 anatase thin films. The water contact angle for a freshly prepared film averaged 15±1. After the sample had been stored in the dark for 2 months, the water contact angle increased to 72±1. When a water droplet touched the UV-illuminated film, it spread immediately, leaving an irregular shape on the surface with a contact angle of 0±1.  The contact angle of glycerol trioleate (GT), a main ingredient of edible oil, for the TiO 2 surface was also measured. Prior to UV illumination, the GT contact angle averaged 10±1, indicating that the surface is hydrophobic and oleophilic. Surprisingly, after UV illumination a GT droplet also spread out, resulting in a contact angle of 0±1 when it touched the TiO 2 surface. Parallel experiments were performed using other liquid species, e.g., hexadecane, ethylene glycol, tetralin. Distinct contact angles resulted for the hydrophobic TiO 2 surface. However, all of the liquids spread completely on a UV-illuminated TiO 2 surface, with a contact angle of 0±1. This leads to the tremendous conclusion that UV illumination has created a surface that is both highly hydrophilic and highly oleophilic. The wettability change was observed on both anatase and rutile TiO 2 surfaces in the form of either polycrystals or a single crystal, independent of their photocatalytic activities. Even after the TiO 2 had been stored in the dark for a few days, the high amphiphilicity of the TiO 2 surface was maintained. A longer storage period induced a gradual increase in the water contact angle, revealing a surface wettability trend towards hydrophobicity. However, the high amphiphilicity was repeatedly regenerated by UV illumination.Surface wettability is generally denoted by the contact angle. According to Young's equation, the contact angle of a liquid drop on a solid surface results from the balance between the cohesive forces in the liquid and the adhesiv...
HUPO initiated the Plasma Proteome Project (PPP) in 2002. Its pilot phase has (1) evaluated advantages and limitations of many depletion, fractionation, and MS technology platforms; (2) compared PPP reference specimens of human serum and EDTA, heparin, and citrate-anticoagulated plasma; and (3) created a publicly-available knowledge base (www.bioinformatics.med.umich.edu/hupo/ppp; www.ebi.ac.uk/pride). Thirty-five participating laboratories in 13 countries submitted datasets. Working groups addressed (a) specimen stability and protein concentrations; (b) protein identifications from 18 MS/MS datasets; (c) independent analyses from raw MS-MS spectra; (d) search engine performance, subproteome analyses, and biological insights; (e) antibody arrays; and (f) direct MS/SELDI analyses. MS-MS datasets had 15 710 different International Protein Index (IPI) protein IDs; our integration algorithm applied to multi- We recommend use of plasma instead of serum, with EDTA (or citrate) for anticoagulation. To improve resolution, sensitivity and reproducibility of peptide identifications and protein matches, we recommend combinations of depletion, fractionation, and MS/MS technologies, with explicit criteria for evaluation of spectra, use of search algorithms, and integration of homologous protein matches.This Special Issue of PROTEOMICS presents papers integral to the collaborative analysis plus many reports of supplementary work on various aspects of the PPP workplan. These PPP results on complexity, dynamic range, incomplete sampling, false-positive matches, and integration of diverse datasets for plasma and serum proteins lay a foundation for development and validation of circulating protein biomarkers in health and disease.
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