Pathogenic bacteria attach to human fibronectin through a tandem beta-zipper

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats in an unfolded region of the protein. The bacterium-binding site in the amino-terminal domain (1-5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3) in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel beta-strands on sequential F1 modules-the first example of a tandem beta-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1-5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem beta-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent FnBP-mediated invasion of host cells.     

Structure of the fibronectin type 1 module

The rapid accumulation of sequence data has provided insight into the evolution of proteins and led to the identification of 'mosaic proteins'. These proteins have evolved by duplication, insertion and deletion of a common pool of structural units or modules, yet their biological functions are diverse. They are involved in cell adhesion and migration, embryogenesis and the pathways of blood clotting, fibrinolysis and complement. The modular units are defined by 'consensus sequences' which often include conserved disulphide bonds. Despite the available sequence information, little is known of the tertiary structure of mosaic proteins. If, however, the 'consensus structure' of the modules were known, valuable structural information could be inferred about a wide variety of proteins and biological systems. An important mosaic protein is fibronectin, an extracellular matrix protein that consists of three types of module (see refs 3, 7 for reviews). Here we describe the structure of the fibronectin type 1 module which appears twelve times in fibronectin and is also found in factor XII and tissue plasminogen activator. The module was produced using a yeast expression system and the structure was determined in solution using 1H NMR. This methodology promises to be extremely powerful in the investigation of modules from a wide range of mosaic proteins.     

UDP-glucose ceramide glucosyltransferase activates AKT,promoted proliferation,and doxorubicin resistance in breast cancer cells

The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance.     

There is no valid record of cliff chipmunk ( Tamias dorsalis ) in the Sandia Mountains, New Mexico

In the American Southwest, the red squirrel ( Tamiasciurus hudsonicus ) occurs as disjunct populations in coniferous forests on mountaintops. There is a paucity of information concerning the species’ distribution and habitat in western New Mexico. I report new records that document and verify the occurrence of red squirrels in additional montane areas in west central New Mexico, including the Mangas Mountains, Canovas Rim, Turner Mountain, Tularosa Mountains, Elk Mountains, Bearwallow Mountain, and Pinos Altos Mountains. I also report observations of red squirrels from an atypical habitat—low-elevation riparian forests. These new records suggest that the geographic distribution of the species in west central New Mexico is broader than indicated by existing records. However, I also document the apparent extirpation of red squirrels from the Zuni Mountains in northwestern New Mexico. The red squirrel is one of several avian and mammalian species associated with mixed coniferous forests that have become extirpated in this mountain range.     

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.     

Systems Practice in China: New Developments and Cross-Cultural Collaborations

This short paper introduces a special issue of Systemic Practice and Action Research on new developments in Chinese systems practice. It focuses on the recent history of systems thinking in China, describing a paradigm shift that is currently taking place from an "objectivist" to a more pluralistic stance. Details are provided of the Hull–Beijing research program, which has contributed to this paradigm shift. In one way or another, all the papers in this special issue can be seen as having a connection with this research program.