Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis

Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.     

Functional and spatial segregation of secretory vesicle pools according to vesicle age

Synaptic terminals and neuroendocrine cells are packed with secretory vesicles, only a few of which are docked at the plasma membrane and readily releasable. The remainder are thought to constitute a large cytoplasmic reserve pool awaiting recruitment into the readily releasable pool (RRP) for exocytosis. How vesicles are prioritized in recruitment is still unknown: the choice could be random, or else the oldest or the newest ones might be favoured. Here we show, using a fluorescent cargo protein that changes colour with time, that vesicles in bovine adrenal chromaffin cells segregate into distinct populations, based on age. Newly assembled vesicles are immobile (morphologically docked) at the plasma membrane shortly after biogenesis, whereas older vesicles are mobile and located deeper in the cell. Different secretagogues selectively release vesicles from the RRP or, surprisingly, selectively from the deeper cytoplasmic pool. Thus, far from being equal, vesicles are segregated functionally and spatially according to age.     

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.     

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.     

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.     

Nonlinear elasticity in biological gels

The mechanical properties of soft biological tissues are essential to their physiological function and cannot easily be duplicated by synthetic materials. Unlike simple polymer gels, many biological materials--including blood vessels, mesentery tissue, lung parenchyma, cornea and blood clots--stiffen as they are strained, thereby preventing large deformations that could threaten tissue integrity. The molecular structures and design principles responsible for this nonlinear elasticity are unknown. Here we report a molecular theory that accounts for strain-stiffening in a range of molecularly distinct gels formed from cytoskeletal and extracellular proteins and that reveals universal stress-strain relations at low to intermediate strains. The input to this theory is the force-extension curve for individual semi-flexible filaments and the assumptions that biological networks composed of these filaments are homogeneous, isotropic, and that they strain uniformly. This theory shows that systems of filamentous proteins arranged in an open crosslinked mesh invariably stiffen at low strains without requiring a specific architecture or multiple elements with different intrinsic stiffness.     

Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia

Homo floresiensis was recovered from Late Pleistocene deposits on the island of Flores in eastern Indonesia, but has the stature, limb proportions and endocranial volume of African Pliocene Australopithecus. The holotype of the species (LB1), excavated in 2003 from Liang Bua, consisted of a partial skeleton minus the arms. Here we describe additional H. floresiensis remains excavated from the cave in 2004. These include arm bones belonging to the holotype skeleton, a second adult mandible, and postcranial material from other individuals. We can now reconstruct the body proportions of H. floresiensis with some certainty. The finds further demonstrate that LB1 is not just an aberrant or pathological individual, but is representative of a long-term population that was present during the interval 95-74 to 12 thousand years ago. The excavation also yielded more evidence for the depositional history of the cave and for the behavioural capabilities of H. floresiensis, including the butchery of Stegodon and use of fire.