Pathogens can Slow Down or Reverse Invasion Fronts of their Hosts

Infectious diseases are often regarded as possible explanations for the sudden collapse of biological invasions. This phenomenon is characterized by a host species, which firstly can successfully establish in a non-native habitat, but then spontaneously disappears again. This study proposes a reaction-diffusion model consisting of a simple SI disease with vital dynamics of Allee effect type. By way of travelling wave analysis, conditions are derived under which the invasion of the host population is slowed down, stopped or reversed as a consequence of a subsequently introduced disease. Hence, pathogens can dramatically control the rate of spread of invasive species.     

Ruthenium red-sensitive cation channels,but not calcitonin gene-related peptide or substance P-mediated mechanisms,protect duodenal villi against acid-induced damage

Intestinal mucosal capsaicin-sensitive afferent nerves mediate, in part, the protective mesenteric hyperemia after intraduodenal acidification. Mechanisms associated the sensory neuropeptides, e.g. calcitonin gene-related peptide (CGRP), substance P, and ruthenium red-sensitive cation channels contribute to acid-induced mesenteric hyperemia, but whether they play a role in protection against acid-induced duodenal villous damage is not known. We tested the hypothesis that in doses that attenuate acid-induced hyperemia, inhibitors of these mechanisms will exacerbate acid-induced duodenal villous damage. Intravenous vehicle, specific receptor antagonists of CGRP (CGRP(8-37)), substance P (CP 96345), intraduodenal ruthenium red or vehicle was administered, followed by intraduodenal perfusion with 0.1 N HCl. Duodenal tissue was processed for hematoxylin and eosin staining. Villous damage was scored by blinded observers. Deep villous injury was significantly increased after treatment with ruthenium red, but not with CGRP(8-37) or CP 96345. These findings support the hypothesis that ruthenium red-sensitive cation channels, but not neuropeptides associated with intestinal mucosal afferent nerves, are involved in the acid-sensing mechanism which mediates the protection against acid-induced duodenal villous damage.     

Human betacellulin structure modeled from other members of EGF family

We have modeled betacellulin (BTC) to gain insight into the structural elements that can explain its properties. The epidermal growth factor (EGF) signal transduction pathway, a significant mediator of several cell functions, is based on four closely related tyrosine kinase receptors. The ErbB receptors are transmembrane glycoproteins and signal transduction is initiated by ligand binding that induces receptor homo- or heterodimerization to form a complex containing two molecules of ligand and two molecules of receptor. The EGF family of ligands can be divided into three groups based on their ability to bind and activate distinct ErbB receptor homo- and heterodimers. Each member of the group formed by BTC, heparin binding EGF (HB-EGF) and epiregulin (EP) can interact with both the EGF receptor (EGFR) and heregulin receptors (ErbB-3 and ErbB-4), and are hence called bispecific ligands. BTC and EP also present the distinctive feature that they activate all possible heterodimeric ErbB receptors. BTC has been modeled with the program MODELLER, using human EGF, human transforming growth factor alpha (hTGF), human HB-EGF and human heregulin one alpha (hHRG-1) as templates. The structure of the model as well as that of the templates were optimized and a simulation of 100 ps was run for all. The main structural properties of the model and the templates were compared and in conclusion the hBTC conformation was closely similar to that of hTGF. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00894-002-0072-2.Electronic Supplementary Material available.     

Nanoparticles for the delivery of genes and drugs to human hepatocytes

Hepatitis B virus envelope L particles form hollow nanoparticles displaying a peptide that is indispensable for liver-specific infection by hepatitis B virus in humans. Here we demonstrate the use of L particles for the efficient and specific transfer of a gene or drug into human hepatocytes both in culture and in a mouse xenograft model. In this model, intravenous injection of L particles carrying the gene for green fluorescent protein (GFP) or a fluorescent dye resulted in observable fluorescence only in human hepatocellular carcinomas but not in other human carcinomas or in mouse tissues. When the gene encoding human clotting factor IX was transferred into the xenograft model using L particles, factor IX was produced at levels relevant to the treatment of hemophilia B. The yeast-derived L particle is free of viral genomes, highly specific to human liver cells and able to accommodate drugs as well as genes. These advantages should facilitate targeted delivery of genes and drugs to the human liver.     

Assembly of protein tertiary structures from secondary structures using optimized potentials

We present a simulated annealing-based method for the prediction of the tertiary structures of proteins given knowledge of the secondary structure associated with each amino acid in the sequence. The backbone is represented in a detailed fashion whereas the sidechains and pairwise interactions are modeled in a simplified way, following the LINUS model of Srinivasan and Rose. A perceptron-based technique is used to optimize the interaction potentials for a training set of three proteins. For these proteins, the procedure is able to reproduce the tertiary structures to below 3 A in root mean square deviation (rmsd) from the PDB targets. We present the results of tests on twelve other proteins. For half of these, the lowest energy decoy has a rmsd from the native state below 6 A and, in 9 out of 12 cases, we obtain decoys whose rmsd from the native states are also well below 5 A.     

Solution structure of betacellulin,a new member of EGF-family ligands

The solution structure of the EGF-like domain of betacellulin (BTCe), a newly discovered member of the epidermal growth factor (EGF) family, has been determined using two-dimensional nuclear magnetic resonance spectroscopy. This is the first report to identify the solution structure of the EGF-family ligand monomers that interact with both ErbB-1 and ErbB-4. The solution structure of BTCe was calculated using 538 NMR-derived restraints. The overall structure of BTCe was stabilized by three disulfide bonds, a hydrophobic core, and 23 hydrogen bonds. It appears that BTCe is comprised of five beta-strands and one short 3(10) helical turn. The secondary structural elements of BTCe are basically similar to those of the other EGF-family proteins, except that several significant variations of the structural properties were found. It is suggested that the structural variations between BTCe and the other EGF-family ligands may affect the specific receptor-recognition properties of EGF-family ligands.     

Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine

We have previously shown that Hes1 is expressed both in putative epithelial stem cells just above Paneth cells and in the crypt base columnar cells between Paneth cells, while Hes1 is completely absent in Paneth cells. This study was undertaken to clarify the role of Hes1 in Paneth cell differentiation, using Hes1-knockout (KO) newborn (P0) mice. Electron microscopy revealed premature appearance of distinct cells containing cytoplasmic granules in the intervillous region in Hes1-KO P0 mice, whereas those cells were absent in wild-type (WT) P0 mice. In Hes1-KO P0 mice, the gene expressions of cryptdins, exclusively present in Paneth cells, were all enhanced compared with WT P0 mice. Immunohistochemistry demonstrated increased number of both lysozyme-positive and cryptdin-4-positive cells in the small intestinal epithelium of Hes1-KO P0 mice as compared to WT P0 mice. Thus, Hes1 appears to have an inhibitory role in Paneth cell differentiation in the small intestine.