Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad

The complex interaction of genetic, microbial, and environmental factors may result in continuous activation of the mucosal immune system leading to inflammatory bowel disease (IBD). Most present treatments for IBD involve altering or suppressing the aberrant immune response; however, the role of the intestinal microbiota in the pathophysiology of IBD is becoming more evident. The epithelial layer is essential for the proper functioning of the gastrointestinal tract, and its increased permeability to the luminal antigens may lead to the inflammatory processes and mucosal damage observed in IBD. Factors affecting the efficacy of the epithelial barrier include presence of pathogenic bacteria (e.g., Helicobacter spp.), presence of probiotic bacteria, availability of selected nutrients, and others. Defective function of the mucosal barrier might facilitate the contact of bacterial antigens and adjuvants with innate and adaptive immune cells to generate prolonged inflammatory responses. This review will briefly describe the complex structure of the epithelial barrier in the context of bacterial-mucosal interactions observed in human IBD and mouse models of colitis.     

Reconstitution of an endosome-lysosome interaction in a cell-free system

A cell-free model for the transfer of endocytosed material to lysosomes is described. Rat liver late endosomes, loaded in vivo with radiolabeled ligand by intravenous injection shortly before killing the animal, showed a specific interaction with lysosomes when incubated at 37 degrees C in the presence of cytosol and an ATP regenerating system. The location of the ligand, generally asialofetuin, was analyzed by isopycnic centrifugation on Nycodenz gradients. Appearance of radiolabel in the lysosomal position on such gradients was maximal after approximately 30 min at 37 degrees C and required the provision of undamaged cytosol, lysosomes, and an ATP regenerating system. It could not be accounted for by nonspecific bulk aggregation of membranes. Transfer occurred only from late endosomes; radiolabel in early endosomes was unaffected. Digestion of the asialofetuin, as shown by the appearance of TCA-soluble radioactivity, occurred on incubation at 37 degrees C and was increased by the provision of an ATP regenerating system.     

IDDI: integrated domain-domain interaction and protein interaction analysis system

Background

Deciphering protein-protein interaction (PPI) in domain level enriches valuable information about binding mechanism and functional role of interacting proteins. The 3D structures of complex proteins are reliable source of domain-domain interaction (DDI) but the number of proven structures is very limited. Several resources for the computationally predicted DDI have been generated but they are scattered in various places and their prediction show erratic performances. A well-organized PPI and DDI analysis system integrating these data with fair scoring system is necessary.

Method

We integrated three structure-based DDI datasets and twenty computationally predicted DDI datasets and constructed an interaction analysis system, named IDDI, which enables to browse protein and domain interactions with their relationships. To integrate heterogeneous DDI information, a novel scoring scheme is introduced to determine the reliability of DDI by considering the prediction scores of each DDI and the confidence levels of each prediction method in the datasets, and independencies between predicted datasets. In addition, we connected this DDI information to the comprehensive PPI information and developed a unified interface for the interaction analysis exploring interaction networks at both protein and domain level.

Result

IDDI provides 204,705 DDIs among total 7,351 Pfam domains in the current version. The result presents that total number of DDIs is increased eight times more than that of previous studies. Due to the increment of data, 50.4% of PPIs could be correlated with DDIs which is more than twice of previous resources. Newly designed scoring scheme outperformed the previous system in its accuracy too. User interface of IDDI system provides interactive investigation of proteins and domains in interactions with interconnected way. A specific example is presented to show the efficiency of the systems to acquire the comprehensive information of target protein with PPI and DDI relationships. IDDI is freely available at http://pcode.kaist.ac.kr/iddi/.

     

Europe uneasy on stem cell developments

A first round rejection of human stem cell research by the European Parliament has given supporters the jitters in member states keen to pursue the potential offered by the new field, shown by a recent landmark appeal court decision on stem cell therapy by a team of Britain's top judges.     

Virus-neuron interaction: an experimental model

Conclusion These examples demonstrate the usefulness of embryonic neurons for investigation ofneurotropic virus pathogenesis studies. The different steps of viral interactions of neurotropicviruses with the brain necessitate studies of the intrinsic neural properties of the infected cells:1) entry of virus into the intra-cellular compartment, 2) transport of virus from one brainstructure to another brain area, 3) replication of virus in the host-cells, 4) altered brainfunctions. Understanding the mechanisms of neural pathogenesis is a prerequisite for theelaboration of antiviral strategies based upon recovery of the brain from functional alterationsusing drugs active on brain functions.     

Antifreeze proteins: an unusual receptor-ligand interaction

Antifreeze proteins (AFPs) help organisms to survive below 0 degrees C by inhibiting ice growth. Although AFPs are structurally diverse, they typically present a large proportion of their surface area for binding to ice. Whereas earlier proposed binding mechanisms relied almost entirely on a hydrogen bond match between the AFP and ice, it now seems probable that van der Waals and hydrophobic interactions make a significant contribution to the enthalpy of adsorption. These interactions require intimate surface-surface complementarity between the receptor (AFP) and its ligand (ice).     

Malaria and HIV: a silent alliance

HIV and malaria are leading causes of morbidity in sub-Saharan Africa. Recently, Abu-Raddad and colleagues explored the synergy between these diseases through a mathematical model that included all documented interactions. It emerges from the model parameter inputs that concomitant infection of both HIV and malaria fuels the spread of both diseases. For the first time, it is shown that, according to the model, transient but repeatedly elevated HIV viral loads due to recurrent co-infections, such as malaria, can also influence and increase HIV prevalence. Probably, these results are conservative and the true impact of the interaction could be even more important.     

Flow and myocardial interaction: an imaging perspective

Heart failure due to coronary artery disease has considerable morbidity and poor prognosis. An understanding of the underlying mechanics governing myocardial contraction is a prerequisite for interpreting and predicting changes induced by heart disease. Gross changes in contractile behaviour of the myocardium are readily detected with existing techniques. For more subtle changes during early stages of cardiac dysfunction, however, a sensitive method for measuring, as well as a precise criterion for quantifying, normal and impaired myocardial function is required. The purpose of this paper is to outline the role of imaging, particularly cardiovascular magnetic resonance (CMR), for investigating the fundamental relationships between cardiac morphology, function and flow. CMR is emerging as an important clinical tool owing to its safety, versatility and the high-quality images it produces that allow accurate and reproducible quantification of cardiac structure and function. We demonstrate how morphological and functional assessment of the heart can be achieved by CMR and illustrate how blood flow imaging can be used to study flow and structure interaction, particularly for elucidating the underlying haemodynamic significance of directional changes and asymmetries of the cardiac looping. Future outlook on combining imaging with engineering approaches in subject-specific biomechanical simulation is also provided.     

Skeletal muscle-smooth muscle interaction: An unusual myoelastic system

The serratus superficailis metapatagialis (SSM) of pigeons is a skeletal muscle with unusual properties. It lies between the ribs and the trailing edge of the wing, where it is attached to the skin by a system of smooth muscles having elastic tendons. Wing movements during flight induce marked changes in this muscle's length. The SSM inserts onto the deep fascia, and at its termination the skeletal muscle contains large numbers of microtubules. Many myofibrils attach to leptomeric organelles, which then attach to the terminal end of the skeletal muscle fiber. The deep fascia next connects to the dermis of the skin by bundles of smooth muscles that have elastic tendons at both ends. This system allows large movements of the muscle while preventing its fibers from overstretching. The movements and presumed forces acting at this muscle make the presence of sensory receptors such as muscle spindles unlikely. Spindles are absent in this muscle.     

Laser microdissection and cryogenic nuclear magnetic resonance spectroscopy: an alliance for cell type-specific metabolite profiling

Laser microdissection was used as a tool to harvest secretory cavities (SC) from leaves of Dilatris pillansii Barker (Haemodoraceae) and from leaves and flowers of herbarium specimens of Dilatris corymbosa Berg. and Dilatris viscosa L. Cryogenic ¹H NMR spectroscopy and HPLC analysis of microdissected samples indicated specific accumulation of methoxyphenylphenalenones in the SC. The structures of two novel and a known natural product in the secretory tissue were confirmed by comparison with authentic compounds isolated from rhizomes and roots from which further phenylphenalenones and phenylphenalenone glucosides were isolated and identified by spectroscopic methods. How it will be possible to use the LMD technique to localize natural products in specific plant cell populations is also discussed. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. An erratum to this article can be found at     

Dmt and opioid peptides: a potent alliance

The introduction of the Dmt (2',6'-dimethyl-L-tyrosine)-Tic pharmacophore into the design of opioid ligands produced an extraordinary family of potent delta-opioid receptor antagonists and heralded a new phase in opioid research. First reviewed extensively in 1998, the incorporation of Dmt into a diverse group of opioid molecules stimulated the opioid field leading to the development of unique analogues with remarkable properties. This overview will document the crucial role played by this residue in the proliferation of opioid peptides with high receptor affinity (K(i) equal to or less than 1 nM) and potent bioactivity. The discussion will include the metamorphosis between delta-opioid receptor antagonists to delta-agonists based solely on subtle structural changes at the C-terminal region of the Dmt-Tic pharmacophore as well as their behavior in vivo. Dmt may be considered promiscuous due to the acquisition of potent mu-agonism by dermorphin and endomorphin derivatives as well as by a unique class of opioidmimetics containing two Dmt residues separated by alkyl or pyrazinone linkers. Structural studies on the Dmt-Tic compounds were enhanced tremendously by x-ray diffraction data for three potent and biologically diverse Dmt-Tic opioidmimetics that led to the development of pharmacophores for both delta-opioid receptor agonists and antagonists. Molecular modeling studies of other unique Dmt opioid analogues illuminated structural differences between delta- and mu-receptor ligand interactions. The future of these compounds as therapeutic applications for various medical syndromes including the control of cancer-associated pain is only a matter of time and perseverance.     

Chemokines and dendritic cells: a crucial alliance

Dendritic cells (DC) are bone marrow-derived professional antigen-presenting cells that function as sentinels of the immune system. Their importance in immunity resides in their unique ability to prime or tolerize T lymphocytes, thereby initiating or inhibiting immune responses. They reside in all tissues and organs and upon appropriate activation, migrate to secondary lymphoid organs to present antigen to T lymphocytes in the T cell zones. Because of this central role in T cell activation, there is a great deal of interest in using DC therapeutically to deliver positive or negative signals to the immune system. The DC system is critically dependent on the ability of DC at different stages of maturation to respond to a range of soluble and cell-bound signals, including members of the chemokine gene superfamily. This review will describe the interactions between DC and the chemokine system.