Prediction of the structure of a receptor-protein complex using a binary docking method.

To validate procedures of rational drug design, it is important to develop computational methods that predict binding sites between a protein and a ligand molecule. Many small molecules have been tested using such programs, but examination of protein-protein and peptide-protein interactions has been sparse. We were able to test such applications once the structures of both the maltose-binding protein (MBP) and the ligand-binding domain of the aspartate receptor, which binds MBP, became available. Here we predict the binding site of MBP to its receptor using a 'binary docking' technique in which two MBP octapeptide sequences containing mutations that eliminate maltose chemotaxis are independently docked to the receptor. The peptides in the docked solutions superimpose on their original positions in the structure of MBP and allow the formation of an MBP-receptor complex. The consistency of the computational and biological results supports this approach for predicting protein-protein and peptide-protein interactions.     

Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.     

Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1.

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.     

An Ig-A-like substance in the chicken's pineal

Summary Immunohistochemistry revealed an Ig-A-like substance on the luminal surface of the pineal follicles and in the parafollicular layer. This substance was observed around 1 week of age and disappeared by 8 weeks at the time when the transformation of the follicular pattern leads to an adult-type pineal tissue.     

Statecharts for Distributed Product Data Management System Modelling

Product data management (PDM) has been accepted as an important tool for the manufacturing industries. In recent years, more and mor e researches have been conducted in the development of PDM. Their research area s include system design, integration of object-oriented technology, data distri bution, collaborative and distributed manufacturing working environment, secur ity, and web-based integration. However, there are limitations on their rese arches. In particular, they cannot cater for PDM in dis...     

Effect of 15(R)-15-methyl-prostaglandin E2 on iron absorption in the rat

Summary The administration of 15(R)-15-methyl prostaglandin E₂ (15(R)-15-M-PGE₂) in vivo significantly diminished the uptake of⁵⁹Fe into blood, spleen, liver, femur and dried intestine of rats, whereas acetylsalicylic acid (ASA) increased the counts significantly. This effect of ASA was counteracted by 15(R)-15-M-PGE₂. It is suggested that prostaglandins (PGs) might play an important role in inhibiting iron absorption at the intestinal level.This work was supported by grant No.6638 from CONICET (Argentina). The technical assistance of Mrs María E. Castro and Norma Rizzo is gratefully acknowleged.     

Leaning Towards Agile in 21~(st) Century

Background: During the last fifteen years there ha s been an increased drive for organisations to reduce costs. From a production po int, this has often centred on lean manufacturing and JIT waste elimination proc esses. However, in 1991, the Iaccocca Institute Bethlehem P.A commissioned a re port specifically to analyse the changing nature of the marketplace. As a result , in the following year, the Agile Manufacturing Forum was initiated and the ter m ‘agile or responsive manufacturing‘ was first intr...     

Pragmatism in Economic Methodology: The Duhem-Quine Thesis Revisited

Contemporary developments in economicmethodology have produced a vibrant agenda ofcompeting positions. These include, amongothers, constructivism, critical realism andrhetoric, with each contributing to the Realistvs. Pragmatism debate in the philosophies of thesocial sciences. A major development in theneo-pragmatist contribution to economicmethodology has been Quine's pragmatic assaulton the dogmas of empiricism, which are nowclearly acknowledged within contemporaryeconomic methodology. This assault isencapsulated in the celebrated Duhem-Quinethesis, which according to a number ofcontemporary leading philosophers of economics,poses a particularly serious methodologicalproblem for economics. This problem, asreflected in Hausman's analysis, consists ofthe inability of economics to learn fromexperience, thereby subverting the capacity totest economic theories. In this paper wedispute this position. Our argument is basedon a combination of Quine's holism with VanFraassen's constructive empiricism, especiallythe latter's analysis of empirical adequacy andhis pragmatic approach to explanation. Theresulting reorientation of economic methodologyrestores the capacity of economics to learnfrom experience and reinstates the imperativeof developing alternatives to orthodoxtheorizing in economics.     

Coalignment of vimentin intermediate filaments with microtubules depends on kinesin.

Intermediate filaments in most types of cultured cells coalign with microtubules. Depolymerization of microtubules results in collapse of vimentin and desmin intermediate filaments to the nucleus where they form a perinuclear cap. Collapse can also be induced by microinjection of antibodies against intermediate filament or microtubule proteins. Thus, two filament systems interact with each other. But the molecules mediating this interaction are unknown. One of the candidates for this role is a microtubule motor kinesin. Recent data showed that kinesin is involved in the plus end-directed movement of the membranous organelles along microtubules such as radial extension of lysosomes in macrophages and centrifugal movement of pigment in melanophores. Here we report that injection of the anti-kinesin antibody into human fibroblasts results in the redistribution of intermediate filaments to a tight perinuclear aggregate but had no effect on the distribution of microtubules. Thus, kinesin is involved not only in organelle movement but also in interaction of the two major cytoskeletal systems, intermediate filaments and microtubules.