Strategies In the Desigh of Antiviral Drugs

Here, the author describe the rationale behind current and future drug-based strategies for combating viral infections.

Relationship Between Fibrinogen Protein and Fibrinogen Function in Postmyocardial Infarction Patients

The present study investigates the association between increases in the concentration and function of plasma fibrinogen in two groups of patients with chronic ischemic heart disease.

Plasminogen activator inhibitor-1 is a major stress-regulated gene: Implications for stressinduced thrombosis in aged individuals

Plasminogen activator inhibitor-1 (PAI-1) is one of the primary inhibitors of the fibrinolytic system and has been implicated in a variety of thrombotic disorders.

Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?

This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials.

Nitric oxide and cytochrome oxidase:substrate, inhibitor or effector?

Endogenously produced nitric oxide (NO) controls oxygen consumption by inhibiting cytochrome c oxidase, the terminal electron acceptor of the mitochondrial electron transport chain.

The molecular architecture of the TNF superfamily

TNF ligands share a common structural motif, the TNF homology domain (THD), which binds to cysteine-rich domains (CRDs) of TNF receptors. CRDs are composed of structural modules, whose variation in number and type confers heterogeneity upon the family.

Tumor necrosis factor-α converting enzyme

Tumor necrosis factor-α converting enzyme (TACE/ADAM17/CD156q) is a member of the ‘A Disintegrin And Metalloprotease’, or ADAM, family.

Function of the voltage gate of gap junction channels: Selective exclusion of molecules

Gap junction channels formed by most connexins are affected by transjunctional voltage. The function of the voltage gate is unclear, because substantial electrical coupling typically remains with activated gates because of the channels dwelling in subconductance rather than closed states.

Multisite Phosphorylation and the Countdown to S Phase

Remarkably, SCFCdc4 ubiquitin ligase binds and ubiquitinates Sic1 decorated with six, but not five, phosphates (Nash et al., 2001). This numerical wizardry suggests how analog inputs can be rectified to digital outputs. Unraveling the counting mechanism promises to generate new insights into the architecture of protein nanoprocessors.

Arp2/3 Complex: Advances on the Inner Workings of a Molecular Machine

Several new papers report progress on the structure and function of Arp2/3 complex. A crystal structure, a cryo-EM structure, and a reconstitution of the complex from subunits have been reported. New results also address the nucleation mechanism and the role of bound nucleotide.

MEF2: a calcium-dependent regulator of cell division, differentiation and death

Recent studies have revealed a central role for the myocyte enhancer factor-2 (MEF2) family of transcription factors in linking calcium-dependent signaling pathways to the genes responsible for cell division, differentiation and death. This article describes the post-translational mechanisms that confer calcium-sensitivity to MEF2 and its downstream target genes, and considers how this transcription factor can control diverse and mutually exclusive cellular decisions.

ITAMs versus ITIMs: striking a balance during cell regulation

Functional immune responses evolve through an exquisitely controlled process integrating signals from activating and inhibitory receptors on the immune cell surface. These complex interactions, which regulate both the quality and magnitude of the ultimate response, depend crucially on two short, loosely conserved motifs found in the intracellular domain of various signaling proteins. These motifs, termed “ITAMs” and “ITIMs” for immunoreceptor tyrosine-based activation (or inhibititory) motifs, provide the basis for two opposed signaling modules that duel for control of cellular activation within the immune system.

Guard Cell Signaling

The plant hormone abscisic acid (ABA) regulates the aperture of the stomatal pore. The recent identification of new intermediates involved in ABA signaling suggests that this complex pathway is organized as a module-based network.

14-3-3 Proteins: Active Cofactors in Cellular Regulation by Serine/Threonine Phosphorylation

The 14-3-3 proteins are a family of abundant, widely expressed 28–33-kDa acidic polypeptides that spontaneously self-assemble as dimers. The 14-3-3 proteins were first detected by virtue of their relatively high abundance in brain extracts and given their unique name (an unfailing source of curiosity) based on their fraction number on DEAE-cellulose chromatography and migration position on starch gel electrophoresis

Recent demonstrations of the specific immune prevention of mammary cancer in female BALB/c mice transgenic for the rat Her-2/neu oncogene (BALB-neuT) have resulted in reconsideration of the immune mechanisms that inhibit tumor growth. All the mammary glands of these mice progress asynchronously, but consistently, from hyperplasia to invasive carcinoma.

Plant Biotechnology in China

A survey of China’s plant biotechnologists shows that China is developing the largest plant biotechnology capacity outside of North America. The list of genetically modified plant technologies in trials, including rice, wheat, potatoes, and peanuts, is impressive and differs from those being worked on in other countries.

Will toxicogenomics turn toxicology into a predictive and preventive science?

Why does one person contract an environment-related disease when their neighbour never shows as much as a symptom? This is one of several perplexing questions that a new national toxicogenomics research consortium hopes to answer.

Running rings around RNA:a superfamily of phosphate-dependent RNases

Protein therapeutics: promises and challenges for the 21st century

Recent advances in massively parallel experimental and computational technologies are leading to radically new approaches to the early phases of the drug production pipeline. The revolution in DNA microarray technologies and the imminent emergence of its analogue for proteins, along with machine learning algorithms, promise rapid acceleration in the identification of potential drug targets, and in high-throughput screens for subpopulationspecific toxicity.

Nitric oxide and cytochrome oxidase: substrate, inhibitor or effector?

Minireview Muscular Dystrophy-Reason for Optimism?

Characterization of the mechanisms underlying various types of muscular dystrophy has been an outstanding triumph of molecular biology. Increasing clarification of the aberrant cellular processes responsible for these conditions may ultimately permit the development of effective means for molecular intervention, allowing correction of the abnormal cellular physiology that results in the dystrophic phenotype.

Health economic evaluation

A glossary is presented on terms of health economic evaluation. Definitions are suggested for the more common concepts and terms.

DRUG DISCOVERY BY DYNAMIC COMBINATORIAL LIBRARIES

Dynamic combinatorial chemistry is a recently introduced supramolecular approach that uses self-assembly processes to generate libraries of chemical compounds. In contrast to the stepwise methodology of classical combinatorial techniques, dynamic combinatorial chemistry allows for the generation of libraries based on the continuous interconversion between the library constituents. Spontaneous assembly of the building blocks through reversible chemical reactions virtually encompasses all possible combinations, and allows the establishment of adaptive processes owing to the dynamic interchange of the library constituents. Addition of the target ligand or receptor creates a driving force that favours the formation of the best-binding constituent — a self-screening process that is capable, in principle, of accelerating the identification of lead compounds for drug discovery.

HIGH-THROUGHPUT CRYSTALLOGRAPHY FOR LEAD DISCOVERY IN DRUG DESIGN

Knowledge of the three-dimensional structures of protein targets now emerging from genomic data has the potential to accelerate drug discovery greatly. X-ray crystallography is the most widely used technique for protein structure determination, but technical challenges and time constraints have traditionally limited its use primarily to lead optimization. Here, we describe how significant advances in process automation and informatics have aided the development of high-throughput X-ray crystallography, and discuss the use of this technique for structure-based lead discovery.

Chloride channels are different

Proteins that conduct chloride ions are vital for a range of cellular processes. The long-awaited crystal structure of a chloride channel shows what these proteins look like, and gives hints about how they work.

The crystal structure of the final component of the three-part anthrax toxin shows how it disables a host signalling molecule, while simultaneously using that molecule to stimulate its own activity.

Animal genomes contain an abundance of small genes that produce regulatory RNAs of about 22 nucleotides in length. These microRNAs are diverse in sequence and expression patterns, and are evolutionarily widespread, suggesting that they may participate in a wide range of genetic regulatory pathways.