Stretching lattice models of protein folding

A new class of experiments that probe folding of individual protein domains uses mechanical stretching to cause the transition. We show how stretching forces can be incorporated in lattice models of folding. For fast folding proteins, the analysis suggests a complex relation between the force dependence and the reaction coordinate for folding.

From cell death to embryo arrest: Mathematical models of human preimplantation embryo development

Human preimplantation embryos exhibit high levels of apoptotic cells and high rates of developmental arrest during the first week in vitro. The relation between the two is unclear and difficult to determine by conventional experimental approaches, partly because of limited numbers of embryos. We apply a mixture of experiment and mathematical modeling to show that observed levels of cell death can be reconciled with the high levels of embryo arrest seen in the human only if the developmental competence of embryos is already established at the zygote stage, and environmental factors merely modulate this. This suggests that research on improving in vitro fertilization success rates should move from its current concentration on optimizing culture media to focus more on the generation of a healthy zygote and on understanding the mechanisms that cause chromosomal and other abnormalities during early cleavage stages.

Web-based access to mouse models of human cancers: the Mouse Tumor Biology (MTB) Database

The Mouse Tumor Biology (MTB) Database serves as a curated, integrated resource for information about tumor genetics and pathology in genetically defined strains of mice (i.e., inbred, transgenic and targeted mutation strains). Sources of information for the database include the published scientific literature and direct data submissions by the scientific community. Researchers access MTB using Web-based query forms and can use the database to answer such questions as ‘What tumors have been reported in transgenic mice created on a C57BL/6J background?’, ‘What tumors in mice are associated with mutations in the Trp53 gene?’ and ‘What pathology images are available for tumors of the mammary gland regardless of genetic background?’. MTB has been available on the Web since 1998 from the Mouse Genome Informatics web site (http://www.informatics.jax.org). We have recently implemented a number of enhancements to MTB including new query options, redesigned query forms and results pages for pathology and genetic data, and the addition of an electronic data submission and annotation tool for pathology data.

Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease

This investigation was pursued to test the use of intracellular antibodies (intrabodies) as a means of blocking the pathogenesis of Huntington's disease (HD). HD is characterized by abnormally elongated polyglutamine near the N terminus of the huntingtin protein, which induces pathological protein–protein interactions and aggregate formation by huntingtin or its exon 1-containing fragments. Selection from a large human phage display library yielded a single-chain Fv (sFv) antibody specific for the 17 N-terminal residues of huntingtin, adjacent to the polyglutamine in HD exon 1. This anti-huntingtin sFv intrabody was tested in a cellular model of the disease in which huntingtin exon 1 had been fused to green fluorescent protein (GFP). Expression of expanded repeat HD-polyQ-GFP in transfected cells shows perinuclear aggregation similar to human HD pathology, which worsens with increasing polyglutamine length; the number of aggregates in these transfected cells provided a quantifiable model of HD for this study. Coexpression of anti-huntingtin sFv intrabodies with the abnormal huntingtin-GFP fusion protein dramatically reduced the number of aggregates, compared with controls lacking the intrabody. Anti-huntingtin sFv fused with a nuclear localization signal retargeted huntingtin analogues to cell nuclei, providing further evidence of the anti-huntingtin sFv specificity and of its capacity to redirect the subcellular localization of exon 1. This study suggests that intrabody-mediated modulation of abnormal neuronal proteins may contribute to the treatment of neurodegenerative diseases such as HD, Alzheimer's, Parkinson's, prion disease, and the spinocerebellar ataxias.

Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease.

DNA vaccines expressing herpes simplex virus type 2 (HSV-2) full-length glycoprotein D (gD), or a truncated form of HSV-2 glycoprotein B (gB) were evaluated for protective efficacy in two experimental models of HSV-2 infection. Intramuscular (i.m.) injection of mice showed that each construction induced neutralizing serum antibodies and protected the mice from lethal HSV-2 infection. Dose-titration studies showed that low doses (< or = 1 microgram) of either DNA construction induced protective immunity, and that a single immunization with the gD construction was effective. The two DNAs were then tested in a low-dosage combination in guinea pigs. Immune sera from DNA-injected animals had antibodies to both gD and gB, and virus neutralizing activity. When challenged by vaginal infection with HSV-2, the DNA-immunized animals were significantly protected from primary genital disease.

Slip complexity in dynamic models of earthquake faults.

We summarize recent evidence that models of earthquake faults with dynamically unstable friction laws but no externally imposed heterogeneities can exhibit slip complexity. Two models are described here. The first is a one-dimensional model with velocity-weakening stick-slip friction; the second is a two-dimensional elastodynamic model with slip-weakening friction. Both exhibit small-event complexity and chaotic sequences of large characteristic events. The large events in both models are composed of Heaton pulses. We argue that the key ingredients of these models are reasonably accurate representations of the properties of real faults.

Computational models of cortical visual processing.

The visual responses of neurons in the cerebral cortex were first adequately characterized in the 1960s by D. H. Hubel and T. N. Wiesel [(1962) J. Physiol. (London) 160, 106-154; (1968) J. Physiol. (London) 195, 215-243] using qualitative analyses based on simple geometric visual targets. Over the past 30 years, it has become common to consider the properties of these neurons by attempting to make formal descriptions of these transformations they execute on the visual image. Most such models have their roots in linear-systems approaches pioneered in the retina by C. Enroth-Cugell and J. R. Robson [(1966) J. Physiol. (London) 187, 517-552], but it is clear that purely linear models of cortical neurons are inadequate. We present two related models: one designed to account for the responses of simple cells in primary visual cortex (V1) and one designed to account for the responses of pattern direction selective cells in MT (or V5), an extrastriate visual area thought to be involved in the analysis of visual motion. These models share a common structure that operates in the same way on different kinds of input, and instantiate the widely held view that computational strategies are similar throughout the cerebral cortex. Implementations of these models for Macintosh microcomputers are available and can be used to explore the models' properties.

Periodicity of strong nucleosome positioning sites around the chicken adult beta-globin gene may encode regularly spaced chromatin.

Positioned nucleosomes contribute to both the structure and the function of the chromatin fiber and can play a decisive role in controlling gene expression. We have mapped, at high resolution, the translational positions adopted by limiting amounts of core histone octamers reconstituted onto 4.4 kb of DNA comprising the entire chicken adult beta-globin gene, its enhancer, and flanking sequences. The octamer displays extensive variation in its affinity for different positioning sites, the range exhibited being about 2 orders of magnitude greater than that of the initial binding of the octamer. Strong positioning sites are located 5' and 3' of the globin gene and in the second intron but are absent from the coding regions. These sites exhibit a periodicity (approximately 200 bp) similar to the average spacing of nucleosomes on the inactive beta-globin gene in vivo, which could indicate their involvement in packaging the gene into higher-order chromatin structure. Overlapping, alternative octamer positioning sites commonly exhibit spacings of 20 and 40 bp, but not of 10 bp. These short-range periodicities could reflect features of the core particle structure contributing to the pronounced sequence-dependent manner in which the core histone octamer interacts with DNA.

Models of speech synthesis.

The term "speech synthesis" has been used for diverse technical approaches. In this paper, some of the approaches used to generate synthetic speech in a text-to-speech system are reviewed, and some of the basic motivations for choosing one method over another are discussed. It is important to keep in mind, however, that speech synthesis models are needed not just for speech generation but to help us understand how speech is created, or even how articulation can explain language structure. General issues such as the synthesis of different voices, accents, and multiple languages are discussed as special challenges facing the speech synthesis community.

Models of natural language understanding.

This paper surveys some of the fundamental problems in natural language (NL) understanding (syntax, semantics, pragmatics, and discourse) and the current approaches to solving them. Some recent developments in NL processing include increased emphasis on corpus-based rather than example- or intuition-based work, attempts to measure the coverage and effectiveness of NL systems, dealing with discourse and dialogue phenomena, and attempts to use both analytic and stochastic knowledge. Critical areas for the future include grammars that are appropriate to processing large amounts of real language; automatic (or at least semi-automatic) methods for deriving models of syntax, semantics, and pragmatics; self-adapting systems; and integration with speech processing. Of particular importance are techniques that can be tuned to such requirements as full versus partial understanding and spoken language versus text. Portability (the ease with which one can configure an NL system for a particular application) is one of the largest barriers to application of this technology.