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PubMed2000

Proteases involved in erythrocyte invasion by the malaria parasite: function and potential as chemotherapeutic targets.

Malaria places an increasing burden on global public health resources. In the face of growing resistance of the malaria parasite to available antimalarial drugs, there is a need for new drugs and the identification of new chemotherapeutic targets. The malaria parasite has a complex life cycle which includes a number of obligate intracellular stages. Clinical malaria results from cyclic asexual replication of the blood-stage parasite in circulating erythrocytes of the human host. Erythrocyte entry and host cell rupture require the activity of parasite proteases, and these enzymes are, therefore, attractive targets for rational approaches to new drug development. Malarial proteases play a role in at least two distinct aspects of host cell invasion; modification of parasite proteins involved in host cell recognition and entry; and restructuring of the host cell itself, during and following invasion, and in order to allow parasite release from the host cell. This review details recent advances in the identification of these proteases, describes current understanding of their activation and functional role, and discusses their potential as targets for protease inhibitor-based drugs.

Animals↗
PubMed2002

The "primitive" microaerophile Giardia intestinalis (syn. lamblia, duodenalis) has specialized membranes with electron transport and membrane-potential-generating functions.

Here it is shown that the flagellated protozoon Giardia intestinalis, commonly regarded as an early branching eukaryote because of its lack of mitochondria, has membraneous structures that partition the cationic, membrane-potential-sensitive fluorophore rhodamine 123. This organism also reduces a tetrazolium fluorogen at discrete plasma-membrane-associated sites. That these functions occur in distinctive specialized membrane systems supports the growing evidence that G. intestinalis may not be primitive, but is derived from an aerobic, mitochondria-containing flagellate.

Animals↗
PubMed2004

Localizing P300 generators in visual target and distractor processing: a combined event-related potential and functional magnetic resonance imaging study.

Constraints from functional magnetic resonance imaging (fMRI) were used to identify the sources of the visual P300 event-related potential (ERP). Healthy subjects performed a visual three-stimulus oddball paradigm with a difficult discrimination task while fMRI and high-density ERP data were acquired in separate sessions. This paradigm allowed us to differentiate the P3b component of the P300, which has been implicated in the detection of rare events in general (target and distractor), from the P3a component, which is mainly evoked by distractor events. The fMRI-constrained source model explained >99% of the variance of the scalp ERP for both components. The P3b was mainly produced by parietal and inferior temporal areas, whereas frontal areas and the insula contributed mainly to the P3a. This source model reveals that both higher visual and supramodal association areas contribute to the visual P3b and that the P3a has a strong frontal contribution, which is compatible with its more anterior distribution on the scalp. The results point to the involvement of distinct attentional subsystems in target and distractor processing.

Adult↗
PubMed1993

Protein anatomy: functional roles of barnase module.

Globular proteins are composed of several modules that are contiguous polypeptide segments of compact conformation. Module boundaries are closely correlated with the intron positions of genes that encode proteins. The modules may thus have a one-to-one correspondence with exons in primordial genes. They may also be vestiges of polypeptide segments that initially appeared as primordial proteins in prebiological evolution. Clarification as to whether modules disconnected from one another have functional potentiality may validate these possibilities. Thus, in this study, each module of a protein was synthesized and assessed for functional potentiality. For this purpose, barnase, a bacterial ribonuclease, was decomposed into six modules (M1-M6), which were examined to determine whether they have an affinity for RNA and RNase activity. M2, M3, and M6, all of which form a shallow but wide cavity for RNA binding in native barnase, were found to bind to RNA and to possess RNase activity. However, M1 and M5, which support the other modules from the back side, and M4 did not bind to RNA and had no RNase activity. Protein modules with catalytic functions are described in this paper for the first time. That some modules of barnase possess catalytic activity indicates that protein modules may possibly have functioned as primitive catalysts in prebiological evolution.

Amino Acid Sequence↗
PubMed2002

Endocochlear potentials and compound action potential recovery: functions in the C57BL/6J mouse.

The C57BL/6J mouse suffers from cochlear degeneration beginning at an early age and has been used as a model of age-related hearing loss (presbyacusis). Here, the endocochlear potential (EP) and compound action potential (CAP) responses were determined in one-, four-, 12- and 24-month-old C57BL/6J mice. CAP measures included thresholds to tone pips, input/output (I/O) functions, and recovery functions to conditioning tones. EP values among the four age groups did not differ significantly (P>0.05) in either the basal or apical turns. CAP thresholds were increased significantly by 10 to 30 dB in the four-month group compared to the one-month controls at 11.3, 16, 20, and 22.6 kHz. CAP I/O functions were shallower in the four-month group compared to controls at all frequencies. In the 12- and 24-month-old mice, CAP responses were absent, despite normal EP values in these animals. Recovery functions after conditioning tones were obtained at 8, 16, 20 and 22.6 kHz; the functions had fast and slow components at all frequencies tested in both the one- and four-month-old groups. The corresponding recovery curves were identical for both age groups, even with significant threshold shifts in the older group. The two component recovery curves provide the first physiological evidence that different spontaneous rate (SR) classes of auditory neurons exist in the C57BL/6J mouse. Moreover, the unchanged recovery functions in the older group suggest that there was no loss of activity of the low-SR fiber population with age under conditions where the EP remains stable, in contrast to the gerbil model of presbyacusis where there is a loss of low-SR fiber activity and EP does decline with age.

Action Potentials↗
PubMed2005

Dependency of the delocalized charge density and of the structural parameters on the pseudorotational parameter phi in 1,1-dicyanocyclopentane.

Encouraged by the results we recently obtained from the exploration of the dependency of the structural parameters of 1,1-dichlorocyclopentane (J. Chem. Phys. A 2004, 108, 4658) on the pseudorotational parameter phi, we decided to reinvestigate the structure and the potential function governing the conformational equilibrium of 1,1-dicyanocyclopentane (DCCP) in the light of these novel results. The improved potential function we developed describes more adequately the dependency of the geometrical parameters on the pseudorotational phase angle phi. In the present work, we also incorporated additional terms into the equations we developed earlier (J. Chem. Phys. A 2004, 108, 4658; J. Mol. Struct. 2002, 612, 181) for describing the dependency of the distribution of the delocalized net charges throughout the ring on phi to account for the observed systematic deviations between the computed atomic distances and those provided by these equations. Although the overall fit of the electron diffraction was not significantly different from that which we presented previously, however, applying these extended equations has led to a better fit by refining a smaller number of parameters.

Cyclopentanes↗
PubMed1996

Apolipoprotein E secretion by macrophages: its potential physiological functions.

Results of numerous studies using varied experimental approaches have established a role for macrophage-derived apolipoprotein E in modulating cholesterol balance in the arterial wall, thereby potentially modulating progression or regression of the vessel wall atherosclerotic lesion. Macrophage-derived apolipoprotein E could also act on the vessel wall by modulating the aggregability of platelets and the proliferation of lymphocytes. In addition, macrophage-derived apolipoprotein E interacts with extracellular matrix and such interactions could influence the retention of lipoproteins in the vessel wall, the bioavailability of cytokines and growth factors sequestered in the extracellular matrix and the regulation of arterial smooth muscle cell growth by matrix components.

Apolipoproteins E↗
PubMed1994

Optimization of the electrostatic interactions in proteins of different functional and folding type.

The 3-dimensional optimization of the electrostatic interactions between the charged amino acid residues was studied by Monte Carlo simulations on an extended representative set of 141 protein structures with known atomic coordinates. The proteins were classified by different functional and structural criteria, and the optimization of the electrostatic interactions was analyzed. The optimization parameters were obtained by comparison of the contribution of charge-charge interactions to the free energy of the native protein structures and for a large number of randomly distributed charge constellations obtained by the Monte Carlo technique. On the basis of the results obtained, one can conclude that the charge-charge interactions are better optimized in the enzymes than in the proteins without enzymatic functions. Proteins that belong to the mixed alpha beta folding type are electrostatically better optimized than pure alpha-helical or beta-strand structures. Proteins that are stabilized by disulfide bonds show a lower degree of electrostatic optimization. The electrostatic interactions in a native protein are effectively optimized by rejection of the conformers that lead to repulsive charge-charge interactions. Particularly, the rejection of the repulsive contacts seems to be a major goal in the protein folding process. The dependence of the optimization parameters on the choice of the potential function was tested. The majority of the potential functions gave practically identical results.

Computer Simulation↗
PubMed2001

Potential space and reflective functioning. Towards conceptual clarification and preliminary clinical implications.

The authors propose that although the psychoanalytic constructs 'reflective functioning' and 'potential space' overlap and are sometimes used interchangeably, a knowledge of their distinctions and the ways in which they interface have important clinical implications. These concepts are similar in that both are capacities considered (1) to originate in the caregiver-child relationship, (2) to involve playing with ideas and symbolic thought, (3) to facilitate the therapeutic process and (4) to represent a desirable treatment outcome. The terms diverge in three important ways. First, potential space is a broader concept that can be applied not only to thinking about internal states but to aspects of human experience (e.g. art, religion) involving a sense of aliveness. Reflective functioning is more circumscribed to representations of mental states and their implications for interpersonal functioning. Second, potential space has more of a conscious introspective element, whereas reflective functioning is based in procedural memory. Third, reflective functioning operates intrapsychically, whereas potential space tends to be thought of as occurring in an interpersonal field. The authors hypothesise and illustrate a possible bi-directional, dialectic relationship between the two constructs. It is suggested that this new understanding might, in some cases, facilitate productive reformulations of clinical formulations, such as working with a perceived resistance.

Awareness↗
PubMed2004

Global gene expression analysis of the developing postnatal mouse retina.

PURPOSE: Postnatal mouse retinal development involves glial and neuronal differentiation, vascularization, and the onset of vision. In the current study, the gene expression profiles of thousands of genes in the developing postnatal mouse retina were analyzed and compared in a large-scale, unbiased microarray gene expression analysis. METHODS: For each of eight different time points during postnatal mouse retinal development, two separate sets of 30 retinas were pooled for RNA isolation, and gene expression was analyzed by hybridization to gene chips in triplicate (Mu74Av2; Affymetrix, Santa Clara, CA). Genes were sorted into clusters based on their expression profiles and intensities. Validation was accomplished by comparing the microarray expression profiles with real-time RT-PCR analysis of selected genes and by comparing selected expression profiles with predicted profiles based on previous studies. RESULTS: The Mu74Av2 chip contains more than 6000 known genes and 6500 estimated sequence tags (ESTs) from the mouse Unigene database. Of these, 2635 known gene sequences and 2794 ESTs were expressed at least threefold above background levels during retinal development. Expressed genes were clustered based on expression profiles allowing potential functions for specific genes during retinal development to be inferred by comparison to developmental events occurring at each time point. Specific data and potential functions for genes with various profiles are discussed. All data can be viewed online at http://www.scripps.edu/cb/friedlander/gene_expression/. CONCLUSIONS: Expression analysis of thousands of different genes during normal postnatal mouse retinal development as reported in this study demonstrates that such an approach can be used to correlate gene expression with known functional differentiation, presenting the opportunity to infer functional correlates between gene expression and specific postnatal developmental events.

Animals↗
PubMed1997

Reconstructing potential energy functions from simulated force-induced unbinding processes.

One-dimensional stochastic models demonstrate that molecular dynamics simulations of a few nanoseconds can be used to reconstruct the essential features of the binding potential of macromolecules. This can be accomplished by inducing the unbinding with the help of external forces applied to the molecules, and discounting the irreversible work performed on the system by these forces. The fluctuation-dissipation theorem sets a fundamental limit on the precision with which the binding potential can be reconstructed by this method. The uncertainty in the resulting potential is linearly proportional to the irreversible component of work performed on the system during the simulation. These results provide an a priori estimate of the energy barriers observable in molecular dynamics simulations.

Binding Sites↗
PubMed2003

Fasciola hepatica cathepsin L-like proteases: biology, function, and potential in the development of first generation liver fluke vaccines.

Fasciola hepatica secretes cathepsin L proteases that facilitate the penetration of the parasite through the tissues of its host, and also participate in functions such as feeding and immune evasion. The major proteases, cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) are members of a lineage that gave rise to the human cathepsin Ls, Ks and Ss, but while they exhibit similarities in their substrate specificities to these enzymes they differ in having a wider pH range for activity and an enhanced stability at neutral pH. There are presently 13 Fasciola cathepsin L cDNAs deposited in the public databases representing a gene family of at least seven distinct members, although the temporal and spatial expression of each of these members in the developmental stage of F. hepatica remains unclear. Immunolocalisation and in situ hybridisation studies, using antibody and DNA probes, respectively, show that the vast majority of cathepsin L gene expression is carried out in the epithelial cells lining the parasite gut. Within these cells the enzyme is packaged into secretory vesicles that release their contents into the gut lumen for the purpose of degrading ingested host tissue and blood. Liver flukes also express a novel multi-domain cystatin that may be involved in the regulation of cathepsin L activity. Vaccine trials in both sheep and cattle with purified native FheCL1 and FheCL2 have shown that these enzymes can induce protection, ranging from 33 to 79%, to experimental challenge with metacercariae of F. hepatica, and very potent anti-embryonation/hatch rate effects that would block parasite transmission. In this article we review the vaccine trials carried out over the past 8 years, the role of antibody and T cell responses in mediating protection and discuss the prospects of the cathepsin Ls in the development of first generation recombinant liver fluke vaccines.

Animals↗
PubMed2003

The bacterial scaffoldin: structure, function and potential applications in the nanosciences.

Natural protein complexes may provide the best templates for nanometer-scale technology and new biomaterials. The bacterial cellulosome is becoming a well-understood multi-protein complex found in cellulolytic microorganisms. The scaffoldin subunits of the bacterial cellulosome function to organize and position other protein subunits into the complex. The scaffoldins can also serve as an attachment device for harnessing the cellulosome onto the cell surface and/or for its targeting to substrate. Biochemical and molecular biological evidence have identified a receptor/adaptor type of protein domain pair, called "cohesin and dockerin," which is responsible for cellulosome self-assembly. The recognition between cohesin and dockerin is generally type and/or species specific. More than 80 cohesin and 100 dockerin sequences have been found, mostly from anaerobic bacteria. X-ray crystallography and NMR have been used to determine the three-dimensional structures of representative cohesin and dockerin domains, respectively. The cohesin peptide is about 140 amino acids in length and highly conserved in sequence and domain structure. The dockerin domain comprises about 70 amino acids and contains two 22 amino acid duplicated regions, each of which includes an "F-hand" modification of the EF-hand calcium-binding motif. Biochemical evidence and site-directed mutagenesis have confirmed that the two F-hand motifs are required for function and calcium dependence; at least two amino acids from each motif are critical for cohesin-dockerin recognition. In this report, we review the structure and function of the scaffoldin of the bacterial cellulosome and emphasize a detailed sequence analysis of the cohesin and dockerin domains. We also speculate about potential applications in nanoscience that may be based on cohesin-dockerin recognition.

Bacteria↗
PubMed1996

Planar asymmetric lipid bilayers of glycosphingolipid or lipopolysaccharide on one side and phospholipids on the other: membrane potential, porin function, and complement activation.

We have determined some physicochemical properties of the monosaccharide-type fraction (GSL-1) of glycosphingolipids, the major glycolipid components of the outer leaflet of the Gram-negative species Sphingomonas paucimobilis. These properties included the state of order of the hydrocarbon moiety, the effective molecular area, surface charge density, and intrinsic transmembrane potential profile of reconstituted planar asymmetric GSL-1/phospholipid bilayer membranes. We have, furthermore, investigated the insertion into and the function of porin channels in the reconstituted bilayers and the complement-activating capability of GSL-1 surfaces. All results were compared with respective data for deep rough mutant lipopolysaccharide of Salmonella minnesota R595. We found a remarkable agreement in most functional properties of the two glycolipids.

Biophysical Phenomena↗
PubMed1977

Stable conformations of aliphatic disulfides: influence of 1,4 interactions involving sulfur atoms.

The present state of knowledge of the stable conformations of the XCCSSCCX fragment (in which X is any saturated group) of aliphatic disulfides is examined. In particular, the evidence for the existence of attractive 1,4 interactions between CH groups and S atoms across C-S bonds and their influence on the potential function for rotation about C-S bonds is discussed. The effects of similar attractive interactions between NH groups and S atoms on the potential function for rotation about C-C bonds also are considered. It is concluded that weak attractive interactions between CH groups and S atoms are capable of stabilizing rotamers with unusually low (about 30 degrees) values of the SS-CC dihedral angle.

Alkanes↗
PubMed1994

IL-2 receptor alpha chain expression during early B lymphocyte differentiation.

The IL-2/IL-2 receptor (IL-2R) has been studied intensively because of its potential function in the development and regulation of the immune system. The IL-2R alpha chain has been shown to be expressed on CD4-CD8- thymocytes and activated T and B cells. In this report, we show that IL-2R alpha is also expressed on precursor B cells in the bone marrow. Its expression is initiated by functional rearrangement and expression of Ig mu heavy chain gene and is down-regulated when immature B cells mature and express IgD. Its potential function in early B cell differentiation is discussed in comparison with its role in thymocyte differentiation.

Animals↗