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PubMed1996

NMR solution structure of an oligodeoxynucleotide duplex containing the exocyclic lesion 3,N4-etheno-2'-deoxycytidine opposite thymidine: comparison with the duplex containing deoxyadenosine opposite the adduct.

The exocyclic 3,N4-etheno-2'-deoxycytidine adduct was incorporated at the center of the oligodeoxynucleotide duplex d(C-G-T-A-C-epsilon C-C-A-T-G-C).d (G-C-A-T-G-T-G-T-A-C-G), and its solution structure was analyzed using high-resolution proton NMR spectroscopy and molecular dynamics simulations. The experimental data indicate that the oligodeoxynucleotide duplex adopts a right-handed helical structure with sugar puckers in the C2'-endo/C3'-exo range and Watson-Crick hydrogen bond alignments for all base pairs. NOE connectivities established a syn orientation for the glycosidic torsion angle of the exocyclic adduct. Restrained molecular dynamics simulations, using the full relaxation matrix approach, produced a three-dimensional model in agreement with the experimental data. The structure shows only minor perturbations in the sugar-phosphate backbone and a 27 degrees bend of the helical axis at the lesion site. On the refined model a well-formed hydrogen bond between T (N3H) and epsilon C(N4) stabilizes the epsilon C(syn).T(anti) base pair alignment, reflecting the preference of the adduct for the syn orientation. Furthermore, the epsilon C(syn).T(anti) base pair stacks with flanking base pairs. We discuss a correlation between the mutagenic properties of the adduct and the three-dimensional structure of the epsilon C.dA and epsilon C.T duplexes.

Base Composition↗
PubMed1997

A leucine zipper-like sequence from the cytoplasmic tail of the HIV-1 envelope glycoprotein binds and perturbs lipid bilayers.

HIV-1 transmembrane envelope glycoprotein (gp41) has an unusually long cytoplasmic domain that has secondary associations with the inner leaflet of the membrane. Two highly amphiphatic alpha-helices in the cytoplasmic domain of gp41 have previously been shown to interact with lipid bilayers. We have detected a highly conserved leucine zipper-like sequence between the two alpha-helices. A peptide corresponding to this segment (residues 789-815, LLP-3) aggregates in aqueous solution, but spontaneously inserts into phospholipid membranes and dissociates into alpha-helical monomers. The peptide perturbs the bilayer structure resulting in the formation of micelles and other non-bilayer structures. Tryptophan fluorescence quenching experiments using brominated phospholipids revealed that the peptide penetrates deeply into the hydrophobic milieu of the membrane bilayer. The peptide interacts equally with zwitterionic and negatively-charged phospholipid membranes and is protected from proteolytic digestion in its membrane-bound state. Polarized attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy showed that the LLP-3 alpha-helix axis is about 70 degrees from the normal to the membrane plane. The ATR-FTIR CH2-stretching dichroic ratio increases when the peptide is incorporated into pure phospholipid membranes, further indicating that the peptide can deeply penetrate and perturb the bilayer structure. Integrating these data with what is already known about the membrane-associating features of adjacent segments, we propose a revised structural model in which a large portion of the cytoplasmic tail of the HIV-1 envelope glycoprotein is associated with the membrane.

Amino Acid Sequence↗
PubMed2004

Nodal and Cripto-1: embryonic pattern formation genes involved in mammary gland development and tumorigenesis.

Members of the TGFbeta superfamily and EGF-CFC family, such as Nodal and Cripto, are important mediators of anterior-posterior and left-right axis specification during embryogenesis. In this paper, we review the role of Nodal and Cripto as critical morphogen-like molecules, with an emphasis on Nodal and EGF-CFC signaling during embryonic pattern formation. New evidence from gene expression and transgenic mouse studies have shown that both Nodal and Cripto-1 are expressed within the mammary duct and that modulation of these genes can disrupt normal branching morphogenesis resulting in epithelial disorganization and defective ductal architecture. We describe these new findings and propose that Cripto and Nodal are candidate mammary morphogens. Finally, the data linking overexpression of Cripto and perturbations of Cripto signaling to cell transformation and tumor formation are discussed. The fact that Cripto can modulate multiple pathways suggests it may act to deregulate growth inhibitors/homeostasis factors early in the cell transformation process and then activate prosurvival pathways dependent on MAPK and PI3K/Akt later in fully transformed phenotypes.

Animals↗
PubMed2002

Nitrogen loss from unpolluted South American forests mainly via dissolved organic compounds.

Conceptual and numerical models of nitrogen cycling in temperate forests assume that nitrogen is lost from these ecosystems predominantly by way of inorganic forms, such as nitrate and ammonium ions. Of these, nitrate is thought to be particularly mobile, being responsible for nitrogen loss to deep soil and stream waters. But human activities-such as fossil fuel combustion, fertilizer production and land-use change-have substantially altered the nitrogen cycle over large regions, making it difficult to separate natural aspects of nitrogen cycling from those induced by human perturbations. Here we report stream chemistry data from 100 unpolluted primary forests in temperate South America. Although the sites exhibit a broad range of environmental factors that influence ecosystem nutrient cycles (such as climate, parent material, time of ecosystem development, topography and biotic diversity), we observed a remarkably consistent pattern of nitrogen loss across all forests. In contrast to findings from forests in polluted regions, streamwater nitrate concentrations are exceedingly low, such that nitrate to ammonium ratios were less than unity, and dissolved organic nitrogen is responsible for the majority of nitrogen losses from these forests. We therefore suggest that organic nitrogen losses should be considered in models of forest nutrient cycling, which could help to explain observations of nutrient limitation in temperate forest ecosystems.

Ecosystem↗
PubMed2026

AI proteomics: from protein identification to virtual cells.

Artificial intelligence (AI) is transforming scientific research, including proteomics. In this Perspective, we highlight key mass spectrometry (MS)-based proteomics areas where AI is driving innovation, ranging from protein identification to building AI virtual cells. These include improving peptide and protein identification and quantification; characterizing protein-protein interactions and protein complexes; advancing spatial and perturbation proteomics; integrating multi-omics data; and, ultimately, enabling AI virtual cells. Finally, we call for global collaboration among data producers, data consumers and other stakeholders to establish an AI-friendly ecosystem for MS-based proteomics, laying the foundation for transformative advancements in proteomics driven by AI.

Proteomics↗
PubMedDate not supplied

Plasmon transmissivity and reflectivity of narrow grooves in a silver film.

Surface plasmon (SP) reflectivity and transmissivity of narrow grooves in silver films are studied. The SP source is the probe of a scanning near-field optical microscope. Locally detected leakage radiation from the SP provides detailed information on the paths of SP propagation, in particular the influence of perturbations. Global detection provides representative average data on the SP properties of a given metal film and its structures. A groove of 200 nm width, for instance, reflects/transmits about 15%/80% of 'blue-green' SP radiation at normal incidence.

Journal Article↗
PubMed1999

The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat.

The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.

Adrenergic alpha-Agonists↗
PubMed1996

Platelet responsiveness in migrainous children during headache-free period.

Results of this study confirm the link between migraine and alterations of platelet responsiveness. Our data suggest that in migraineurs the perturbated platelet microviscosity, analyzed by means of fluorescence polarization, appears responsible for the decrease of stimulation-induced influx of external calcium through the platelet membrane. These findings suggest that platelet membrane microviscosity may be considered as a more significant platelet marker of migraine rather than the well-known and nonspecific phenomenon of platelet hyperaggregation, evaluated by time-transmittance variations induced by adenosine diphosphate and collagen.

Blood Platelets↗
PubMed2005

Time-dependent four-component relativistic density-functional theory for excitation energies. II. The exchange-correlation kernel.

We extend our previous formulation of time-dependent four-component relativistic density-functional theory [J. Gao, W. Liu, B. Song, and C. Liu, J. Chem. Phys. 121, 6658 (2004)] by using a noncollinear form for the exchange-correlation kernel. The new formalism can deal with excited states involving moment (spin)-flipped configurations which are otherwise not accessible with ordinary exchange-correlation functionals. As a first application, the global potential-energy curves of 16 low-lying omega omega-coupled electronic states of the AuH molecule have been investigated. The derived spectroscopic parameters, including the adiabatic and vertical excitation energies, equilibrium bond lengths, harmonic and anharmonic vibrational constants, fundamental frequencies, and dissociation energies, are grossly in good agreement with those of ab initio multireference second-order perturbation theory and the available experimental data.

Journal Article↗
PubMed2003

Targeting Schwann cells by nonlytic arenaviral infection selectively inhibits myelination.

Members of the arenavirus family, famous for their hemorrhagic syndromes, cause distinct neurological disorders; however, cellular and molecular targets as well as pathogenesis of peripheral nervous system disorders associated with these viruses are unknown. Using noncytolytic lymphocytic choriomeningitis virus, the prototype arenavirus, and pseudotyped Lassa fever virus, we showed that the Schwann cells, but not the neurons, were preferentially targeted and harbored the virus. This permissiveness was caused by the viral glycoprotein usage of its receptor alpha-dystroglycan, which was highly abundant on Schwann cell membranes. Persistent lymphocytic choriomeningitis virus infection rendered immature Schwann cells defective or incapable of forming compact myelin sheathes when they differentiated to myelinating phenotype in an in vitro differentiation model of Schwann cells. Persistent infection did not cause Schwann cell apoptosis or cytopathic effect. Defects in myelination coincided with the down-regulation of dystroglycan expression and disruption of the laminin-2 organization and basal lamina assembly on Schwann cell-axon units. The data provide evidence for a selective perturbation of laminin-2-laminin-2 receptor communication pathway in the peripheral nervous system by a nonlytic virus and the resulting myelin defects, which may partly contribute to neurological abnormalities associated with arenaviral infection.

Animals↗
PubMed1998

Antiproliferative mechanism of action of cryptophycin-52: kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends.

Cryptophycin-52 (LY355703) is a new synthetic member of the cryptophycin family of antimitotic antitumor agents that is currently undergoing clinical evaluation. At high concentrations (>/=10 times the IC50), cryptophycin-52 blocked HeLa cell proliferation at mitosis by depolymerizing spindle microtubules and disrupting chromosome organization. However, low concentrations of cryptophycin-52 inhibited cell proliferation at mitosis (IC50 = 11 pM) without significantly altering spindle microtubule mass or organization. Cryptophycin-52 appears to be the most potent suppressor of microtubule dynamics found thus far. It suppressed the dynamic instability behavior of individual microtubules in vitro (IC50 = 20 nM), reducing the rate and extent of shortening and growing without significantly reducing polymer mass or mean microtubule length. Using [3H]cryptophycin-52, we found that the compound bound to microtubule ends in vitro with high affinity (Kd, 47 nM, maximum of approximately 19.5 cryptophycin-52 molecules per microtubule). By analyzing the effects of cryptophycin-52 on dynamics in relation to its binding to microtubules, we determined that approximately 5-6 molecules of cryptophycin-52 bound to a microtubule were sufficient to decrease dynamicity by 50%. Cryptophycin-52 became concentrated in cells 730-fold, and the resulting intracellular cryptophycin-52 concentration was similar to that required to stabilize microtubule dynamics in vitro. The data suggest that cryptophycin-52 potently perturbs kinetic events at microtubule ends that are required for microtubule function during mitosis and that it acts by forming a reversible cryptophycin-52-tubulin stabilizing cap at microtubule ends.

Antineoplastic Agents↗
PubMed2000

A novel protein that binds juvenile hormone esterase in fat body tissue and pericardial cells of the tobacco hornworm Manduca sexta L.

Juvenile hormone esterase degrades juvenile hormone, which acts in conjunction with ecdysteroids to control gene expression in insects. Circulating juvenile hormone esterase is removed from insect blood by pericardial cells and degraded in lysosomes. In experiments designed to characterize proteins involved in the degradation of juvenile hormone esterase, a pericardial cell cDNA phage display library derived from the tobacco hornworm moth Manduca sexta L. was constructed and screened for proteins that bind juvenile hormone esterase. A 732-base pair cDNA encoding a novel 29-kDa protein (P29) was isolated. Western and Northern analyses indicated that P29 is present in both pericardial cell and fat body tissues and is expressed in each larval instar. In immunoprecipitation experiments, P29 bound injected recombinant juvenile hormone esterase taken up by pericardial cells and native M. sexta juvenile hormone esterase in fat body tissue, where the enzyme is synthesized. Binding assays showed that P29 bound juvenile hormone esterase more strongly than it did a mutant form of the enzyme with mutations that perturb lysosomal targeting. Based on these data, we propose that P29 functions in pericardial cells to facilitate lysosomal degradation of juvenile hormone esterase.

Amino Acid Sequence↗
PubMed1994

Evidence for defects in membrane traffic in Paramecium secretory mutants unable to produce functional storage granules.

The ciliated protozoan Paramecium has a regulated secretory system amenable to genetic analysis. The secretory storage granules, known as trichocysts, enclose a crystalline matrix with a genetically determined shape whose biogenesis involves proteolytic maturation of a family of precursor molecules into a heterogeneous set of small acidic polypeptides that crystallize within the maturing vesicles. We have developed an original pulse-chase protocol for monoxenic Paramecium cultures using radiolabeled bacteria to study the processing of trichocyst matrix proteins in wild-type and mutant cells. In wild-type cells, proteolytic processing is blocked in the presence of monensin and otherwise rapidly completed after approximately 20 min of chase, suggesting that the conversion occurs in the trans-Golgi and/or in small vesicles soon after sorting to the regulated pathway, probably before crystallization begins. In trichless mutant cells, which contain no visible trichocysts, secretory proteins are synthesized but not processed and we report constitutive secretion of the uncleaved precursor molecules. The mutation thus appears to affect sorting to the regulated pathway and should prove useful for analysis of the sorting machinery and of the relationship between sorting and proteolytic processing of secretory proteins. In mutants bearing misshapen trichocysts with poorly crystallized contents (tam33, tam38, stubbyA), the proteolytic processing of the trichocyst matrix proteins appears to be normal, while both pulse-chase and morphological data indicate that intracellular transport is perturbed, probably between ER and Golgi. Precursor molecules are present in the mutant trichocysts but not in wild-type trichocysts and may account for the defective crystallization. Our analysis of these mutants suggests that the temporal coordination of intracellular traffic plays a regulatory role in granule maturation.

Animals↗
PubMed1998

Inefficient postural responses to unexpected slips during walking in older adults.

BACKGROUND: Slips account for a high percentage of falls and subsequent injuries in community-dwelling older adults but not in young adults. This phenomenon suggests that although active and healthy older adults preserve a mobility level comparable to that of young adults, these older adults may have difficulty generating efficient reactive postural responses when they slip. This study tested the hypothesis that active and healthy older adults use a less effective reactive balance strategy than young adults when experiencing an unexpected forward slip occurring at heel strike during walking. This less effective balance strategy would be manifested by slower and smaller postural responses, altered temporal and spatial organization of the postural responses, and greater upper trunk instability after the slip. METHODS: Thirty-three young adults (age range=19-34 yrs, mean=25+/-4 yrs) and 32 community-dwelling older adults (age range=70-87 yrs, mean=74+/-14 yrs) participated. Subjects walked across a movable forceplate which simulated a forward slip at heel strike. Surface electromyography was recorded from bilateral leg, thigh, hip, and trunk muscles. Kinematic data were collected from the right (perturbed) side of the body. RESULTS: Although the predominant postural muscles and the activation sequence of these muscles were similar between the two age groups, the postural responses of older adults were of longer onset latencies, smaller magnitudes, and longer burst durations compared to young adults. Older adults also showed a longer coactivation duration for the ankle, knee, and trunk agonist/antagonist pairs on the perturbed side and for the knee agonist/antagonist pair on the nonperturbed side. Behaviorally, older adults became less stable after the slips. This was manifested by a higher incidence of being tripped (21 trials in older vs 5 trials in young adults) and a greater trunk hyperextension with respect to young adults. Large arm elevation was frequently used by older adults to assist in maintaining trunk stability. In an attempt to quickly reestablish the base of support after the slips, older adults had an earlier contralateral foot strike and shortened stride length. CONCLUSION: The combination of slower onset and smaller magnitude of postural responses to slips in older adults resulted in an inefficient balance strategy. Older adults needed secondary compensatory adjustments, including a lengthened response duration and the use of the arms, to fully regain balance and prevent a fall. The shorter stride length and earlier contralateral foot strike following the slip indicate use of a more conservative balance strategy in older adults.

Accidental Falls↗
PubMed1999

Phase-dependent modulation of proximal and distal postural responses to slips in young and older adults.

BACKGROUND: Phase-dependent modulation of postural responses plays an important functional role in integrating reflexes into ongoing locomotion behaviors. This study tested the hypotheses that proximal and distal postural responses are modulated differently according to the phases of the gait cycle in young adults and that there is a decline in this modulatory ability with normal aging. METHODS: Thirty-three healthy young adults (age = 25 +/- 4 years) and 32 healthy older adults (mean age 74 +/- 14 years) participated. Subjects walked across a movable force plate with its movement timed to heel strike or midstance to simulate a forward slip occurring at different times during the gait cycle. Surface electromyography was recorded from bilateral leg, thigh, hip, and trunk muscles. Kinematic data were collected from the right (perturbed) side of the body. RESULTS: Postural responses to the heel strike slips occurred more frequently, and were of shorter latency, longer burst duration, and greater burst magnitude, than those in response to the midstance slips. Whereas the early and predominant postural responses came from bilateral tibialis anterior, rectus femoris, and biceps femoris muscles in heel strike slips, early postural responses were observed in bilateral erector spinae muscles in midstance slips. The late postural responses in midstance slips (from bilateral biceps femoris muscles and medial gastrocnemius and tibialis anterior of the nonperturbed leg) assisted in foot liftoff of the perturbed leg and earlier and safe landing with the nonperturbed leg. In response to the heel strike versus midstance slips, older adults preserved the phase-dependent modulatory abilities of the occurrence, onset latency, and burst duration of their postural responses, but not the ability to modulate burst magnitude, as compared to young adults. CONCLUSION: Postural responses from the proximal and distal muscles in reaction to different temporal phasing of slips during the step cycle showed differential modulation to meet the different task requirements. Older adults preserve this modulatory ability but with limited capacity. Physiological or psychological factors may influence older adults' phase-dependent modulatory capacity.

Accidental Falls↗
PubMed1982

Envelope protein synthesis and inhibition of cell division in Escherichia coli during inactivation of the B subunit of DNA gyrase.

The rates of synthesis of inner and outer membrane proteins of Escherichia coli K12 during inhibition of cell division have been studied. When cell division was inhibited, either by treatment of wild-type cells with the antibiotic clorobiocin (an inhibitor of the B subunit of DNA gyrase) or by a temperature shift of a gyrB-ts mutant, a 40% reduction in the rate of synthesis of total outer membrane protein relative to that of the inner membrane was observed. When a gyrB-ts mutant was shifted to high temperature under conditions which allowed continued cell division, this large reduction in the rate of synthesis of outer membrane protein relative to inner membrane protein was not observed. In contrast to the results obtained with clorobiocin, inhibition of cell division by the beta-lactam antibiotic cefuroxime did not cause any detectable disturbance in the rate of synthesis of either inner or outer membrane protein. This demonstrates that inhibition of septum formation per se does not perturb synthesis of envelope protein. The data obtained are consistent with a model in which the rate of synthesis and therefore expansion of outer membrane is one of many conditions which must be satisfied before septum formation can occur. The results are discussed in relation to such a model, and to previous findings which have shown that the rate of synthesis of outer membrane proteins displays a linear mode with an abrupt doubling in rate at a discrete point in the cell cycle.

Bacterial Proteins↗
PubMed1999

Independent statistical observables for ultrametric disordered populations.

It is not exceptional that a sample of N random data X(i), i=1,...,N contains ultrametric covariations, namely the matrix C with matrix elements - is ultrametric. We define independent (decorrelated) "collective" observables by diagonalizing this matrix. Symmetry properties of such eigenvectors are discussed. Often also, however, while the existence of an ultrametric tree is known, the degrees of parentage of the data are unknown, because a random perturbation confuses the labeling of the leaves of the tree. We sort out those observables which are more robust with respect to such labeling mistakes.

Genetic Heterogeneity↗
PubMed2001

Determination of the quadratic slope parameter in eta-->3pi(0) decay.

We have determined the quadratic slope parameter alpha for eta-->3pi(0) to be alpha = -0.031(4) from a 99% pure sample of 10(6)eta-->3pi(0) decays produced in the reaction pi(-)p-->n(eta) close to the eta threshold using the Crystal Ball detector at the AGS. The result is four times more precise than the present world data and disagrees with current chiral perturbation theory calculations by about four standard deviations.

Journal Article↗