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PubMedDate not supplied

Molecular characterization of surface topology in protein tertiary structures by amino-acylation and mass spectrometric peptide mapping.

Amino-acetylation and -succinylation reactions in combination with mass spectrometric peptide mapping of tryptic peptide mixtures have been employed for surface topology-probing of lysine residues in bovine ribonuclease A, lysozyme, and horse heart myoglobin as model proteins of different surface structures. Direct molecular weight determinations identifying the precise number of acyl groups in partially modified proteins were obtained by electrospray and 252Cf-plasma desorption mass spectrometry. Electrospray mass spectra of multiply protonated molecular ions and deuterium exchange experiments provided a relative conformational characterization of protein derivatives and enabled the direct determinations of intact, partially acylated heme-myoglobin derivatives. Tryptic peptide mapping analysis, using plasma desorption and fast atom bombardment mass spectrometry, ascertained by mass spectrometric characterization of HPLC-separated modified peptides, yielded the exact identification of acylation sites. Relative reactivities of the amino acylation were derived from the peptide mapping data and from quantitative estimations of modified peptides upon acetylation/trideuteroacetylation and provided direct correlations with the relative surface accessibilities of lysine-epsilon-amino groups taken from X-ray crystallographic structure data of the proteins. The reactive lysine-41 residue in ribonuclease A which is part of the substrate binding site was directly identified from the mass spectrometric data. These results indicate tertiary structure-selective acylation combined with mass spectrometric peptide mapping as an efficient approach for the molecular characterization of surface topology and reactive fundamental lysine residues in proteins.

Acylation↗

PubMed1991

Conformational studies of a peptide corresponding to a region of the C-terminus of ribonuclease A: implications as a potential chain-folding initiation site.

Conformational properties of the OT-16 peptide, the C-terminal 20 amino acids of RNase A, were examined by nonradiative energy transfer. A modified OT-16 peptide was prepared by solid-phase synthesis with the inclusion of diaminobutyric acid (DABA) at the C-terminus. The OT-16-DABA peptide was labeled with a fluorescent 1,5-dimethylaminonaphthalene sulfonyl (dansyl, DNS) acceptor at the N-terminal amine and a fluorescent naphthoxyacetic acid (NAA) donor at the gamma-amine of the DABA located at the C-terminus of the peptide by using an orthogonal protection scheme. Energy transfer was monitored in DNS-OT-16-DABA-NAA by using both fluorescence intensity (sensitized emission) and lifetime (donor quenching) experiments. The lifetime data indicate that the peptide system is a dynamic, flexible one. A detailed analysis, based on a dynamic model that includes a skewed Gaussian function to model the equilibrium distribution of interprobe distances and a mutual diffusion coefficient between the two probes to model conformational dynamics in the peptide [Beechem & Haas (1989) Biophys. J. 55, 1225.], identified the existence of a partially ordered structure (relatively narrow distribution of interprobe distances) at temperatures greater than or equal to 20 degrees C in the absence of denaturant. The width and the position of the average of the distributions decrease with increasing temperature, in this range; this suggests that the structure is stabilized by hydrophobic interactions. In addition, the peptide undergoes cold denaturation at around 1.5 degrees C as indicated by broadening of the distance distribution. The addition of 6 M guanidine hydrochloride (Gdn-HCl) also broadens the distance distribution significantly, presumably by eliminating the hydrophobic interactions and unfolding the peptide. The results of the analysis of the distance distribution demonstrate that (1) nonradiative energy transfer can be used to study the conformational dynamics of peptides on the nanosecond time scale, (2) a partially ordered structure of OT-16-DABA exists in solution under typical refolding conditions, and (3) structural constraints (presumably hydrophobic interactions) necessary for the formation of a chain-folding initiation site in RNase A are also present in the OT-16-DABA peptide in the absence of denaturant and are disrupted by Gdn-HCl.

Amino Acid Sequence↗

PubMed1992

Isolation of dominant negative mutants and inhibitory antisense RNA sequences by expression selection of random DNA fragments.

Selective inhibition of specific genes can be accomplished using genetic suppressor elements (GSEs) that encode antisense RNA, dominant negative mutant proteins, or other regulatory products. GSEs may correspond to partial sequences of target genes, usually identified by trial and error. We have used bacteriophage lambda as a model system to test a concept that biologically active GSEs may be generated by random DNA fragmentation and identified by expression selection. Fragments from eleven different regions of lambda genome, encoding specific peptides or antisense RNA sequences, rendered E. coli resistant to the phage. Analysis of these GSEs revealed some previously unknown functions of phage lambda, including suppression of the cellular lambda receptor by an 'accessory' gene of the phage. The random fragment selection strategy provides a general approach to the generation of efficient GSEs and elucidation of novel gene functions.

Bacterial Outer Membrane Proteins↗

PubMed1992

Protecting the ischemic spinal cord during aortic clamping. The influence of anesthetics and hypothermia.

Infrarenal circumaortic occlusion devices were operatively placed in 74 New Zealand white rabbits. Two days after operation the animals were randomly assigned to one of seven treatment groups: I, control, n = 23; II, halothane, n = 8; III, thiopental, n = 12; IV, ketamine (30 mg/kg intravenously), n = 6; V, halothane+hypothermia, n = 8; VI, thiopental+hypothermia, n = 12; VII, ketamine+hypothermia, n = 5. In each group, the infrarenal aorta was occluded for 21 minutes. Final neurologic recovery after restitution of blood flow was graded as acute paraplegia, delayed paraplegia (neurologic deficit developing after initial recovery), or normal. Halothane alone was of no benefit. Hypothermia with any anesthetic was completely protective and reduced neurologic deficits to 0% compared with 91% in controls (p less than 0.05). Thiopental and ketamine treatment each reduced acute paraplegia to 17% (as compared with 61% in controls) and increased delayed paraplegia from 30% in controls to 75% and 50%, respectively (p less than 0.05 for thiopental, p = 0.10 for ketamine). The authors interpret the increase in delayed deficits and decrease in acute deficits as being the result of partial spinal cord protection. These findings document that this model of spinal cord ischemia is sufficiently sensitive to identify interventional treatments that protect the ischemic spinal cord.

Anesthetics↗

PubMed1992

Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants.

1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1982

Discrete versus continuous stage models of human information processing: in search of partial output.

This article introduces a new technique designed to study the flow of information through processing stages in choice reaction time tasks. The technique was designed to determine whether response preparation can begin before stimulus identification is complete ("continuous" models), or if a stimulus must be fully identified prior to any response activation ("discrete" models). To control the information available at various times during stimulus identification, some relevant stimulus characteristics were made easy to discriminate and some were made hard to discriminate. The experimental strategy was to look for effects of partial output based on information conveyed by characteristics that were easy to discriminate. The technique capitalized on the fact, demonstrated in Experiment 1, that preparation of two response fingers on the same hand is more effective than preparation of two response fingers on different hands. The usefulness of partial output was varied by manipulating the assignments of stimuli to responses. For some mappings partial information could contribute to effective response preparation because the responses consistent with partial information were assigned to fingers on the same hand. For other mappings partial information could not contribute to effective response preparation because the responses consistent with partial information were assigned to fingers of different hands. Performance differences between these mappings were considered evidence that partial information about a stimulus was transmitted to response activation processes before the stimulus was uniquely identified, and thus were considered evidence against discrete transmission of information about the stimulus as a whole. A variety of stimulus sets were studied; the results suggest that information is transmitted discretely with respect to stimulus codes, although distinct codes activated by a single stimulus may be transmitted at different times.

Adult↗

PubMed2024

Synergistic removal of total petroleum hydrocarbons and antibiotic resistance genes in Yellow River Delta wetlands contaminated soil composting regulated by biogas slurry addition.

The interactive effects between the emerging contaminant antibiotic resistance genes (ARGs) and the traditional pollutant total petroleum hydrocarbons (TPHs) in contaminated soils remain unclear. The synergistic removal of TPHs and ARGs from composted contaminated soil, along with the microbial mechanisms driven by the addition of biogas slurry, have not yet been investigated. This study explored the impact of biogas slurry on the synergistic degradation mechanisms and bacterial community dynamics of ARGs and TPHs in compost derived from contaminated soil. The addition of biogas slurry resulted in a reduction of targeted ARGs and mobile genetic elements (MGEs) by 9.96%-95.70% and 13.32%-97.66%, respectively. Biogas slurry changed the succession of bacterial communities during composting, thereby reducing the transmission risk of ARGs. Pseudomonas, Cellvibrio, and Devosia were identified as core microorganisms in the synergistic degradation of ARGs and TPHs. According to the partial least squares path model, temperature and NO3- indirectly influenced the removal of ARGs and TPHs by directly regulating the abundance and composition of host microbes and MGEs. In summary, the results of this study contribute to the high-value utilization of biogas slurry and provide methodological support for the low-cost remediation of contaminated soils.

Composting↗

PubMed1987

Muscle models: what is gained and what is lost by varying model complexity.

Three structurally different types of models have evolved over the years to describe muscle-joint systems. The first, based on an input-output analysis of a given task, results in a simple second-order differential equation description that is adequate over a certain movement operating range. The second, based on the classic structural model of Hill (1938), results in a higher-order nonlinear model described by ordinary differential equations. The third, based on an analysis of the biophysical contractile mechanism, results in a complex partial differential equation description. The advantages and disadvantages of each type of model are considered, based on the criteria of identifying the simplest model that can adequately simulate any fundamental type of human movement without modifying model parameters for different tasks. It is shown that an eighth-order Hill-based antagonistic muscle-joint model is able to satisfy these criteria for a given joint if each of the four basic mechanically-significant non-linearities of the system are included in the model. This same model structure has been used successfully for eight different muscle-joint systems, ranging in size from knee flexion-extension to eye rotation--the only difference between the models is in the parameter values. Second-order models are shown to be task-specific special cases of the input-output behavior of the eighth-order model, while the more complex biophysical models are hypothesized to have insignificant advantages and many disadvantages over the Hill-based model during normal human movement.

Animals↗

PubMedDate not supplied

Evaluation of amniotic membrane as adhesion prophylaxis in a novel surgical gastroschisis model.

Adhesions are a leading cause of bowel obstruction and infertility. The coverage of peritoneal defects, as in gastroschisis, is still a crucial problem. Despite biodegradable substitutes and synthetic implants such as PTFE membrane, a satisfactory replacement for gastroschisis has not been identified. The amniotic membrane, which is available at birth with a low antigenicity, was evaluated as a peritoneal substitute. Viable, partially viable, and inversed-used amniotic membranes were compared in a rat model. A full-thickness abdominal wall defect was made and the amniotic membrane sutured into this defect. The skin was closed over the amniotic membrane. Reoperation was performed 3 weeks after initial surgery, and the adhesion formation was measured by computerized area calculation. Viable amniotic membrane showed 0 to 3% area adhesion formation, while partially viable (50%) amniotic membrane demonstrated 33% area adhesion formation. Inversed-used amniotic membrane, with the stromal side directed toward the abdominal cavity, showed 70% of the amniotic membrane area to be covered with adhesions. The same amount was found in the control group, in which no substitute was sutured into the defect. This animal model is suitable for the straightforward evaluation of peritoneal substitutes with regard to adhesion formation. It is easy to perform and mimics surgical needs. Viable amniotic membrane proved to be an excellent antiadhesive tissue.

Abdominal Muscles↗

PubMed1986

Effects of tumor growth on host defenses.

Monocytes and macrophages play an important role in host defense against neoplasia. Studies from our and other laboratories have demonstrated that patients with a variety of cancers have a defect in monocyte chemotactic responses. Tumor-bearing mice are also inhibited in their ability to accumulate macrophages to inflammatory foci. We have shown that extracts prepared from murine tumors, as well as the plasma and urine of tumor-bearing mice, contain anti-inflammatory proteins which are antigenically and physicochemically related to the immunosuppressive retroviral envelope protein p15E. Similarly, proteins capable of inhibiting monocyte chemotactic responses are present in human cancerous effusions and can be specifically absorbed by monoclonal antibodies to p15E. Furthermore, we have demonstrated that human malignant and mitogen-transformed cells contain p15E-related antigens. These findings led us to propose a two stage model of tumorigenesis: the first stage involves neoplastic transformation of a cell while the second stage involves activation of a gene coding for a p15E-like protein which allows the transformed cell to escape immune surveillance and go on to become a tumor. Support for this model has come from recent studies which have identified within the human genome an endogenous retrovirus sequence whose envelope gene is partially homologous to a highly conserved region of p15E. Using a synthetic peptide, termed CKS-17, we have shown that this region may be responsible for many of the biological activities of p15E and is capable of suppressing lymphocyte and natural killer cell immune functions as well as those of monocytes and macrophages. Thus tumors may be capable of evading host defense mechanisms by activation of a normal gene related to the immunosuppressive retroviral protein p15E.

Animals↗

PubMed1992

Molecular mimicry of hepatitis B surface antigen by an anti-idiotype-derived synthetic peptide.

Monoclonal antibody 2F10 is an "internal-image" anti-idiotype (anti-id) antibody capable of mimicking the group-specific "a" determinant of human hepatitis B surface antigen (HBsAg). By mRNA sequencing and computer-assisted molecular modeling of monoclonal antibody 2F10, we identified a 15-amino acid region of the heavy-chain hypervariable region that has partial residue homology with sequences of the "a" determinant epitopes of HBsAg. We have established that a linear 15-mer peptide from a contiguous region on the anti-id antibody can (i) generate anti-HBsAg-specific antibodies when injected into mice, (ii) prime murine lymph node cells for in vitro HBsAg-specific T-cell proliferative responses, and (iii) stimulate in vitro human CD4+ T cells that were primed in vivo to HBsAg by natural infection with hepatitis B virus or vaccination with a commercially available HBsAg vaccine. Significantly, this peptide could also stimulate CD4+ T cells of human hepatitis B virus carriers. We conclude that a 15-mer peptide derived from the anti-id sequence can duplicate the B- and T-cell stimulatory activity of the intact anti-id antibody and the antigen that is mimicked, HBsAg.

Amino Acid Sequence↗

PubMed1990

Novel monoclonal antibodies identify antigenic determinants unique to cellular senescence.

Normal human diploid fibroblasts exhibit a limited lifespan in vitro and are used as a model to study in vivo aging. Monoclonal antibodies were generated against partially purified surface membranes from human diploid fibroblasts at the end of their lifespan (senescent). Three hybridomas were isolated that secreted antibodies reacting to cellular determinants expressed specifically on senescent human fibroblasts of different origin, including neonatal foreskin, embryonic lung, and adult skin punch biopsy, but not expressed on matched young cells. The antibodies did not bind to immortal human cells and normal young cells made reversibly nondividing, indicating the antigens are not expressed in cells that are not senescent. The antibodies identified senescent cells in a mixed cell population and expression of the senescent cell antigens correlated strongly with the cells inability to synthesize DNA at the onset of senescence. The antigens appeared to be cell surface or extracellular matrix associated, and the epitopes were destroyed by mild trypsin treatment. Western analysis indicated all three antibodies reacted with fibronectin. Though the antigenic determinants on the fibronectin molecule were not accessible in the intact young cell, the epitopes were present in fibronectin extracted from both senescent and young cells, as well as purified human plasma fibronectin. These antibodies and the senescent specific expression of the antigens provide powerful tools to investigate the mechanisms leading to in vitro senescence. This may enable us to investigate directly the relationship between cellular aging and aging of the individual.

Aging↗

PubMed1991

Prognostic modeling of clinical outcomes: an illustration with data from patients with membranous nephropathy.

Probabilities that a patient will occupy any of five clinically defined compartments at different future times are generated and graphed by a personal computer. The probabilities are functions of a patient's relevant baseline characteristics (treated or control group), clinical status, and follow-up time at which the prognosis is made. The illustrative prognostic model is based on a reanalysis of detailed individual records for 81 patients with idiopathic membranous nephropathy (42 treated with methylprednisolone and chlorambucil; 39 controls) in a randomized clinical trial. The compartments to and from which patients may pass are identified as (1) complete remission, (2) partial remission, (3) the nephrotic syndrome, (4) renal failure, and (5) death. Estimated risk functions for transitions between compartments involve baseline treatment, and intermediate and temporal variables, together with their relevant interactions. The model illustrates how, despite the overall advantage of treated over control patients, the comparative prognoses can change greatly and can even sometimes be reversed, depending on a variety of follow-up experiences.

Computer Simulation↗

PubMed1990

Serine proteinase requirement for the extra-cellular metabolism of pulmonary surfactant.

Pulmonary surfactant as lavaged from the alveoli exists in at least three structural subtypes, lamellar body-like, tubular myelin and vesicular forms that can be separated on the basis of their buoyant densities. Previous studies have suggested that surfactant is secreted in the lamellar body form and metabolized through the other subtypes in sequence. This metabolic sequence can be reproduced in vitro by cyclic expansion and contraction ('cycling') of the surface area of nascent surfactant at 38 degrees C. Cycling of nascent secretion, which is predominantly of lamellar body-like buoyant density, rapidly converted it to the buoyant density of tubular myelin and then to that of the vesicular subtype. We examined the role of proteinases in the conversion of nascent surfactant subtypes in vitro. Addition of metallo-, cysteine- and acid-proteinase inhibitors to the cycling mix did not inhibit the conversion of tubular myelin to vesicular subtype. However, a variety of serine proteinase inhibitors inhibited the formation of vesicular subtype. Their inhibitory effect was dose-related and most marked for alpha 1-antitrypsin where a concentration equal to that found in the alveolar fluid lining layer resulted in 50% inhibition of the generation of light subtype, suggesting physiological relevance. The enzyme(s) responsible for promoting the generation of light subtype was sedimentable and therefore presumably in particulate form. By differential centrifugation of lung secretions it was separable from alveolar macrophages and partially separable from surfactant itself. It has not been identified, nor has its substrate. We conclude that in vitro cycling provides a model for the study of alveolar surfactant metabolism and that the conversion of tubular myelin to vesicular forms of surfactant requires serine proteinase activity.

Animals↗

PubMed1979

A stochastic compartment model of stomach cancer with correlated waiting time distributions.

The incidence and growth rate of stomach cancer in the US population is modelled, for each sex, as a partially observed, discrete state stochastic process. Explicit evaluation of the transition rates between the states of the model is made possible by identifying them as specific functions of the time spent within each state. The functions used in the model were selected from the medical and epidemiological literature. With the model it was found possible to obtain fits to the age distribution of deaths due to stomach cancer for white males in 1975 and for selected age ranges for white females. These results suggested that the natural history of stomach cancer is different for females above and below age 65.

Adult↗

PubMed1991

Additive and multiplicative relative risk in the two-stage clonal expansion model of carcinogenesis.

The effects of exposure to two carcinogens are explored within the context of the two-stage clonal expansion model of carcinogenesis. This biologically based model provides a useful framework for the quantitative description of carcinogenesis, and for defining carcinogenic agents that act as initiators, promoters, and completers. This paper addresses the combined effects of simultaneous lifetime exposure to two carcinogens as well as nonoverlapping partial lifetime exposure to each agent. Whereas the age-specific relative risk for exposure to two initiators or two completers is additive, a multiplicative relative risk model holds for exposure to an initiator and a completer, or to a promoter and a completer. Exposure to two promoters yields supra-multiplicative relative risk. Exposure to an initiator and promoter leads to multiplicative and supra-multiplicative relative risks for simultaneous lifetime and nonoverlapping partial lifetime exposures, respectively. Although departures from the additive relative risk model may thus occur at moderate to high doses, conditions are identified under which additivity will provide a good approximation to the joint risk at low doses. The methods of analysis used in this paper can also be used to determine the joint effects of exposure to two carcinogens which may affect more than one stage (initiation, promotion, completion) of the process of carcinogenesis. In general, the joint effects of exposure to such agents depends on the relative magnitude of the effects on individual stages.

Animals↗

PubMed1994

Premature strand transfer by the HIV-1 reverse transcriptase during strong-stop DNA synthesis.

Reverse transcription of retroviral genomes starts near the 5' end of the viral RNA by use of an associated tRNA primer. According to the current model of reverse transcription, the initial cDNA product, termed minus-strand strong-stop DNA, 'jumps' to a repeated sequence (R region) at the 3' end of the RNA template. The human retroviruses have relatively long R regions (97-247 nucleotides) when compared to murine and avian viruses (16-68 nucleotides). This suggests that the full complement of the R region is not required for strand transfer and that partial cDNA copies of the 5' R can prematurely jump to the 3' R. To test this hypothesis, we generated mutants of the human immunodeficiency virus with R region changes and analyzed whether 5' or 3' R sequences were inherited by the progeny. We found that in most cases, 5' R-encoded sequences are dominant, which is consistent with the model of reverse transcription. Using a selection protocol, however, we were also able to identify progeny viruses with R sequences derived from the original 3' R element. These results suggest that partial strong stop cDNAs can be transferred with R region homologies much shorter than 97 nucleotides.

Base Sequence↗

PubMed1983

Identification of a trans-acting regulatory factor involved in the control of the pyrimidine pathway in E. coli.

A pyrimidine auxotroph of Escherichia coli was isolated which contained a defect in its ability to synthesize both oroate phosphoribosyl transferase, the product of the gene pyrE, and orotidine monophosphate decarboxylase, product of the gene pyrF. A single location on the E. coli linkage map was found to be responsible for the loss of both enzyme activities. This gene was located near cysE at 80.55 min by a combination of Hfr crosses and P1 transductions. The pyrimidine requirement was also corrected by episome F'140 which was found not to carry any pyrimidine structural genes. These data confirm the existence of a new gene, pyrS, unlinked to any previously mapped pyrimidine structural gene, responsible for partial control of pyrimidine biosynthesis. A spontaneous revertant of the mutant strain was also identified which displayed constitutive levels of aspartate transcarbamylase, dihydroorotase, dihydroorotate dehydrogenase, orotidine monophosphate decarboxylase, and limited levels of orotate phosphoribosyl transferase. A model is proposed in which the pyrS gene product is an activator protein, necessary for the transcription of the pyrE and pyrF genes. This activator protein is nonfunctional in the original mutant strain, and partially functional in the revertant strain. The data presented here cannot rule out an alternative mechanism involving a repressor.

Escherichia coli↗