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PubMed1981

An electrical tuning mechanism in turtle cochlear hair cells.

1. Intracellular recordings were made from single cochlear hair cells in the isolated half-head of the turtle. The electrical responses of the cells were recorded under two conditions: (a) when the ear was stimulated with low-intensity tones of different frequencies and (b) when current steps were injected through the intracellular electrode. The aim of the experiments was to evaluate the extent to which the cochlea's frequency selectivity could be accounted for by the electrical properties of the hair cells.2. At low levels of acoustic stimulation, the amplitude of the hair cell's receptor potential was proportional to sound pressure. The linear tuning curve, which is defined as the sensitivity of the cell as a function of frequency when the cell is operating in its linear range, was measured for a number of hair cells with characteristic frequencies from 86 Hz to 425 Hz.3. A rectangular current passed into a hair cell elicited a membrane potential change consisting of a damped oscillation superimposed on a step. Small currents produced symmetrical oscillations at the beginning and end of the pulse. Larger currents increased the initial ringing frequency if depolarizing and decreased it if hyperpolarizing.4. For small currents the frequency of the oscillations and the quality factor (Q) of the electrical resonance derived from the decay of the oscillations were close to the characteristic frequency and Q of the hair-cell linear tuning curve obtained from sound presentations.5. The hair cell's membrane potential change to small-current pulses or low-intensity tone bursts could be largely described by representing the hair cell as a simple electrical resonator consisting of an inductance, resistor and capacitor.6. When step displacements of 29-250 nm were applied to a micropipette, placed just outside a hair cell in the basilar papilla, an initial periodic firing of impulses could be recorded from single fibres in the auditory nerve. Currents of up to 1 nA, injected through the same micropipette, failed to produce any change in the auditory nerve discharge. The experiment demonstrates that current injection does not produce gross movements of the electrode tip.7. The contribution of the electrical resonance to hair-cell tuning was assessed by dividing the linear tuning curve by the cell's impedance as a function of frequency. The procedure assumes that the electrical resonance is independent of other filtering stages, and on this assumption the resonance can account for the tip of the acoustical tuning curve.8. The residual filter produced by the division was broad; it exhibited a high-frequency roll-off with a corner frequency at 500-600 Hz, similar in all cells, and a low-frequency roll-off, with a corner frequency from 30 to 350 Hz which varied from cell to cell but was uncorrelated with the characteristic frequency of the cell.9. The phase of the receptor potential relative to the sound pressure at the tympanum was measured in ten cells. For low intensities the phase characteristic was independent of the sound pressure. At low frequencies the receptor potential led the sound by 270-360 degrees , and in the region of the characteristic frequency there was an abrupt phase lag of 90-180 degrees ; the abruptness of the phase change depended upon the Q of the cell.10. The calculated phase shift of the electrical resonator as a function of frequency was subtracted from the phase characteristic of the receptor potential. The subtraction removed the sharp phase transition around the characteristic frequency, and in this frequency region the residual phase after subtraction was approximately constant at +180 degrees . This is consistent with the idea that the hair cells depolarize in response to displacements of the basilar membrane towards the scala vestibuli. The high-frequency region of the residual phase characteristic was similar in all cells.11. It is concluded that each hair cell contains its own electrical resonance mechanism which accounts for most of the frequency selectivity of the receptor potential. All cells also show evidence of a broad band-pass filter, the high frequency portion of which may be produced by the action of the middle ear.

Animals↗

PubMed1997

Fully automatic identification of AC and PC landmarks on brain MRI using scene analysis.

We describe a method for identification of brain structures from MRI data sets. The bulk of the paper concerns an automatic system for finding the anterior and posterior commissures [(AC) and (PC)] in the midsagittal plane. These landmarks are key for the definition of the Talairach space, commonly used in stereotactic neurosurgery, in the definition of common coordinate systems for the pooling of functional positron emission tomography (PET) images and for neuroanatomy studies. The process works according to a step-by-step procedure: it first analyzes the skull limits. A grey-level histogram is then calculated and allows an automated selection of thresholds. Then, the interhemispheric plane is detected. Following an advanced scene analysis in the midsagittal plane for anatomical structures, the AC and the PC are identified. Experimentally, with a set of 200 patients, the process never failed. Its performances and limits are comparable to that of neuroanatomy experts. Those results are due to a high degree of robustness at each step of the program.

Algorithms↗

PubMed1987

Measurement of postcryopreservation viability.

For any tissue, there is a cell viability threshold below which the ability of the tissue to maintain itself and function will eventually be compromised. During cryopreservation and subsequent thawing of tissues there are many steps involved, each with attendant potential risks for reduction of viability. To determine the effectiveness of any cryopreservation procedure it is important to select appropriate assays. In this manuscript viability assays, in general, are reviewed from a biological viewpoint prior to review of methods employed for assessment of heart valve viability. Both in situ and in vitro assays of heart valve viability indicate that valve mechanical properties and the majority of fibroblasts, which are responsible for maintenance of the valve connective tissue, are retained after cryopreservation.

Cryopreservation↗

PubMed1994

Quinolone resistance mutations in the DNA gyrase gyrA and gyrB genes of Staphylococcus aureus.

A 6.4-kb DNA fragment containing the DNA gyrase gyrA and gyrB genes was cloned and sequenced from the quinolone-susceptible Staphylococcus aureus type strain ATCC 12600. An expression plasmid was constructed by inserting the cloned genes into the Escherichia coli-S. aureus shuttle vector pAT19, and deletion plasmids carrying only functional gyrA and gyrB genes were derived from this plasmid. An efficient transformation system for S. aureus RN4220 was established by using these plasmids. Quinolone-resistant mutants of S. aureus RN4220 were isolated by three-step selection with quinolones. The first- and second-step mutants were considered to be transport mutants, and the third-step mutants were divided into five groups with respect to their resistance patterns and transformation results with gyrA and gyrB genes. Sequencing analysis of the resulting mutant gyrase genes showed that they had the following point mutations: group 1, Ser-84 (TCA) to Leu (TTA) in GyrA; group 2, Ser-84 (TCA) to Ala (GCA), Ser-85 (TCT) to Pro (CCT), or Glu-88 (GAA) to Lys (AAA) in GyrA; group 3, Asp-437 (GAC) to Asn (AAC) in GyrB; group 4, Arg-458 (CGA) to Gln (CAA) in GyrB; and group 5, Ser-85 (TCT) to Pro (CCT) in GyrA and Asp-437 (GAC) to Asn (AAC) in GyrB. When the gyrA and/or gyrB mutants were transformed with the wild-type gyrA and/or gyrB plasmids, they became quinolone susceptible, but transformants with the plasmids having the same mutations on the gyrA and/or gyrB genes did not confer susceptibility. These results indicate that mutations in both gyrA and gyrB can be responsible for quinolone resistance in S. aureus.

Amino Acid Sequence↗

PubMed1988

Isolation and analysis of hepatoma nuclear proteins using monoclonal antibodies.

Monoclonal antibodies were prepared to nuclear nonhistone proteins from a 2-aminoacetyl fluorine-induced transplantable rat hepatocellular carcinoma. These antibodies recognized a total of six distinct antigens as revealed by molecular weight analysis. Studies of antigen specificity with respect to various tissues, tumors, cultured cells, and oncodevelopmental stages indicated that these nuclear species could be divided into two categories. Four antigens were classified as tumor related since they were significantly enriched in tumor tissue as compared to tissues of the normal adult rat. The remaining two antigens were detected only in tumors and transformed cells; one, only in certain hepatomas. Thus, these antigens were classified as tumor specific. As an initial step toward elucidating the function of these proteins, each antigen was isolated by immunoaffinity chromatography, radioiodinated in situ, and analyzed for the ability to bind DNA. Three antigens were positive for DNA binding, and one of these was selectively released from tumor nuclei with the transcriptionally active chromatin upon digestion with micrococcal nuclease. The implications of these results for the possible functional contribution of the six tumor antigens to transformation is discussed.

2-Acetylaminofluorene↗

PubMedDate not supplied

[Thiamine diphosphate level and metabolism in allergic myocarditis and treatment with peloid].

Enzymatic systems involved in thiamin metabolism were studied in experimental allergic myocarditis. Development of inflammation in myocardium was accompanied by a distinct activation of thiamin pyrophosphatase which catalyzed the most important step responsible for deterioration of the coenzyme functions. The stabilizing effect of peloid on the intracellular pool and compartmentalization of thiamin in myocarditis involved equilibration of the anabolic and catabolic reactions in the coenzyme metabolism, mainly due to selective inhibition of the thiamin pyrophosphatase activity stimulated under these conditions.

Animals↗

PubMed1994

Therapy for hepatitis B virus infection.

Major advances have been made in the therapy of chronic viral hepatitis B during the past several years. This period has witnessed the publication of large, multicenter trials of recombinant interferon alfa for chronic hepatitis B in the United States and the completion of several similarly designed studies in North America, Europe and Asia. These studies have defined an initial response rate of approximately 40% to 50%. In contrast to the experience with chronic hepatitis C, loss of viral replication is generally sustained. Repeat courses of therapy are likely to result in the same type of response as that observed initially. Quantitative assessment of viral replication (HBV DNA, HBeAg) is important in predicting the likelihood of response and in monitoring patients during therapy. Perhaps the most compelling reason to treat chronic hepatitis B with interferon is the disappearance of circulating HBsAg in one third of responders with a further increase in frequency of this phenomenon as follow-up continues. Another important advantage to treatment is the striking degree of histologic improvement that is frequently observed years after a response has been achieved. Although a substantial number of patients do not respond to interferon, several promising agents that should allow for a greater degree of success, when used either alone or in combination with interferon, are under study. A short course of corticosteroids prior to interferon appears to improve response rates in patients who have low ALT levels at baseline and has been the preferred approach for these patients at our medical center. Progress is being made in the development of safer interferon regimens for patients with mild-to-moderate hepatic decompensation. Nonetheless, even patients with marginal synthetic function, as reflected by albumin levels within the low-normal range, appear to be at greater risk for complications during therapy and should preferably be referred for inclusion in research programs. Appropriate patient selection remains a critical step for maximizing the safety as well as efficacy of interferon treatment.

Adrenal Cortex Hormones↗

PubMedDate not supplied

Circulatory assist techniques after cardiomyoplasty. Determinants for clinical outcome and later consequences.

Cardiomyoplasty, in spite of recent improvements, remains a high risk operation. The early postoperative period is sometimes very critical, even for patients selected from preoperative New York Heart Association functional class IV. During the surgical period, poor hemodynamics may be responsible for early death, as well as influence latissimus dorsi muscle long-term viability. Circulatory assist, including pharmacologic support with enoximone, intraaortic balloon counterpulsation (IABP), and ventricular assist devices (VAD), may be needed. From February, 1993 to September, 1994, 14 clinical dynamic cardiomyoplasty procedures were performed using the Medtronic (Minneapolis, MN) system at Hôpital La Timone, Marseille, France. Eight patients suffered from early and severe postoperative heart failure. Enoximone was used in three patients and IABP in five patients. Two days after cardiomyoplasty, one of the IABP patients required an implantable left VAD (Thermocardio Systems, Woburn, MA) as a bridge to cardiac transplantation. Overall hospital mortality was 7%. The authors studied the preoperative clinical data and surgical techniques to find specific risk factors that could have influenced postoperative events. Another aim of this study was to evaluate long-term benefits in these particular patients. Results showed that cardiomyoplasty patients may require complex means to overcome postoperative hemodynamic failure, but without necessarily poor long-term results. This should be an important step in improving future patient selection.

Adult↗

PubMed1992

(H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate.

[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1992

A systematic search for protein signature sequences.

Signature sequences are contiguous patterns of amino acids 10-50 residues long that are associated with a particular structure or function in proteins. These may be of three types (by our nomenclature): superfamily signatures, remnant homologies, and motifs. We have performed a systematic search through a database of protein sequences to automatically and preferentially find remnant homologies and motifs. This was accomplished in three steps: 1. We generated a nonredundant sequence database. 2. We used BLAST3 (Altschul and Lipman, Proc. Natl. Acad. Sci. U.S.A. 87:5509-5513, 1990) to generate local pairwise and triplet sequence alignments for every protein in the database vs. every other. 3. We selected "interesting" alignments and grouped them into clusters. We find that most of the clusters contain segments from proteins which share a common structure or function. Many of them correspond to signatures previously noted in the literature. We discuss three previously recognized motifs in detail (FAD/NAD-binding, ATP/GTP-binding, and cytochrome b5-like domains) to demonstrate how the alignments generated by our procedure are consistent with previous work and make structural and functional sense. We also discuss two signatures (for N-acetyltransferases and glycerol-phosphate binding) which to our knowledge have not been previously recognized.

Amino Acid Sequence↗

PubMed1995

The molecular biology of multidomain proteins. Selected examples.

The aim of this review is to give an overview of the contribution molecular biology can make to an understanding of the functions and interactions within multidomain proteins. The contemporary advantages ascribed to multidomain proteins include (a) the potential for metabolite channelling and the protection of unstable intermediates; (b) the potential for interactions between domains catalysing sequential steps in a metabolic pathway, thereby giving the potential for allosteric interactions; and (c) the facility to produce enzymic activities in a fixed stoichiometric ratio. The alleged advantages in (a) and (b) however apply equally well to multi-enzyme complexes; therefore, specific examples of these phenomena are examined in multidomain proteins to determine whether the proposed advantages are apparent. Some transcription-regulating proteins active in the control of metabolic pathways are composed of multiple domains and their control is exerted and modulated at the molecular level by protein-DNA, protein-protein and protein-metabolite interactions. These complex recognition events place strong constraints upon the proteins involved, requiring the recognition of and interaction with different classes of cellular metabolites and macromolecules. Specific examples of transcription-regulating proteins are examined to probe how their multidomain nature facilitates a general solution to the problem of multiple recognition events. A general unifying theme that emerges from these case studies is that a basic unitary design of modules provided by enzymes is exploited to produce multidomain proteins by a complex series of gene duplication and fusion events. Successful modules provided by enzymes are co-opted to new function by selection apparently acting upon duplicated copies of the genes encoding the enzymes. In multidomain transcription-regulating proteins, former enzyme modules can be recruited as molecular sensors that facilitate presumed allosteric interactions necessary for the molecular control of transcription.

Animals↗

PubMed1981

Role of blood platelets and prostaglandins in coronary artery disease.

In the last decade, several studies evaluating blood platelet function in patients with coronary heart disease have been reported. Although several platelet function abnormalities such as enhanced platelet aggregation, decreased platelet survival and increase in platelet release reaction in the stable condition and during stress in patients with myocardial ischemia have been recognized, the mechanism of these abnormalities is just beginning to be understood. Discovery of certain platelet and endothelium-generated prostaglandins has provided some information as to the possible mechanism of platelet dysfunction. Abnormalities of prostaglandin production and platelet sensitivity to various prostaglandins may have an important bearing on the enhanced platelet aggregation in vivo, genesis of atherosclerosis and probably precipitation of acute ischemic events. Since the discovery of these prostaglandins, the precise mode of action of several commonly used platelet-active drugs has been clarified. Development of new drugs acting at selective steps in the prostaglandin pathways may provide some exciting novel therapeutic procedures in patients with coronary heart disease.

Acute Disease↗

PubMed1997

CD3 delta deficiency arrests development of the alpha beta but not the gamma delta T cell lineage.

The CD3 complex found associated with the T cell receptor (TCR) is essential for signal transduction following TCR engagement. During T cell development, TCR-mediated signalling promotes the transition from one developmental stage to the next and controls whether a thymocyte undergoes positive or negative selection. The roles of particular CD3 components in these events remain unclear. Indeed, it is unknown whether they have specialized or overlapping roles. However, the multiplicity of CD3 components and their evolutionary conservation suggest that they serve distinct functions. Here the developmental requirement for the CD3 delta chain is analyzed by generating a mouse line specifically lacking this component (delta-/- mice). Strikingly, CD3 delta is shown to be differentially required during development. In particular, CD3 delta is not needed for steps in development mediated by pre-TCR or gamma delta TCR, but is required for further development of thymocytes expressing alpha beta TCR. Absence of CD3 delta specifically blocks the thymic selection processes that mediate the transition from the double-positive to single-positive stages of development.

Animals↗

PubMed1996

Influence of lateral destabilization on compensatory stepping responses.

Previous studies of compensatory stepping, in response to postural perturbation, have focussed on forward or backward stepping; however, the ability to step in other directions is of equal functional importance, since the perturbations encountered in daily life may often include a lateral component. The primary objective of this study was to determine how lateral destabilization affects the compensatory stepping response, in terms of: (1) swing-leg selection, (2) preparatory unloading of the swing leg, and (3) spatial and temporal characteristics of the swing trajectory. A novel multi-directional moving platform was used to apply transient perturbations in eight horizontal directions, in 10 healthy young adults. Perturbation magnitude was varied unpredictably over a wide range and subjects were instructed to try not to step, so as to discourage preplanned 'volitional' foot movement. The predominant strategy, seen in 96% of stepping responses to lateral destabilization, was to swing the leg that was unloaded by the perturbation. This strategy allowed a much more rapid foot-lift but required a longer and more complex swing trajectory, compared to responses where the perturbation-loaded leg was swung. When compared to forward and backward steps, the addition of a lateral component to the perturbation led to a 20% (90 ms) reduction in time to foot-off, a 20% (7 cm) increase in step length and a 70% (110 ms) increase in swing duration, on average. The results clearly demonstrate that compensatory stepping responses to non-sagittal perturbations are strongly influenced by biomechanical constraints and affordances that do not affect the forward and backward stepping behaviour that has been studied traditionally. These findings underscore the need to assess postural responses in multiple directions, in order to understand more fully how balance is maintained in the exigencies of everyday life.

Adult↗

PubMed1998

Antibodies specific for (6-4) DNA photoproducts: cloning, antibody modeling and construction of a single-chain Fv derivative.

We have investigated a series of four monoclonal antibodies that specifically recognize pyrimidine (6-4) pyrimidone photoproducts. One of these antibodies (64M4), bound all four possible pyrimidine-pyrimidone photoadducts with equal affinities whereas the others (64M2, 64M3 and 64M5) were selective for TC and TT sequences. In addition, 64M5 had the highest binding affinity for photodamaged DNA of the four [T. Mori et al., Photochem. Photobiol. 54 (1991) 225-232]. To help understand the differences between these antibodies, we have cloned and sequenced the variable region genes from all four. Comparing these sequences revealed that all four were highly similar to one another, although there were some differences in potential antigen-contact regions. To assess the influences of these sequence differences at the structural level, computer models were constructed for all four antibodies. Most of the sequence differences occurred in potential antigen contact regions, suggesting specific positions that might account for the observed differences in binding affinities and selectivities. A single-chain Fv derivative of 64M5 was therefore constructed and characterized to provide an experimental system in which structure-function relationships can be tested. This derivative could be isolated from Escherichia coli using two chromatographic steps and possessed the same binding specificity as the parent monoclonal antibody.

Amino Acid Sequence↗

PubMed1985

Genetic analysis of spontaneous resistance to ampicillin in Neisseria gonorrhoeae.

Step-wise intrinsic resistance to ampicillin in Neisseria gonorrhoeae was analyzed genetically by DNA-mediated transformation experiments. A first-step ampicillin-resistant (Ampr1) mutant and a second-step ampicillin-resistant (Ampr2) mutant generated during sequential selection were used in these studies. Each selection step was accompanied by an approximate twofold increase in resistance. Four amp alleles were found to account for full resistance of the Ampr2 phenotype. All four amp alleles lie among a cluster of genes which code for ribosomal functions. This region has the map order rif str fus tet cam. First-step resistance was caused by two amp alleles, ampA2 and ampB1, neither of which independently caused detectable ampicillin resistance. Outcrossing of the ampA2 or the ampB1 mutation resulted in wild-type susceptibility to ampicillin. Mapping studies indicate that ampB1 lies between str and fus, whereas ampA2 lies to the right of cam. Second-step resistance required two mutations, ampC3 and ampD4, in addition to ampB1 and ampA2. Transformation of ampC3 to ampC3+ in an Ampr2 mutant resulted in the Ampr1 phenotype. Both ampC3 and ampD4 showed transformation linkage to rif and str. ampC3 was positioned at a site between rif and str. ampD4 apparently occupied a site, outside of the rif-str region, proximal to rif and distal to str. We postulate the gene order to be ampD rif ampC str ampB fus tet cam ampA.

Alleles↗

PubMed1984

Asparagine-linked glycosylation in Saccharomyces cerevisiae: genetic analysis of an early step.

Asparagine-linked glycosylation is a form of covalent modification that distinguishes proteins that are either membrane bound or are in cellular compartments topologically outside of the cell from those proteins that remain soluble in the cytoplasm. This type of glycosylation occurs stepwise, with core oligosaccharide added in the endoplasmic reticulum and subsequent modifications occurring in the golgi. We used tunicamycin, an inhibitor of one of the earliest steps in the synthesis of N-linked oligosaccharide, to select for mutants that are resistant to this antibiotic. Genetic, biochemical, and physiological experiments led to the following conclusions. The synthesis of N-linked oligosaccharide is an essential function in cells. In contrast to mammalian cells, yeast cells do not transport tunicamycin by a glucosamine transport function. We identified a gene, ALG7, that is probably the structural gene for UDP-N-acetylglucosamine-1-P transferase, the enzyme inhibited by tunicamycin. Dominant mutations in this gene result in increased activity of the transferase and loss of the ability of the cell to sporulate. In addition, we identified another gene, TUN1, in which recessive mutations result in resistance to tunicamycin. The ALG7 and TUN1 genes both map on chromosome VII.

Asparagine↗

PubMedDate not supplied

Cytoskeleton and epithelial polarity.

The membrane surface of polarized epithelial cells can be divided in apical and basolateral domains that differ in molecular composition and function. Components of the cytoskeleton are involved in critical steps of both generation and maintenance of cell polarity. Generation of polarity is controlled by microtubules that serve as uniformly aligned and polarized cytoplasmic guiding structures for the vectorial and selective transport of Golgi-derived carrier vesicles to the apical cell surface. Targeting of membrane proteins to the basolateral cell surface does not depend on microtubules but follows the constitutive bulk flow of membranes. Once inserted into the lipid bilayer several membrane proteins such as the kidney anion exchanger 1 (AE1) and the sodium pump become immobilized at specialized microdomains of the lateral cell surface. Evidence is provided that both membrane proteins are linked via ankyrin to the spectrin-based membrane cytoskeleton that underlies the basolateral membrane domain. Linkage of these and other integral membrane proteins to the cytoskeleton may not only place them to specialized sites of the plasma membrane but may also prevent these transporters from clustering and endocytosis, thus helping them to stay at the cell surface. In search of sequence motifs involved in binding of integral membrane proteins to components of the cytoskeleton we found that the binding interface of AE1 to protein 4.1 (an actin and spectrin cross-linking protein) consists of a cluster of five amino acid residues, namely IRRRY in AE1 and LEEDY on protein 4.1. This motif may play a more general role in cytoskeleton membrane linkages.

Amino Acid Sequence↗