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PubMed2000

Centennial of the string galvanometer and the electrocardiogram.

This article is a review of the history of the string galvanometer and of the electrocardiogram (ECG) on the occasion of the centennial of the instrument. Einthoven most likely developed the string galvanometer prior to 1901, the date of the first publication. The galvanometer made electrocardiography practical creating a new branch of medicine and even a new industry. In 1791 Galvani, in 1842 Mateucci and in 1855 Kolliker and Muller recorded, using the nerve muscle preparation, contraction of injured muscle, contraction of muscle when laid across a beating heart, and occasionally two contractions. In 1872 Lippmann introduced the capillary manometer. Using the capillary manometer Waller recorded for the first time from body surface voltage changes generated by the heart. Einthoven and Lewis dominated the early years of electrocardiography. The former made his contributions by 1913 while Lewis continued the studies of arrhythmias until 1920. The period following 1920 was influenced largely by Wilson. None did as much to advance ECG knowledge as did Wilson. The interest shifted to the theory of the ECG, abnormalities of wave form and of ECG leads. A major contribution of the ECG is in evaluation of ischemic heart disease and cardiac arrhythmias. Issues facing electrocardiography in the year 2000 include a shortage of experienced electrocardiographers, the advent of new noninvasive procedures and, paradoxically, wide acceptance of the ECG by the medical profession. The role of the computer in analysis of the clinical ECG is limited. The technique, while reasonably reliable for analysis of the normal tracing and some ECG waveforms, has serious limitations when applied to arrhythmias. The early hopes for "stand-alone" programs are yet to be realized.

Cardiology↗
PubMed2000

Cysteine string protein regulates G protein modulation of N-type calcium channels.

Cysteine string proteins (CSPs) are secretory vesicle proteins bearing a "J domain" and a palmitoylated cysteine-rich "string" region that are critical for neurotransmitter release. The precise role of CSP in neurotransmission is controversial. Here, we demonstrate a novel interaction between CSP, receptor-coupled trimeric GTP binding proteins (G proteins), and N-type Ca2+ channels. G. subunits interact with the J domain of CSP in an ATP-dependent manner; in contrast, Gbetagamma subunits interact with the C terminus of CSP in both the presence and absence of ATP. The interaction of CSP with both G proteins and N-type Ca2+ channels results in a tonic G protein inhibition of the channels. In view of the crucial importance of N-type Ca2+ channels in presynaptic vesicle release, our data attribute a key role to CSP in the fine tuning of neurotransmission.

Adenosine Triphosphate↗
PubMed2003

Player sensitivity to changes in string tension in a tennis racket.

Forty-one advanced recreational tennis players were tested to determine their ability to detect differences in string tension in a tennis racket. Subjects were given pairs of rackets that varied in tension by up to 98 N (10 kg) and were asked whether they noticed a difference in tension and if so, which racket was strung at a higher tension. Only 11 (27%) of those tested could correctly identify a tension difference of 5 kg (11 lb) or less. Fifteen (37%) could not pick a difference of 10 kg (22 lb). To examine the importance of sound as a means of discrimination, an additional test was undertaken where participants wore earplugs. Of the 26 subjects undertaking this additional test, only 6 (23%) were successful. It was concluded that advanced recreational tennis players demonstrated limited ability to correctly identify differences in string tension and that impact sound was an important factor for those participants who were successful at various levels of discrimination.

Adult↗
PubMed1987

The DNA sequence of the human beta-globin region is strongly biased in favor of long strings of contiguous purine or pyrimidine residues.

The DNA sequence of the human beta-globin region, comprising over 67 kilobase pairs, has been analyzed for the occurrence of strings of contiguous purine or pyrimidine residues. Tracts of 10 or more contiguous residues are found 4 times more frequently than would be expected with a random distribution of bases, so that a long string occurs at an average of every 250 base pairs. A survey of six other human gene sequences, totaling 86 kilobase pairs, shows a remarkably similar result. No such overrepresentation of contiguous purine or pyrimidine residues is found in the bacteriophages lambda or T7.

Base Sequence↗
PubMed2004

The variable C-terminus of cysteine string proteins modulates exocytosis and protein-protein interactions.

Cysteine string proteins (Csps) are vesicle proteins involved in neurotransmission and hormone exocytosis. They are composed of distinct domains: a variable N-terminus, a J-domain followed by a linker region, a cysteine-rich string, and a C-terminus which diverges among isoforms. Their precise function and interactions are not fully understood. Using insulin exocytosis as a model, we show that the linker region and the C-terminus, but not the variable N-terminus, regulate overall secretion. Moreover, endogenous Csp1 binds in a calcium-dependent manner to monomeric VAMP2, and this interaction requires the C-terminus of Csp. The interaction is isoform specific as recombinant Csp1 binds VAMP1 and VAMP7, but not VAMP3. Cross-linking in permeabilized clonal beta-cells revealed homodimerization of Csp which is stimulated by Ca(2+) and again modulated by the variant C-terminus. Our data suggest that both interactions of Csp occur during exocytosis and may explain the effect of the variant C-terminus of this chaperon protein on peptide hormone secretion.

Calcium↗
PubMed2000

Cysteine-string protein: the chaperone at the synapse.

Cysteine-string protein (Csp) is a major synaptic vesicle and secretory granule protein first discovered in Drosophila and Torpedo. Csps were subsequently identified from Xenopus, Caenorhabditis elegans, and mammalian species. It is clear from the study of a null mutant in Drosophila that Csp is required for viability of the organism and that it has a key role in neurotransmitter release. In addition, other studies have directly implicated Csp in regulated exocytosis in mammalian neuroendocrine and endocrine cell types, and its distribution suggests a general role in regulated exocytosis. An early hypothesis was that Csp functioned in the control of voltage-gated Ca2+ channels. Csp, however, must have an additional function as a direct regulator of the exocytotic machinery as changes in Csp expression modify the extent of exocytosis triggered directly by Ca2+ in permeabilised cells. Csps possess a cysteine-string domain that is highly palmitoylated and confers membrane targeting. In addition, Csps have a conserved "J" domain that mediates binding to an activation of the Hsp70/ Hsc70 chaperone ATPases. This and other evidence implicate Csps as molecular chaperones in the synapse that are likely to control the correct conformational folding of one or more components of the vesicular exocytotic machinery. Targets for Csp include the vesicle protein VAMP/synaptobrevin and the plasma membrane protein syntaxin 1, the significance of which is discussed in possible models to account for current knowledge of Csp function.

Amino Acid Sequence↗
PubMed2000

Stellate purse-string closure.

BACKGROUND: There are fundamental concepts we use in managing surgical defects. Whether planning a primary closure or a local flap, we frequently modify the basic design to maximize aesthetic outcomes, taking into consideration a number of factors including the location of the defect and tissue availability. OBJECTIVE: We describe the stellate modified purse-string closure, a novel flap modification. METHOD: Report of an illustrated case. RESULT: A patient with vertex scalp defect was reconstructed using the stellate purse-string flap. CONCLUSION: Certain modifications of commonly used reconstructive techniques can be utilized in specific situations to enhance cosmesis. Advantages of this modification are discussed.

Aged↗
PubMed1983

[Vaginal closure using the purse string suture method in elderly women with total prolapse].

The occlusion of the vagina by a shirodkar type string suture is an emergency procedure. As a temporary measure in old patients with procedentia this procedure relieves the symptoms of the prolapse during the time needed to prepare the patient for surgery or the time needed by the patient to decide to have the operation performed. For severely ill in-operable patients the purse string occlusion of the vagina is a simple method to eliminate the discomfort of the procedentia. The procedure can be done under local anaesthesia and can be repeated.

Aged↗
PubMed2005

Transition pathways in complex systems: Application of the finite-temperature string method to the alanine dipeptide.

The finite-temperature string method proposed by E, et al. [W. E, W. Ren, and E. Vanden-Eijnden, Phys. Rev. B 66, 052301 (2002)] is a very effective way of identifying transition mechanisms and transition rates between metastable states in systems with complex energy landscapes. In this paper, we discuss the theoretical background and algorithmic details of the finite-temperature string method, as well as the application to the study of isomerization reaction of the alanine dipeptide, both in vacuum and in explicit solvent. We demonstrate that the method allows us to identify directly the isocommittor surfaces, which are approximated by hyperplanes, in the region of configuration space where the most probable transition trajectories are concentrated. These results are verified subsequently by computing directly the committor distribution on the hyperplanes that define the transition state region.

Alanine↗
PubMed2006

String method in collective variables: minimum free energy paths and isocommittor surfaces.

A computational technique is proposed which combines the string method with a sampling technique to determine minimum free energy paths. The technique only requires to compute the mean force and another conditional expectation locally along the string, and therefore can be applied even if the number of collective variables kept in the free energy calculation is large. This is in contrast with other free energy sampling techniques which aim at mapping the full free energy landscape and whose cost increases exponentially with the number of collective variables kept in the free energy. Provided that the number of collective variables is large enough, the new technique captures the mechanism of transition in that it allows to determine the committor function for the reaction and, in particular, the transition state region. The new technique is illustrated on the example of alanine dipeptide, in which we compute the minimum free energy path for the isomerization transition using either two or four dihedral angles as collective variables. It is shown that the mechanism of transition can be captured using the four dihedral angles, but it cannot be captured using only two of them.

Journal Article↗
PubMed1980

Bounds for the rth characteristic frequency of a beaded string or of an electrical filter.

The fundamental mode of vibration of a beaded string has a shape without change of sign. The rth higher normal mode of vibration has r changes of sign. Given any virtual shape of the string with r changes of sign, an algorithm is found that gives upper and lower bounds for the rth characteristic frequency as a function of the virtual shape. By making a certain transformation it is found that this algorithm holds for the characteristic frequencies of an inductor-capacitor network. Other transformations show that it applies to the rth eigenvalue of a Hermitian matrix.

Journal Article↗
PubMed1986

Semi-infinite cohomology and string theory.

We develop the theory of semi-infinite cohomology of graded Lie algebras first introduced by Feigin. We show that the relative semi-infinite cohomology has a structure analogous to that of the de Rham cohomology in Kähler geometry. We prove a vanishing theorem for a special class of modules, and we apply our results to the case of the Virasoro algebra and the Fock module. In this case the zero cohomology is identified as the physical subspace of the Fock module and the no-ghost theorem follows. We reveal the profound relation of semi-infinite cohomology theory to the gauge-invariant free string theory constructed by Banks and Peskin. We then indicate the connection between gauge-invariant interacting string theories and the geometric realizations of the infinite-dimensional Lie algebras.

Journal Article↗
PubMed1996

Cysteine string proteins are associated with chromaffin granules.

In this work, we have examined the subcellular distribution of cysteine string proteins (Csps) in bovine adrenal medullary chromaffin cells. Csps did not leak from digitonin-permeabilized chromaffin cells, suggesting that there is no cytosolic pool of the protein in these cells. Subcellular fractionation studies confirmed that there was essentially no Csp immunoreactivity in the cytosolic fraction. However, immunoreactivity was detected in the membrane fractions of these cells. Csp immunoreactivity codistributed with dopamine beta-hydroxylase, a granule marker protein, in sucrose gradient-separated granule fractions. Immunofluorescence studies showed that all chromaffin cells in culture were stained with a punctate appearance consistent with a granular localization. These results were confirmed by immunogold labeling, which demonstrated specific labeling of chromaffin granule membranes. In addition to its presence on synaptic vesicles, cysteine string protein is therefore a bona fide chromaffin granule membrane protein.

Adrenal Medulla↗
PubMed1996

The cysteine string secretory vesicle protein activates Hsc70 ATPase.

Cysteine string protein (CSP) is a 34 kDa secretory vesicle protein bearing a "J-domain" as well as a palmitoylated cysteine-rich "string" region used for membrane attachment. Mutation of the CSP gene causes impaired presynaptic neuromuscular transmission in Drosophila melanogaster, implicating CSP as part of the exocytotic protein machinery. The J-domain of CSP shares homology with the universally conserved DnaJ family, a group of proteins that act as co-chaperones with Hsc70 and its homologs. Hsc70 is an abundant neural protein with coupled protein binding and ATPase activities. We have investigated the CSP modulation of Hsc70 ATPase activity. Here we demonstrated that CSP enhances Hsc70 ATPase activity in a dose-dependent manner. CSP activation of Hsc70 was maximal ( approximately 12 times) at 1:1 stoichiometry and above. We show that a J-domain-containing fragment (amino acids 1-82) of CSP is sufficient for the activation of Hsc70. Neither CSP nor the amino-terminal fragment stimulate the activity of the isolated Hsc70 ATPase domain (amino acids 1-386). CSP does not significantly increase the activity of N-ethylmaleimide-sensitive fusion protein, another ATPase required for transport vesicle function. Our results suggest that CSP, a DnaJ family member associated with the secretory vesicle cycle regulates Hsc70 functions. Hsc70 may function within the biochemical pathways of exo- and endocytosis to promote the formation or dissociation of multimeric complexes or to regulate conformational changes.

Adenosine Triphosphatases↗
PubMed2003

A brain-specific isoform of small glutamine-rich tetratricopeptide repeat-containing protein binds to Hsc70 and the cysteine string protein.

Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) is a ubiquitously expressed cochaperone of heat shock cognate protein of 70 kDa (Hsc70). SGT binds to the C terminus of Hsc70, a site used by several tetratricopeptide repeat-containing binding partners to recruit Hsc70 into complexes of diverse function. We describe here an isoform of SGT with 60% amino acid sequence identity that we name betaSGT. In contrast to the previously published alphaSGT, betaSGT is almost exclusively expressed in brain. Both isoforms of SGT possess similar binding properties toward Hsc70 and cysteine string protein, a synaptic vesicle-associated J-domain-containing protein. In addition, SGTs oligomerize without preferences among isoforms. The distribution of protein binding motifs on SGTs reveals a modular structure. The N-terminal domains mediate oligomerization. Binding to Hsc70 is impaired by mutations of basic residues within the central tetratricopeptide repeat domain of betaSGT, indicating a two-carboxylate clamp as the binding mode. The tetratricopeptide repeats are also necessary for binding to the cysteine string protein. However, this binding mode is distinct from the two-carboxylate clamp that is involved in Hsc70 binding. The C-terminal regions of SGTs might constitute independent protein interaction domains. We conclude that betaSGT is likely to cooperate with alphaSGT as co-chaperone of Hsc70 in the brain. The modular structure of SGTs allows them to recruit client proteins to Hsc70 and to direct the resulting complex toward downstream proteins that take over the respective client proteins.

Amino Acid Motifs↗
PubMed2005

Characterization of the G alpha(s) regulator cysteine string protein.

Cysteine string protein (CSP) is an abundant regulated secretory vesicle protein that is composed of a string of cysteine residues, a linker domain, and an N-terminal J domain characteristic of the DnaJ/Hsp40 co-chaperone family. We have shown previously that CSP associates with heterotrimeric GTP-binding proteins (G proteins) and promotes G protein inhibition of N-type Ca2+ channels. To elucidate the mechanisms by which CSP modulates G protein signaling, we examined the effects of CSP(1-198) (full-length), CSP(1-112), and CSP(1-82) on the kinetics of guanine nucleotide exchange and GTP hydrolysis. In this report, we demonstrate that CSP selectively interacts with G alpha(s) and increases steady-state GTP hydrolysis. CSP(1-198) modulation of G alpha(s) was dependent on Hsc70 (70-kDa heat shock cognate protein) and SGT (small glutamine-rich tetratricopeptide repeat domain protein), whereas modulation by CSP(1-112) was Hsc70-SGT-independent. CSP(1-112) preferentially associated with the inactive GDP-bound conformation of G alpha(s). Consistent with the stimulation of GTP hydrolysis, CSP(1-112) increased guanine nucleotide exchange of G alpha(s). The interaction of native G alpha(s) and CSP was confirmed by coimmunoprecipitation and showed that G alpha(s) associates with CSP. Furthermore, transient expression of CSP in HEK cells increased cellular cAMP levels in the presence of the beta2 adrenergic agonist isoproterenol. Together, these results demonstrate that CSP modulates G protein function by preferentially targeting the inactive GDP-bound form of G alpha(s) and promoting GDP/GTP exchange. Our results show that the guanine nucleotide exchange activity of full-length CSP is, in turn, regulated by Hsc70-SGT.

Animals↗
PubMed1987

Visually-presented letter strings typically are encoded phonologically: some converging evidence.

Three experiments were conducted to show that phonological encoding is typical for visually-presented letter strings, and that an interactive activation model with a phonological route to the mental lexicon accounts adequately for the word-superiority effect. In Experiment 1, pseudohomophones produced a word-superiority effect that was as great as that produced by words. More accurate target discrimination in homophones than in nonhomophones in Experiment 2 was interpreted to mean that excitability of entries in the mental lexicon increases with frequency of access. Target discrimination accuracy was inversely related to the phonological complexity of strings containing targets in Experiment 3, supposedly because lexical access through which target discrimination is enhanced becomes more difficult as phonological complexity increases.

Attention↗