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PubMed1998

Positive inotropic effects of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium.

The aim of this study was to investigate the inotropic properties of the novel Na+-channel modulator BDF 9198 in human nonfailing and failing myocardium. For comparison the Na+-channel modulator BDF 9148, the beta-adrenoceptor-agonist isoprenaline, and calcium were studied. Concentration-response curves for BDF 9198 (0.01-30 microM), BDF 9148 (0.01-30 microM), isoprenaline (0.001-1 microM), and calcium (1.8-15 mM) were obtained in electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilated cardiomyopathy, NYHA IV, heart transplantation; nonfailing, donor hearts). Whereas isoprenaline was significantly less effective and less potent in increasing the force of contraction in failing human myocardium than in nonfailing myocardium (p < 0.01), BDF 9198 and BDF 9148 were (in NYHA IV) as effective as in nonfailing human tissue. In both tissues, BDF 9198 and BDF 9148 exerted similar positive inotropic effects as calcium, with the novel Na+-channel modulator BDF 9198 being more potent in increasing force of contraction than was the preceding agent BDF 9148. The potencies of both Na+-channel modulators, BDF 9198 and BDF 9148, were enhanced in human failing myocardium when compared with nonfailing myocardium. In summary, the novel Na+-channel modulator BDF 9198 increases force of contraction to the same extent as calcium and with a higher potency than BDF 9148. The sensitivity of failing human myocardium to Na+-channel modulators is increased when compared with nonfailing myocardium, which might be the result of an altered Na+ homeostasis in human heart failure.

Azetidines↗
PubMed2005

The PedsQL: reliability and validity of the short-form generic core scales and Asthma Module.

OBJECTIVE: We sought to assess the reliability and validity of the PedsQL 4.0 SF15, a shortened version of the 23-item PedsQL 4.0 Generic Core Scales, which is a pediatric health-related quality of life (HRQoL) instrument, and the PedsQL 3.0 SF22 Asthma Module, a short-form of the PedsQL 3.0 Asthma Module. METHODS: The PedsQL 4.0 SF15 and the PedsQL 3.0 SF22 Asthma Module were administered by telephone to 125 adolescents (aged 12-18) and 338 parents of children with asthma (aged 2-11). Healthy (n = 451) and chronically ill (n = 422) children, matched by age, respondent status, and ethnicity to the asthma sample, provided data for selected validity tests. RESULTS: The Total Score from the PedsQL 4.0 SF15 and the Asthma Symptoms scale and Treatment Problems scale from the PedsQL 3.0 SF22 Asthma Module were sufficiently reliable for group comparisons (alpha > or = 0.70 across all age groups) in the asthma sample. The PedsQL 4.0 SF15 and the PedsQL 3.0 SF22 Asthma Module were able to distinguish between children of different clinical status and correlated as expected with measures of productivity and family functioning in the asthma sample. The psychometric properties of the PedsQL 4.0 SF15 were generally comparable to those of the original instrument. CONCLUSION: The Total Score of the PedsQL 4.0 SF15 and the Asthma Symptoms scale of the PedsQL 3.0 SF22 Asthma Module demonstrated the best reliability and validity and should be suitable for group-level comparisons of generic and asthma-specific HRQoL in clinical research studies of children with asthma.

Adolescent↗
PubMed1997

Physical fitness as a determinant of vagal modulation.

The association between increasing age and decreasing vagal modulation is well known. However, the importance of fitness as a determinant of the decline in vagal modulation with age is not established. To test the hypothesis that decreasing vagal modulation is largely a function of declining fitness rather than increasing age, we studied a sample of healthy volunteers with a wide range of fitness levels, but a narrow age range. We assessed fitness by measuring the maximal oxygen uptake (VO2max) achieved during incremental bicycle exercise. Vagal modulation was assessed by calculating high frequency power (0.15-0.40 Hz) of the RR variability power spectrum from 24-h ECG recordings. We studied 37 healthy volunteers who were 22-44 yr old. In our sample, VO2max ranged from 25 to 70 mL.min-1.kg-1 (mean of 45 +/- 13). Age was not significantly related to high frequency power, but VO2max was highly correlated with high frequency power (r = 0.74, P = 0.0001), indicating that physical fitness is strongly associated with vagal modulation. Thus, the decline in vagal modulation often attributed to increasing age may, instead, be the result of a decline in fitness.

Adult↗
PubMedDate not supplied

Development of theory-based, online health learning modules for older adults: Lessons learned.

Recently, the number of older adult online users has increased rapidly. In 2004, 22% of Americans aged 65 years or older (about 8 million) used the Internet, and 66% of them performed online searches for health information. The Web, therefore, can serve as a useful medium to educate older adults on selected health topics. In this study, the researchers developed four Web-based learning modules related to hip fracture prevention and tested the usability of these modules employing eight older adult online users. The findings from the usability tests demonstrated that the online learning modules were usable to the older adult participants. Additionally, these individuals could acquire health knowledge using these online modules. The important lessons learned through the research process will assist the researchers in conducting further studies in using health Web learning modules for older adults. A further study will be conducted to test the effects of these modules on preventing hip fractures.

Aged↗
PubMedDate not supplied

Intensity-modulated radiotherapy.

Intensity-modulated radiotherapy represents a recent advancement in conformal radiotherapy. It employs specialized computer-driven technology to generate dose distributions that conform to tumor targets with extremely high precision. Treatment planning is based on inverse planning algorithms and iterative computer-driven optimization to generate treatment fields with varying intensities across the beam section. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Thus far, data have demonstrated improved precision of tumor targeting in carcinomas of the prostate, head and neck, thyroid, breast, and lung, as well as in gynecologic, brain, and paraspinal tumors and soft tissue sarcomas. In prostate cancer, intensity-modulated radiotherapy has resulted in reduced rectal toxicity and has permitted tumor dose escalation to previously unattainable levels. This experience indicates that intensity-modulated radiotherapy represents a significant advancement in the ability to deliver the high radiation doses that appear to be required to improve the local cure of several types of tumors. The integration of new methods of biologically based imaging into treatment planning is being explored to identify tumor foci with phenotypic expressions of radiation resistance, which would likely require high-dose treatments. Intensity-modulated radiotherapy provides an approach for differential dose painting to selectively increase the dose to specific tumor-bearing regions. The implementation of biologic evaluation of tumor sensitivity, in addition to methods that improve target delineation and dose delivery, represents a new dimension in intensity-modulated radiotherapy research.

Abdominal Neoplasms↗
PubMedDate not supplied

The use of rectal balloon during the delivery of intensity modulated radiotherapy (IMRT) for prostate cancer: more than just a prostate gland immobilization device?

PURPOSE: The purpose of this study was to investigate the role of a rectal balloon for prostate immobilization and rectal toxicity reduction in patients receiving dose-escalated intensity-modulated radiotherapy for prostate cancer. PATIENTS AND METHODS: Patients with localized prostate cancer who were undergoing intensity-modulated radiotherapy were treated in a prone position, immobilized with a customized Vac-Lok bag (MED-TEC, Orange City, IA). A rectal balloon with 100 cc of air was used to immobilize the prostate. The prostate displacements were measured using computed tomography (CT)-CT fusion on 10 patients who received radioactive seed implant before intensity-modulated radiotherapy. They were scanned twice weekly during 5 weeks of intensity-modulated radiotherapy, and breathing studies were also performed. Rectal toxicity was evaluated by use of Radiation Therapy Oncology Group scoring in 100 patients. They were treated to a mean dose of 76 Gy over 35 fractions (2.17-Gy fraction size). Dose-volume histogram of the rectum was assessed. A film phantom was constructed to simulate the 4-cm diameter air cavity that was created by the rectal balloon. Kodak XV2 films (Rochester NY) were used to measure and compare dose distribution with and without the air cavity. A fraction of 1.25 Gy was delivered to the phantom at isocenter with 15-MV photons by use of the NOMOS Peacock system and the MIMiC treatment delivery system (Sewickley, PA). RESULTS: The anterior-posterior and lateral prostate displacements were minimal, on the order of measurement uncertainty (approximately 1 mm). The standard deviation of superior-inferior displacement was 1.78 mm. Breathing studies showed no organ displacement during normal breathing when the rectal balloon was in place. The rectal toxicity profile was very favorable: 83% (83/100) patients had no rectal complaint, and 11% and 6% had grade 1 and 2 toxicity, respectively. Dose-volume histogram analysis revealed that in all of the patients, no more than 25% of the rectum received 70 Gy or greater. As visualized by film dosimetry, the dose at air-tissue interface was approximately 15% lower than that without an air cavity. The dose built up rapidly so that at 1 and 2 mm, the differential was approximately 8% and 5%, respectively. The dosimetric coverage at the depth of the posterior prostate wall was essentially equal, with or without the air cavity. DISCUSSION: The use of a rectal balloon during intensity-modulated radiotherapy significantly reduces prostate motion. Prostate immobilization thus allows a safer and smaller planning target volume margin. It has also helped spare the anterior rectal wall (by its dosimetric effects) and reduced the rectal volume that received high-dose radiation (by rectal wall distension). All these factors may have further contributed to the decreased rectal toxicity achieved by intensity-modulated radiotherapy, despite dose escalation and higher-than-conventional fraction size.

Catheterization↗
PubMed2005

A posterior tether for fusionless modulation of sagittal plane growth in a sheep model.

STUDY DESIGN: This was an in vivo and in vitro investigation of a minimally invasive posterior tether system for fusionless modulation of sagittal plane growth in an immature sheep model. OBJECTIVE: To determine whether fusionless modulation of spinal growth in the sagittal plane of an immature sheep model can be successfully performed. SUMMARY OF BACKGROUND DATA: Scheuermann's disease has been reported to affect 1% to 8% of the pediatric population. Varying degrees of spinal bone growth modulation has been successfully performed in the coronal plane of animal models. This represents the first attempt to modulate spinal growth in the sagittal plane in an animal model. Modulation of spinal growth in the sagittal plane may play a role in the treatment of pediatric kyphosis when brace treatment is unsuccessful. METHODS: There were nine immature sheep posteriorly tethered and five control animals, all with identical follow-ups. Pedicle screws were placed in adjacent vertebrae, bilaterally, at the thoracolumbar junction and the lower lumbar spine. Polyethylene cords were passed subcutaneously, and tensioned to 20 lbs. Tethers were released in four sheep at 6 months and four at 12 months. At 12 months and 2 weeks, all animals were sacrificed. RESULTS: At 13 months after surgery, the tethered groups had significantly less kyphosis and vertebral body wedging than the control group. In both the tethered groups, at 13 months after surgery, there was significantly less vertebral body wedging compared with the preoperative values. There was no evidence of facet arthropathy, but heterotopic ossification was seen in several specimens. Tethered spines had significantly less motion than control spines. Histologic evaluation demonstrated no detrimental results. CONCLUSIONS: Fusionless modulation of sagittal plane growth in an immature sheep model was successfully performed with changes in the overall sagittal profile of the instrumented segments and vertebral body wedging. Increased stiffness of the instrumented segments posttether release was thought to be related to heterotopic ossification. Results suggest that this may be a potential treatment for adolescents with Scheuermann's disease.

Animals↗
PubMed2006

The prevalence and onset of gaze modulation of tinnitus and increased sensitivity to noise after translabyrinthine vestibular schwannoma excision.

OBJECTIVE: To determine the prevalence and timing of onset of gaze-modulated tinnitus and increased sensitivity to noise in patients who had undergone translabyrinthine excision of a vestibular schwannoma. STUDY DESIGN: Retrospective questionnaire study. SETTING: University hospital departments of audiology and neurotology. PATIENTS: A cohort of 359 patients who had undergone translabyrinthine excision of a vestibular schwannoma in the period 1997 to 2003. INTERVENTION: Translabyrinthine excision of a unilateral sporadic vestibular schwannoma. MAIN OUTCOME MEASURES: Patient reports and visual analogue scale measures of the timing of onset of gaze-modulated tinnitus and the presence, timing of onset, and persistence of increased sensitivity to noise after surgery. RESULTS: Completed questionnaires were returned by 275 patients (77%), of whom 132 (48%) were men and 143 (52%) were women. Preoperative tinnitus was reported in 150 patients (55%). In 124 of these 150 (83%) the tinnitus persisted, and in 26 of 150 (17%) it abated. Of the 125 patients without preoperative tinnitus, 43 (34%) developed it postoperatively. In 167 (61%) patients of the total group of 275, postoperative tinnitus was reported. Gaze-modulated tinnitus was reported in 53 patients (19%). Somatic-evoked or -modulated tinnitus was reported in 38 patients (14%). In response to the question, "Did you notice being extra sensitive to noise after your operation?," 138 patients (50%) replied that they did. In 111 patients, this persisted. The onset of the modulation of tinnitus was distributed throughout the postoperative period, whereas the onset of increased sensitivity to noise was overwhelmingly in the first 2 months after surgery. CONCLUSION: Gaze modulation of tinnitus after vestibular schwannoma removal was identified in 19% of patients in this series. The onset data did not convincingly argue for any specific mechanism. The prevalence of increased sensitivity to noise is surprising and may represent central hyperacusis in response to unilateral deafferentation of the auditory system.

Adult↗
PubMed2001

The binding pattern of two carbohydrate-binding modules of laminarinase Lam16A from Thermotoga neapolitana: differences in beta-glucan binding within family CBM4.

Carbohydrate-binding modules (CBMs) are often part of the complex hydrolytic extracellular enzymes from bacteria and may modulate their catalytic activity. The thermostable catalytic domain of laminarinase Lam16A from Thermotoga neapolitana (glycosyl hydrolase family 16) is flanked by two CBMs, 148 and 161 aa long. They share a sequence identity of 30%, are homologous to family CBM4 and are thus called CBM4-1 and CBM4-2 respectively. Recombinant Lam16A proteins deleted for one or both binding modules and the isolated module CBM4-1 were characterized. Proteins containing the N-terminal module CBM4-1 bound to the soluble polysaccharides laminarin (1,3-beta-glucan) and barley 1,3/1,4-beta-glucan, and proteins containing the C-terminal module CBM4-2 bound additionally to curdlan (1,3-beta-glucan) and pustulan (1,6-beta-glucan), and to insoluble yeast cell wall beta-glucan. The activity of the catalytic domain on soluble 1,3-beta-glucans was stimulated by the presence of CBM4-1, whereas the presence of CBM4-2 enhanced the Lam16A activity towards gelatinized and insoluble or mixed-linkage 1,3-beta-glucan. Thermostability of the catalytic domain was not affected by the truncations. Members of family CBM4 can be divided into four subfamilies, members of which show different polysaccharide-binding specificities corresponding to the catalytic specificities of the associated hydrolytic domains.

Amino Acid Sequence↗
PubMed2003

The di-leucine motif in the cytoplasmic tail of CD4 is not required for binding to human immunodeficiency virus type 1 Nef, but is critical for CD4 down-modulation.

The human immunodeficiency virus type 1 (HIV-1) nef gene encodes a 205 residue, myristoylated phosphoprotein that has been shown to play a critical role in the replication and pathogenesis of the virus. One of the most studied functions of the Nef protein is the down-modulation of cell surface CD4. Nef has been reported to interact with both the cytoplasmic tail of CD4 and proteins that are components of the endocytic machinery, thereby enhancing the endocytosis of CD4 through clathrin-coated pits. A di-leucine motif in the cytoplasmic tail of CD4 (residues 413/414) was reported to be essential both for Nef mediated down-modulation and for Nef binding. In order to further characterize the involvement of this di-leucine motif in CD4 down-modulation we generated a CD4 mutant in which the leucines were substituted by alanines, termed CD4(LL-AA). We demonstrate here that, contrary to previous data obtained with the cytoplasmic tail of CD4 alone, full-length CD4(LL-AA) bound to Nef both in vivo, in recombinant baculovirus-infected Sf9 cells, and in vitro. In contrast the di-leucine motif was required for both Nef-mediated and phorbol ester-induced CD4 down-modulation, suggesting that the essential requirement for the di-leucine motif in CD4 down-modulation reflects the fact that this motif is needed for the interactions of CD4 with the endocytic machinery, not for the interaction with Nef. We have also exploited the observation that CD4(LL-AA) is refractory to Nef-mediated down-modulation to provide the first experimental evidence for a physical interaction between Nef and CD4 in intact mammalian cells.

Amino Acid Motifs↗
PubMed2006

Identification and analysis of evolutionarily cohesive functional modules in protein networks.

The increasing number of sequenced genomes makes it possible to infer the evolutionary history of functional modules, i.e., groups of proteins that contribute jointly to the same cellular function in a given species. Here we identify and analyze those prokaryotic functional modules, whose composition remains largely unchanged during evolution, and study their properties. Such "cohesive" modules have a large number of internal functional connections, encode genes that tend to be in close proximity in prokaryotic genomes, and correspond to physical complexes or complex functional systems like the flagellar apparatus. Cohesive modules are enriched in processes such as energy and amino acid metabolism, cell motility, and intracellular trafficking, or secretion. By grouping genes into modules we achieve a more precise estimate of their age and find that the young modules are often horizontally transferred between species and are enriched in functions involved in interactions with the environment, implying that they play an important role in the adaptation of species to new environments.

Computational Biology↗
PubMed2000

Temporal modulation of the control parameter in electroconvection in the nematic liquid crystal I52

I report on the effects of a periodic modulation of the control parameter on electroconvection in the nematic liquid crystal I52. Without modulation, the primary bifurcation from the uniform state is a direct transition to a state of spatiotemporal chaos. This state is the result of the interaction of four degenerate traveling modes: right and left zig and zag rolls. Periodic modulations of the driving voltage at approximately twice the traveling frequency are used. For a large enough modulation amplitude, standing waves that consist of only zig or zag rolls are stabilized. The standing waves exhibit regular behavior in space and time. Therefore, modulation of the control parameter represents a method of eliminating spatiotemporal chaos. As the modulation frequency is varied away from twice the traveling frequency, standing waves that are a superposition of zig and zag rolls, i.e., standing rectangles, are observed. These results are compared with existing predictions based on coupled complex Ginzburg-Landau equations.

Journal Article↗
PubMed2001

Resonantlike phenomenon in short-pulse free-electron-laser oscillators with modulated desynchronism.

Recently a new method of controlling the pulse length of a short-pulse free-electron laser (FEL) has been developed. By modulating the synchronism between the optical and electron pulses in the FEL cavity, it was found that the output power and the micropulse length of the FEL beam oscillates at the modulation frequency. In this paper, we study theoretically the behavior of the micropulse length, both in the high loss (steady state) regime and the low loss (limit cycle) regime, when a modulated desynchronism is applied. In order to do this, we analyze the dynamics of a short-pulse FEL oscillator. The modulation frequency value plays an important role in the dynamics. We find that there is a resonantlike phenomenon between the externally applied desynchronism modulation and the limit cycle oscillation without modulation of a free-electron laser.

Journal Article↗
PubMed2004

Electrostatic shocks excited by velocity modulation of an ion beam in a plasma.

Nonlinear evolutions of electrostatic shocks excited by a velocity-modulated ion beam along a magnetized plasma column are investigated by computer simulation for a Q-machine experiment. In the case of a beam velocity modulation, the perturbations grow spatially with subsequent saturation due to an ion bunching of the beam. With an increase in modulation ratio an electrostatic shock is formed, accompanied with a steepening of the propagating front. In the case of a beam density-modulation, however, the initial density jump decays simply. The velocity modulation method is quite effective for an excitation of electrostatic shocks in the Q-machine plasma with finite Landau damping. The simulation results using velocity modulation are consistent with the experimental results.

Journal Article↗
PubMed2003

superspace description of trigonal and orthorhombic A(1)+(x)A(x)'B(1)-(x)O(3) compounds as modulated layered structures; application to the refinement of trigonal Sr(6)Rh(5)O(15).

The structures of the trigonal compounds A(1+x)A(x')B(1-x)O(3) are described, to a first approximation, as a hexagonal close-packed stacking of A(3)O(9) and A(3)A'O(6) layers. However, quantitative analyses are usually performed in superspace, with the structures considered as modulated composites made of two subsystems: chains of A cations, and columns of trigonal prisms, A'O(6), and octahedra, BO(6). It is demonstrated that an alternative superspace description as a single modulated structure can be found in terms of the aforementioned layers, with a composition-dependent modulation parameter and discontinuous atomic domains. In this approach, these compounds fulfill layer-stacking rules analogous to those observed in other layered compounds. These rules translate into a so-called closeness condition for the discontinuous atomic domains in superspace; this condition is analogous to that postulated in quasicrystals. Both superspace models, the composite and the layered model, when considered without displacive modulations, can be taken as two limiting idealized paradigms and can be used as the starting point of a structure refinement. As an example, the structure of the trigonal phase Sr(6)Rh(5)O(15), which was previously refined as a modulated composite [Stitzer, El Abed et al. (2001), J. Am. Chem. Soc. 123, 8790-8796], has been refined anew, with equivalent results, as a single modulated structure taking as reference the ideal layered structure. A similar superspace layer description is applied to the recently reported orthorhombic family A(4m+4n)A(n')B(4m+2n)O(12m+9n). This description allows the a priori derivation of a refineable superspace model that includes the superspace symmetry and crenel functions and is valid for the whole family. This model has been successfully applied to the refinement of the compound Ba(12)Co(11)O(33) [Darriet et al. (2002), Chem. Mater. 14, 3349-3363].

Journal Article↗
PubMed1999

Cluster configurations in modulated EuVxMo8+/-yO14 crystals.

Three orthorhombic crystals of chemical formula Eu(x)V(y)Mo(8+/-z)O(14) were investigated by X-ray diffraction (Mo Kalpha radiation, lambda = 0.71073 Å). They have nearly the same lattice parameters (a approximately 11.3, b approximately 10.0, c approximately 9.2 Å), display one-dimensional incommensurate modulations of wavevector q* = gammac* and are characterized by the same superspace group Cmca(00gamma)s00. The crystals differ both in their compositions (namely Eu(0.976(6))V(1.13(5))Mo(7.10(5))O(14), Eu(0.986(4))V(1.10(3))Mo(7.30(1))O(14) and EuMo(7.96(1))O(14)) and in their gamma components [0.195 (2), 0.245 (2) and 0.286 (3), respectively]. The average structures of these crystals appear closely related to the structures of LaMo(7.7)O(14) (not modulated) and LaMo(8)O(14) (modulated); however, two main differences are outlined: first, the modulation direction is c in the Eu-containing crystals but b in the modulated La-containing crystal [q* = (1/3)b*], second, the Eu-containing crystals have centrosymmetric structures while the La-containing crystals have polar structures (space group C2ca). The Mo (or Mo and V) atoms are stacked to form (001) layers of metallic clusters. The density modulation of these structures implies the existence of the new types of clusters Mo(9), Mo(10), Mo(6)V(4), Mo(7)V(3) and Mo(8)V(2) besides the clusters M(8) (Mo(8), Mo(6)V(2) and Mo(7)V) and M(7) (Mo(7) and Mo(6)V) which are already known. Mo(8) units with cis and trans configurations and Mo(6)V(2) units with a trans configuration appear as the main cluster types in these crystals. The nature of the metallic clusters changes along c, but inside one (001) layer it is likely that only one cluster type with a given configuration is present. The main structural result is the formation, in some unit cells, of strong intercluster Mo-Mo, Mo-V or V-V bonds with distances close to 2.6 Å within a layer as well as between two neighbouring layers.

Journal Article↗
PubMed2004

Preparation and preliminary X-ray analysis of the catalytic module of beta-1,3-xylanase from the marine bacterium Vibrio sp. AX-4.

Beta-1,3-xylanase (1,3-beta-D-xylan xylanohydrolase; EC 3.2.1.32) is an enzyme capable of hydrolyzing beta-1,3-xylan. The newly cloned beta-1,3-xylanase from the marine bacterium Vibrio sp. AX-4 (XYL4) exhibited a modular structure consisting of three modules: an N-terminal catalytic module belonging to glycoside hydrolase family 26 and two C-terminal xylan-binding modules belonging to carbohydrate-binding module family 31. Despite substantial crystallization screening, crystallization of the recombinant XYL4 was not accomplished. However, the deletion mutant of XYL4, composed of a catalytic module without a xylan-binding module, was crystallized. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 51.6, b = 75.8, c = 82.0 A. X-ray diffraction data were collected to 1.44 A resolution.

Catalytic Domain↗
PubMed2002

Generation of ligand-receptor alliances by "SEA" module-mediated cleavage of membrane-associated mucin proteins.

A mechanism is described whereby one and the same gene can encode both a receptor protein as well as its specific ligand. Generation of this receptor-ligand partnership is effected by proteolytic cleavage within a specific module located in a membrane resident protein. It is postulated here that the "SEA" module, found in a number of heavily O-linked glycosylated membrane-associated proteins, serves as a site for proteolytic cleavage. The subunits generated by proteolytic cleavage of the SEA module reassociate, and can subsequently elicit a signaling cascade. We hypothesize that all membrane resident proteins containing such a "SEA" module will undergo cleavage, thereby generating a receptor-ligand alliance. This requires that the protein subunits resulting from the proteolytic cleavage reassociate with each other in a highly specific fashion. The same SEA module that serves as the site for proteolytic cleavage, probably also contains the binding sites for reassociation of the resultant two subunits. More than one type of module can function as a site for proteolytic cleavage; this can occur not only in one-pass membrane proteins but also in 7-transmembrane proteins and other membrane-associated proteins. The proposal presented here is likely to have significant practical consequences. It could well lead to the rational design and identification of molecules that, by binding to one of the cleaved partners, will act either as agonists or antagonists, alter signal transduction and, hence, cellular behavior.

Amino Acid Sequence↗