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PubMed1999

Structural analysis of phospholipase A2 from functional perspective. 1. Functionally relevant solution structure and roles of the hydrogen-bonding network.

Bovine pancreatic phospholipase A2 (PLA2), a small (13.8 kDa) Ca2+-dependent lipolytic enzyme, is rich in functional and structural character. In an effort to examine its detailed structure-function relationship, we determined its solution structure by multidimensional nuclear magnetic resonance (NMR) spectroscopy at a functionally relevant pH. An ensemble of 20 structures generated has an average root-mean-square deviation (RMSD) of 0.62 +/- 0.08 A for backbone (N, Calpha, C) atoms and 0.98 +/- 0.09 A for all heavy atoms. The overall structure shows several notable differences from the crystal structure: the first three residues at the N-terminus, the calcium-binding loop (Y25-T36), and the surface loop (V63-N72) appear to be flexible; the alpha-helical conformation of helix B (E17-F22) is absent; helix D appears to be shorter (D59-V63 instead of D59-D66); and the hydrogen-bonding network is less defined. These differences were analyzed in relation to the function of PLA2. We then further examined the H-bonding network, because its functional role or even its existence in solution has been in dispute recently. Our results show that part of the H-bonding network (the portion away from N-terminus) clearly exists in solution, as evidenced by direct observation (at 11.1 ppm) of a strong H-bond between Y73 and D99 and an implicated interaction between D99 and H48. Analyses of a series of mutants indicated that the existence of the Y73.D99 H-bond correlates directly with the conformational stability of the mutant. Loss of this H-bond results in a loss of 2-3 kcal/mol in the conformational stability of PLA2. The unequivocal identification and demonstration of the structural importance of a specific hydrogen bond, and the magnitude of its contribution to conformational stability, are uncommon to the best of our knowledge. Our results also suggest that, while the D99.H48 catalytic diad is the key catalytic machinery of PLA2, it also helps to maintain conformational integrity.

Animals↗

PubMed1999

The flow-function relationship in patients with chronic coronary artery disease and reduced regional function: a Doppler transesophageal and bidimensional transthoracic echocardiography study.

BACKGROUND: Infra-low dose dipyridamole allows one to selectively explore myocardial viability. Transesophageal echocardiography Doppler measurement of left anterior descending coronary artery flow at baseline and following dipyridamole is an efficient tool to assess coronary flow response. Aim of this study was to determine the flow-function relationship during coronary vasodilatory stress in patients with coronary artery disease and baseline dysfunction. METHODS AND RESULTS: Twelve patients with resting dyssynergies and 6 controls underwent assessment of regional function and of left anterior descending blood flow velocity. Flow and function were evaluated at rest and following infra-low dose dipyridamole (0.28 mg/Kg over 4 min). Controls showed a normal function at rest and after dipyridamole. Six patients ('Responders') with resting dyssynergies showed an improvement in segments of left anterior descending artery territory, whereas the other six ones ('Non-responders') showed no functional change. Controls and 'Responders' had similar values of resting peak diastolic left anterior descending artery flow velocity both at rest and after dipyridamole, whereas 'Non-responders' showed a blunted flow response to dipyridamole. CONCLUSION: Myocardial segments with a resting dysfunction and a contractile reserve more often exhibit a residual flow response, whereas segments with fixed pattern show a flat flow response during coronary vasodilator stress.

Blood Flow Velocity↗

PubMed1997

Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes.

This paper describes the development of a simple empirical scoring function designed to estimate the free energy of binding for a protein-ligand complex when the 3D structure of the complex is known or can be approximated. The function uses simple contact terms to estimate lipophilic and metal-ligand binding contributions, a simple explicit form for hydrogen bonds and a term which penalises flexibility. The coefficients of each term are obtained using a regression based on 82 ligand-receptor complexes for which the binding affinity is known. The function reproduces the binding affinity of the complexes with a cross-validated error of 8.68 kJ/mol. Tests on internal consistency indicate that the coefficients obtained are stable to changes in the composition of the training set. The function is also tested on two test sets containing a further 20 and 10 complexes, respectively. The deficiencies of this type of function are discussed and it is compared to approaches by other workers.

Binding Sites↗

PubMed1993

Assessing selfcare status in quadriplegia: comparison of the quadriplegia index of function (QIF) and the functional independence measure (FIM).

The purpose of this study was to compare the quadriplegia index of function (QIF) to the functional independence measure (FIM) in assessing the daily performance of selfcare activities by individuals with cervical spinal cord injury. This study evaluated feeding, grooming and bathing activities in 22 C4-C7, Frankel A-D spinal cord injury patients between 3 and 12 months postinjury. The manual muscle test (MMT) was performed on 17 of these subjects during the same window of time as the QIF and the FIM. An upper extremity motor score (UEMS) was derived from the MMT. In order to relate motor power to functional ability, the UEMS was used as a measure of neurological function to test the hypothesis that the QIF scores are more highly correlated to motor power than are the FIM scores for this population. Spearman coefficients were calculated to correlate the QIF, the FIM and the UEMS. For the bathing and grooming categories, both the QIF and the FIM showed significant and similar correlations to the UEMS. For the feeding category, however, the QIF had a significantly better correlation to the UEMS than did the FIM (Rho = 0.90 vs 0.53, p < 0.01). Use of the QIF feeding scale may allow the detection of changes in function as individuals recover that the FIM scale would miss. Further evaluation of the remaining selfcare and mobility scales is needed. Modification of the FIM with more sensitive portions of the QIF would improve the discriminative ability of outcome studies and program evaluations.

Adolescent↗

PubMed2002

Peripheral blood markers of inflammation predict mortality and functional decline in high-functioning community-dwelling older persons.

OBJECTIVES: Several peripheral blood markers of inflammation have demonstrated prognostic ability, but the value of combining multiple markers as a measure of inflammatory burden remains unknown. The objective of this study was to determine the prognostic value of combining four peripheral blood measures of inflammation in healthy older persons. DESIGN: Inception cohort study with 7 years of follow-up. SETTING: Three communities. PARTICIPANTS: Eight hundred seventy high-functioning subjects aged 70 to 79 who had serum albumin, cholesterol, interleukin (IL)-6, and C-reactive protein (CRP) levels measured at baseline. MEASUREMENTS: Three- and 7-year mortality and Rosow- Breslau functional decline. RESULTS: A summary score was created that assigned one point each for the following blood levels: albumin <3.8 g/dL, cholesterol <170 mg/dL (bottom decile), IL-6>3.8 pg/mL (top tertile), and CRP>2.65 mg/L (top tertile). By 3 years, 6% of subjects had died, and, by 7 years, 23% had died. In subjects with three or four markers of inflammation, the adjusted odds ratios (AORs) for 3- and 7-year mortality were 6.6 and 3.2, respectively, compared with those who had no abnormal markers. Subjects with one or two markers were at more moderate and statistically insignificant increased risk of 3- and 7-year mortality with AORs of 1.5 and 1.3, respectively. The risks for functional decline at 3- and 7-years were generally small (AOR = 1.1-1.9) and not statistically significant. CONCLUSIONS: In high-functioning older persons, a measure of inflammation can identify those at a much higher risk of mortality and a possibly higher risk of functional decline. Whether therapies directed at reducing inflammation can attenuate such risk remains to be determined.

Aged↗

PubMed2001

Aesthetic and functional results of harvesting radial forearm flap, especially with regard to hand function.

There is controversy in the literature regarding donor site morbidity following radial forearm flap harvesting. The aim of this study was to verify possible functional and aesthetic impairments at the donor site. Thirty-five patients who underwent maxillofacial reconstruction using radial forearm flap were asked to give their subjective assessment of the aesthetic outcome at the donor site and of postoperative hand function. They were also examined for trophic status; cold intolerance and tactile sensitivity of split-thickness skin graft, palm and finger pads; grip strength and finger-to-thumb pinch strength; range of movement for the wrist and finger joints; as well as functional hand testing. Slight impairments regarding hand strength and mobility were observed. However, due to their small extent they were of no clinical relevance, as shown by 85.7% of our patients displaying optimal functional hand testing values (80-100%), and 88.6% giving a positive subjective assessment (80-100%) of postoperative vs preoperative hand function. The results show that donor site morbidity following radial forearm flap harvesting is low.

Cold Temperature↗

PubMed1996

New infinite families of exact sums of squares formulas, Jacobi elliptic functions, and Ramanujan's tau function.

In this paper, we give two infinite families of explicit exact formulas that generalize Jacobi's (1829) 4 and 8 squares identities to 4n(2) or 4n(n + 1) squares, respectively, without using cusp forms. Our 24 squares identity leads to a different formula for Ramanujan's tau function tau(n), when n is odd. These results arise in the setting of Jacobi elliptic functions, Jacobi continued fractions, Hankel or Turánian determinants, Fourier series, Lambert series, inclusion/exclusion, Laplace expansion formula for determinants, and Schur functions. We have also obtained many additional infinite families of identities in this same setting that are analogous to the eta-function identities in appendix I of Macdonald's work [Macdonald, I. G. (1972) Invent. Math. 15, 91-143]. A special case of our methods yields a proof of the two conjectured [Kac, V. G. and Wakimoto, M. (1994) in Progress in Mathematics, eds. Brylinski, J.-L., Brylinski, R., Guillemin, V. & Kac, V. (Birkhäuser Boston, Boston, MA), Vol. 123, pp. 415-456] identities involving representing a positive integer by sums of 4n(2) or 4n(n + 1) triangular numbers, respectively. Our 16 and 24 squares identities were originally obtained via multiple basic hypergeometric series, Gustafson's C(l) nonterminating (6)phi(5) summation theorem, and Andrews' basic hypergeometric series proof of Jacobi's 4 and 8 squares identities. We have (elsewhere) applied symmetry and Schur function techniques to this original approach to prove the existence of similar infinite families of sums of squares identities for n(2) or n(n + 1) squares, respectively. Our sums of more than 8 squares identities are not the same as the formulas of Mathews (1895), Glaisher (1907), Ramanujan (1916), Mordell (1917, 1919), Hardy (1918, 1920), Kac and Wakimoto, and many others.

Journal Article↗

PubMed1996

Structure-function relationship of lipoprotein lipase-mediated enhancement of very low density lipoprotein binding and catabolism by the low density lipoprotein receptor. Functional importance of a properly folded surface loop covering the catalytic center.

We examined the structure-function relationship of human lipoprotein lipase (hLPL) in its ability to enhance the binding and catabolism of very low density lipoproteins (VLDL) in COS cells. Untransfected COS cells did not bind to or catabolize normal VLDL. Expression of wild-type hLPL by transient transfection enhanced binding, uptake, and degradation of the VLDL (a property of LPL that we call bridge function). Heparin pretreatment and a monoclonal antibody ID7 that blocks LDL receptor-binding domain of apoE both inhibited binding, and apoE2/E2 VLDL from a Type III hyperlipidemic subject did not bind. However, LDL did not reduce 125I-VLDL binding to the hLPL-expressing cells, whereas rabbit beta-VLDL was an effective competitor. By contrast, LDL reduced uptake and degradation of 125I-VLDL to the same extent as excess unlabeled VLDL or beta-VLDL. These data suggest that binding occurs by direct interaction of VLDL with LPL but the subsequent catabolism of the VLDL is mediated by the LDL receptor. Mutant hLPLs that were catalytically inactive, S132A, S132D, as well as the partially active mutant, S251T, and S172G, gave normal enhancement of VLDL binding and catabolism, whereas the partially active mutant S172D had markedly impaired capacity for the process; thus, there is no correlation between bridge function and lipolytic activity. A naturally occurring genetic variant hLPL, S447-->Ter, has normal bridge function. The catalytic center of LPL is covered by a 21-amino acid loop that must be repositioned before a lipid substrate can gain access to the active site for catalysis. We studied three hLPL loop mutants (LPL-cH, an enzymatically active mutant with the loop replaced by a hepatic lipase loop; LPL-cP, an enzymatically inactive mutant with the loop replaced by a pancreatic lipase loop; and C216S/C239S, an enzymatically inactive mutant with the pair of Cys residues delimiting the loop substituted by Ser residues) and a control double Cys mutant, C418S/C438S. Two of the loop mutants (LPL-cH and LPL-cP) and the control double Cys mutant C418S/C438S gave normal enhancement of VLDL binding and catabolism, whereas the third loop mutant, C216S/C239S, was completely inactive. We conclude that although catalytic activity and the actual primary sequence of the loop of LPL are relatively unimportant (wild-type LPL loop and pancreatic lipase loops have little sequence similarity), the intact folding of the loop, flanked by disulfide bonds, must be maintained for LPL to express its bridge function.

Animals↗

PubMed1998

Functional food science and gastrointestinal physiology and function.

The gut is an obvious target for the development of functional foods, acting as it does as the interface between diet and the metabolic events which sustain life. The key processes in digestive physiology which can be regulated by modifying diet are satiety, the rate and extent of macronutrient breakdown and absorption from the small bowel, sterol metabolism, the colonic microflora, fermentation, mucosal function and bowel habit, and the gut immune system. The intestinal microflora is the main focus of many current functional foods. Probiotics are foods which contain live bacteria which are beneficial to health whilst prebiotics, such as certain non-digestible oligosaccharides which selectively stimulate the growth of bifidobacteria in the colon, are already on the market. Their claimed benefits are to alleviate lactose maldigestion, increase resistance to invasion by pathogenic species of bacteria in the gut, stimulate the immune system and possibly protect against cancer. There are very few reports of well-designed human intervention studies with prebiotics as yet. Certain probiotic species have been shown to shorten the duration of rotavirus diarrhoea in children but much more work is needed on the mechanism of immunomodulation and of competitive exclusion and microflora modification. The development of functional foods for the gut is in its infancy and will be successful only if more fundamental research is done on digestive physiology, the gut microflora, immune system and mucosal function.

Bacteria↗

PubMedDate not supplied

Lung function in an Australian population: contributions of polygenic factors and the Pi locus to individual differences in lung function in a sample of twins.

A study of lung function in 203 twin pairs aged 18-34 years living in Sydney detected significant genetic variation in females and males. There was no evidence of family environmental effects in either sex and most of the repeatable variation in females was heritable. However, there was evidence for systematic environmental differences between males affecting lung function so that the heritability was lower in males (about 0.6) than females (about 0.8). An effect of smoking on lung function was detected but accounted for less than 3% of the variance. Lung function in females was greater in the M subtype heterozygotes at the Pi locus than in the M subtype homozygotes or in other Pi phenotypes with low alpha 1-antitrypsin activity. The Pi polymorphism accounted for approximately 9% of the total variance in female lung function. No effect of the Pi locus was found in males.

Adolescent↗

PubMed2000

Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and beta1 integrins.

Elevated extracellular K(+) ([K(+)](o)), in the absence of "classical" immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K(+) channels (Kv1.3) appears to be the crucial "decision-making" step, through which various physiological factors, including elevated [K(+)](o) levels, affect the T cell beta1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1beta, the neuropeptide calcitonin gene-related peptide (CGRP), as well as elevated [K(+)](o) levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the beta1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K(+)](o)). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.

Cell Adhesion↗

PubMed1988

The use of gamma functions in the calculation of organ perfusion functions for non-diffusible radioactive tracers.

This paper introduces a method for quantification of mean organ perfusion by the impulse response function using the experimental time-activity curves for the organ of interest and its supplying artery. These are approximated by gamma functions and a general expression for the impulse response function is then derived. In any particular case, the impulse response function can be calculated simply by insertion of the numerical parameters. The procedure combines speed with freedom from random measurement errors. As an example of a clinical application, the impulse response function of healthy brain tissue is calculated and some clinically important parameters are tabulated.

Blood Circulation↗

PubMed1998

Quadriceps function, proprioceptive acuity and functional performance in healthy young, middle-aged and elderly subjects.

BACKGROUND: Muscle functions to generate force-producing movement and also has a role in proprioception. If ageing compromises these sensorimotor functions of muscle, the ability of older subjects to detect and correct postural sway may be impeded, resulting in impairment of functional performance. METHOD: To see if age-related changes occurred and, if so, what their effects might be. Quadriceps strength, proprioception, postural stability and functional performance were assessed in young (n = 20, mean age 23 years), middle-aged (n = 10, mean age 56 years) and elderly (n = 15, mean age 72 years) subjects. RESULTS: With increasing age there were decreases in quadriceps strength (r = -0.511; P < 0.001), acuity of joint position sense (r = -0.603; P < 0.001) and postural stability (ANOVA < 0.002) during stance conditions which placed a greater reliance on muscle proprioceptors. These changes may decrease postural stability confidence, resulting in impaired performance of common activities of daily living (r = 0.635; P < 0.001). CONCLUSIONS: The age-related deterioration in sensorimotor function of muscle may contribute to the increased fear and frequency of falls in elderly subjects, thereby decreasing independence.

Accidental Falls↗

PubMed2000

Proteasome mutants, pre4-2 and ump1-2, suppress the essential function but not the mitochondrial RNase P function of the Saccharomyces cerevisiae gene RPM2.

The Saccharomyces cerevisiae nuclear gene RPM2 encodes a component of the mitochondrial tRNA-processing enzyme RNase P. Cells grown on fermentable carbon sources do not require mitochondrial tRNA processing activity, but still require RPM2, indicating an additional function for the Rpm2 protein. RPM2-null cells arrest after 25 generations on fermentable media. Spontaneous mutations that suppress arrest occur with a frequency of approximately 9 x 10(-6). The resultant mutants do not grow on nonfermentable carbon sources. We identified two loci responsible for this suppression, which encode proteins that influence proteasome function or assembly. PRE4 is an essential gene encoding the beta-7 subunit of the 20S proteasome core. A Val-to-Phe substitution within a highly conserved region of Pre4p that disrupts proteasome function suppresses the growth arrest of RPM2-null cells on fermentable media. The other locus, UMP1, encodes a chaperone involved in 20S proteasome assembly. A nonsense mutation in UMP1 also disrupts proteasome function and suppresses Deltarpm2 growth arrest. In an RPM2 wild-type background, pre4-2 and ump1-2 strains fail to grow at restrictive temperatures on nonfermentable carbon sources. These data link proteasome activity with Rpm2p and mitochondrial function.

Alleles↗

PubMed1978

Experimental evolution of a new enzymatic function. II. Evolution of multiple functions for ebg enzyme in E. coli.

The evolution of ebgo enzyme of Escherichia coli, an enzyme which is unable to hydrolyze lactose, lactulose, lactobionate, or galactose-arabinoside effectively, has been directed in successive steps so that the evolved enzyme is able to hydrolyze these galactosides effectively. I show that in order for a strain of E. coli with a lacZ deletion to evolve the ability to use lactobionate as a carbon source, a series of mutations must occur in the ebg genes, and that these mutations must be selected in a particular order. The ordered series of mutations constitutes an obligatory evolutionary pathway for the acquisition of a new function for ebgo enzyme. A comparison of newly evolved strains with parental strains shows that when ebg enzyme acquires a new function, its old functions often suffer; but that in several cases old functions are either unaffected or are improved. I conclude that divergence of functions catalyzed by an enzyme need not require gene duplication.

Biological Evolution↗

PubMed2000

The joint effect of apolipoprotein E epsilon4 and MRI findings on lower-extremity function and decline in cognitive function.

BACKGROUND: Cognitive decline and poor physical function are risk factors for disability in old age and may occur more often in subjects with the apolipoprotein E epsilon4 (ApoE-epsilon4) allele. The objective of this study was to investigate the joint effect of ApoE-epsilon4 and structural changes detected on MRI brain scans on cognitive decline and lower-extremity function. METHODS: Brain MRI (1.5 T), neuropsychological tests, and lower-extremity physical function tests were administered to World War II male veteran twins ages 69 to 80. Quantification of MRI scans used a previously published algorithm to segment brain images into total cerebral brain (TCB), cerebrospinal fluid (CSF), and white-matter hyperintensity (WMH) volumes. A short battery of physical performance tests was used to assess lower-extremity function. Ten-year changes in performance on the Mini-Mental State Exam (MMSE), the Benton Visual Retention Test (BVRT), and the Digit Symbol Substitution (DSS) test were used to assess cognitive decline. RESULTS: For the sample as a whole, the comparison of subjects by median split of total cerebral brain volume found that those with brain volumes below the median performed worse on tests of gait and balance (p < .01) and experienced greater cognitive decline on the MMSE and BVRT cognitive test batteries (both p < .01). In addition, subjects with WMH volumes above the median had poor performance on the standing balance tasks and experienced greater decline on the DSS test (p < .01). Stratified analyses revealed that the joint effect of radiological findings and the ApoE-epsilon4 allele on cognitive decline and lower-extremity function was often greater than that expected from the separate effects combined. CONCLUSIONS: We conclude that radiological findings in conjunction with ApoE-epsilon4 may single out a group at higher risk for dementia. We speculate that the observed interaction effect may be due to increased susceptibility to brain injury or impaired repair mechanisms in subjects with ApoE-epsilon4.

Aged↗

PubMed2001

A reevaluation of the common factor theory of shared variance among age, sensory function, and cognitive function in older adults.

The common cause hypothesis of the relationship among age, sensory measures, and cognitive measures in very old adults was reevaluated. Both sensory function and processing speed were evaluated as mediators of the relationship between age and cognitive function. Cognitive function was a latent variable that comprised 3 factors including memory, speed, and verbal ability. The sample was population based and comprised very old adults (n = 894; mean age = 77.7, SD = 5.6 years) from the Australian Longitudinal Study of Ageing. The results showed that there was common variance in the cognitive factor shared by age, speed, vision, and hearing but that specific effects of age on cognition remained. Furthermore, speed did not fully mediate the effect of age or sensory function on cognition. Some age differences in cognitive performance are not explained by the same processes that explain age differences in sensory function and processing speed.

Aged↗

PubMed1986

Non invasive assessment of regional diastolic left ventricular function with first pass radionuclide functional imaging in ischaemic heart disease.

Functional images of regional distribution of rapid filling (RF) rates have been developed and applied at rest and on exercise for regional analysis of 301 coronary artery territories (103 compromised by coronary narrowings, 198 normal). The observed time-interval of RF averaged 209 ms at rest (range 200 to 280) and 172 ms on exercise (range 125 to 200 ms). Normal RF is directed to the apex, and it is deviated from territories with reduced compliance to normal territories. Sensitivity in detection and localization of territories compromised by coronary narrowings exceeds 90% at rest for the anterior and infero-posterior wall and is higher than that obtained from systolic functional images. Specificity amounts also to over 90% and is much higher than that observed with systolic functional images. During RF, moderate to severe loss in compliance results in initial regional paradoxical inward motion in 40 to 45% of anterior or postero-inferior segments eventually accompanied by significant inward displacement of blood. Thus, with functional imaging of regional RF rates one can establish dysfunction and functional significance of coronary narrowings.

Adult↗