Biomedical subjects

M R Jones

Publications and source records attributed to M R Jones.

At least 37 records · Page 2Linked to original sources

PubMed2001

Improving the reliability of stroke subgroup classification using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria.

BACKGROUND AND PURPOSE: We sought to improve the reliability of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of stroke subtype for retrospective use in clinical, health services, and quality of care outcome studies. The TOAST investigators devised a series of 11 definitions to classify patients with ischemic stroke into 5 major etiologic/pathophysiological groupings. Interrater agreement was reported to be substantial in a series of patients who were independently assessed by pairs of physicians. However, the investigators cautioned that disagreements in subtype assignment remain despite the use of these explicit criteria and that trials should include measures to ensure the most uniform diagnosis possible. METHODS: In preparation for a study of outcomes and management practices for patients with ischemic stroke within Department of Veterans Affairs hospitals, 2 neurologists and 2 internists first retrospectively classified a series of 14 randomly selected stroke patients on the basis of the TOAST definitions to provide a baseline assessment of interrater agreement. A 2-phase process was then used to improve the reliability of subtype assignment. In the first phase, a computerized algorithm was developed to assign the TOAST diagnostic category. The reliability of the computerized algorithm was tested with a series of synthetic cases designed to provide data fitting each of the 11 definitions. In the second phase, critical disagreements in the data abstraction process were identified and remaining variability was reduced by the development of standardized procedures for retrieving relevant information from the medical record. RESULTS: The 4 physicians agreed in subtype diagnosis for only 2 of the 14 baseline cases (14%) using all 11 TOAST definitions and for 4 of the 14 cases (29%) when the classifications were collapsed into the 5 major etiologic/pathophysiological groupings (kappa=0.42; 95% CI, 0.32 to 0.53). There was 100% agreement between classifications generated by the computerized algorithm and the intended diagnostic groups for the 11 synthetic cases. The algorithm was then applied to the original 14 cases, and the diagnostic categorization was compared with each of the 4 physicians' baseline assignments. For the 5 collapsed subtypes, the algorithm-based and physician-assigned diagnoses disagreed for 29% to 50% of the cases, reflecting variation in the abstracted data and/or its interpretation. The use of an operations manual designed to guide data abstraction improved the reliability subtype assignment (kappa=0.54; 95% CI, 0.26 to 0.82). Critical disagreements in the abstracted data were identified, and the manual was revised accordingly. Reliability with the use of the 5 collapsed groupings then improved for both interrater (kappa=0.68; 95% CI, 0.44 to 0.91) and intrarater (kappa=0.74; 95% CI, 0.61 to 0.87) agreement. Examining each remaining disagreement revealed that half were due to ambiguities in the medical record and half were related to otherwise unexplained errors in data abstraction. CONCLUSIONS: Ischemic stroke subtype based on published TOAST classification criteria can be reliably assigned with the use of a computerized algorithm with data obtained through standardized medical record abstraction procedures. Some variability in stroke subtype classification will remain because of inconsistencies in the medical record and errors in data abstraction. This residual variability can be addressed by having 2 raters classify each case and then identifying and resolving the reason(s) for the disagreement.

Acute Disease↗

PubMed2001

RNA-mediated interference as a tool for identifying drug targets.

The nematode Caenorhabditis elegans is the first multicellular organism with a fully sequenced genome. As a model organism, C. elegans is playing a special role in functional genomic analyses because it is experimentally tractable on many levels. Moreover, the lessons learned from C. elegans are often applicable across phyla because many of the key biologic processes involved in development and disease have been well conserved. Many global approaches for analysing gene activity are being pursued in C. elegans. RNA-mediated interference (RNAi) is an efficient high-throughput method to disrupt gene function. The basic technique of RNAi involves introducing sequence-specific double-stranded RNA into C. elegans in order to generate a nonheritable, epigenetic knockout of gene function that phenocopies a null mutation in the targeted gene. This technique drastically reduces the time needed to jump from the identification of an interesting gene sequence to achieving an understanding of its function. Thus, RNAi facilitates the high-throughput functional analysis of gene targets identified during drug discovery. RNAi can also help to identify the biochemical mode of action of a drug or pesticide and to identify other genes encoding products that may respond or interact with specific compounds.

Animals↗

PubMed2000

The development of rhythmic attending in auditory sequences: attunement, referent period, focal attending.

This paper is divided into three sections. The first section is theoretical; it extends Dynamic Attending Theory (Jones, M. R. Psychological Review 83 (1976) 323; Jones, M. R. Perception and Psychophysics 41(6) (1987) 631; Jones, M. R. Psychomusicology 9(2) (1990) 193; Jones, M. R., & Boltz, M. Psychological Review 96(3) (1989) 459) to developmental questions concerning tempo and time hierarchies. Generally Dynamic Attending Theory proposes that, when listening to a complex auditory sequence, listeners spontaneously focus on events occurring at an intermediate rate (the referent level), and they then may shift attention to events occurring over longer or shorter time spans, that is at lower (faster) or higher (slower) hierarchical levels (focal attending). The second section of the paper is experimental. It examines maturational changes of three dynamic attending activities involving referent period and level, attunement, and focal attending. Tasks involve both motor tapping (including spontaneous motor tempo and synchronization with simple sequences and music) and tempo discrimination. We compare performances by 4-, 6-, 8-, and 10-year-old children and adults, with or without musical training. Results indicate three changes with increased age and musical training: (1) a slowing of the mean spontaneous tapping rate (a reflection of the referent period) and mean synchronization rate (a reflection of the referent level), (2) enhanced ability to synchronize tapping and discriminate tempo (improved attunement), and (3) an enlarged range of tapping rates towards slower rates and higher hierarchical levels (improved focal attending). A final section considers results in light of the theory proposed here. It is suggested that growth trends can be expressed in terms of listeners' engagement of slower attending oscillators with age and experience, accompanied by the passage from the initial use of a single oscillator towards the coupling of multiple oscillators.

Adult↗

PubMed2000

Steady-state cyclic electron transfer through solubilized Rhodobacter sphaeroides reaction centres.

The mechanism, thermodynamics and kinetics of light-induced cyclic electron transfer have been studied in a model energy-transducing system consisting of solubilized Rhodobacter sphaeroides reaction center/light harvesting-1 complexes (so-called core complexes), horse heart cytochrome c and a ubiquinone-0/ubiquinol-0 pool. An analysis of the steady-state kinetics of cytochrome c reduction by ubiquinol-0, after a light-induced steady-state electron flow had been attained, showed that the rate of this reaction is primarily controlled by the one-electron oxidation of the ubiquinol-anion. Re-reduction of the light-oxidized reaction center primary donor by cytochrome c was measured at different reduction levels of the ubiquinone-0/ubiquinol-0 pool. These experiments involved single turnover flash excitation on top of background illumination that elicited steady-state cyclic electron transfer. At low reduction levels of the ubiquinone-0/ubiquinol-0 pool, the total cytochrome c concentration had a major control over the rate of reduction of the primary donor. This control was lost at higher reduction levels of the ubiquinone/ubiquinol-pool, and possible reasons for this behaviour are discussed.

Animals↗

PubMed2000

Ubiquinone binding, ubiquinone exclusion, and detailed cofactor conformation in a mutant bacterial reaction center.

The X-ray crystal structure of a Rhodobacter sphaeroides reaction center with the mutation Ala M260 to Trp (AM260W) has been determined. Diffraction data were collected that were 97.6% complete between 30.0 and 2.1 A resolution. The electron density maps confirm the conclusions of a previous spectroscopic study, that the Q(A) ubiquinone is absent from the AM260W reaction center (Ridge, J. P., van Brederode, M. E., Goodwin, M. G., van Grondelle, R., and Jones, M. R. (1999) Photosynthesis Res. 59, 9-26). Exclusion of the Q(A) ubiquinone caused by the AM260W mutation is accompanied by a change in the packing of amino acids in the vicinity of the Q(A) site that form part of a loop that connects the DE and E helices of the M subunit. This repacking minimizes the volume of the cavity that results from the exclusion of the Q(A) ubiquinone, and further space is taken up by a feature in the electron density maps that has been modeled as a chloride ion. An unexpected finding is that the occupancy of the Q(B) site by ubiquinone appears to be high in the AM260W crystals, and as a result the position of the Q(B) ubiquinone is well-defined. The high quality of the electron density maps also reveals more precise information on the detailed conformation of the reaction center carotenoid, and we discuss the possibility of a bonding interaction between the methoxy group of the carotenoid and residue Trp M75. The conformation of the 2-acetyl carbonyl group in each of the reaction center bacteriochlorins is also discussed.

Alanine↗

PubMed2000

An examination of how structural changes can affect the rate of electron transfer in a mutated bacterial photoreaction centre.

A series of reaction centres bearing mutations at the (Phe) M197 position were constructed in the photosynthetic bacterium Rhodobacter sphaeroides. This residue is adjacent to the pair of bacteriochlorophyll molecules (P(L) and P(M)) that is the primary donor of electrons (P) in photosynthetic light-energy transduction. All of the mutations affected the optical and electrochemical properties of the P bacteriochlorophylls. A mutant reaction centre with the change Phe M197 to Arg (FM197R) was crystallized, and a structural model constructed at 2.3 A (1 A=0.1 nm) resolution. The mutation resulted in a change in the structure of the protein at the interface region between the P bacteriochlorophylls and the monomeric bacteriochlorophyll that is the first electron acceptor (B(L)). The new Arg residue at the M197 position undergoes a significant reorientation, creating a cavity at the interface region between P and B(L). The acetyl carbonyl substituent group of the P(M) bacteriochlorophyll undergoes an out-of-plane rotation, which decreases the edge-to-edge distance between the macrocycles of P(M) and B(L). In addition, two new buried water molecules partially filled the cavity that is created by the reorientation of the Arg residue. These waters are in a suitable position to connect the macrocycles of P and B(L) via three hydrogen bonds. Transient absorption measurements show that, despite an inferred decrease in the driving force for primary electron transfer in the FM197R reaction centre, there is little effect on the overall rate of the primary reaction in the bulk of the reaction-centre population. Examination of the X-ray crystal structure reveals a number of small changes in the structure of the reaction centre in the interface region between the P and B(L) bacteriochlorophylls that could account for this faster-than-predicted rate of primary electron transfer.

Crystallography, X-Ray↗

PubMed2000

Re-emerging structures: continuing crystallography of the bacterial reaction centre.

The reaction centre is nature's solar battery, and is found in a number of variations on a common theme in plants, algae and photosynthetic bacteria. During the last 20 years, a combination of X-ray crystallography, spectroscopy and mutagenesis has provided increasingly detailed insights into the mechanism of light energy transduction in the bacterial reaction centre. This mini-review looks at the application of X-ray crystallography to the bacterial reaction centre, focussing in particular on recent information on the structural consequences of site-directed mutagenesis, the roles played by water molecules in the reaction centre, the mechanism of ubiquinone reduction, and studies of the phospholipid environment of the protein.

Crystallography, X-Ray↗

PubMed2000

Electrochromic detection of a coherent component in the formation of the charge pair P(+)H(L)(-) in bacterial reaction centers.

We demonstrate coupling of an intraprotein electron transfer reaction to coherent vibrational motions. The kinetics of charge separation toward the radical pair state P(+)H(L)(-) were studied in reaction centers of Rhodobacter sphaeroides at 15 K. The electrochromic shift of the bacteriochlorophyll monomers is the most prominent spectral feature associated with this charge displacement. The newly reported absolute absorption spectrum of the P(+)H(L)(-) state is discussed in terms of this shift. In wild-type reaction centers, the rise kinetics of the electrochromic shift display a small but significant 30 cm(-)(1) periodic modulation (period of approximately 1 ps). This modulation is also present in FL181Y mutant reaction centers, where overall charge separation is somewhat more rapid than in the wild-type reaction center. In contrast, in YM210L mutant reaction centers, where the charge separation is much slower, the modulation is absent. The conclusion that the motion along the reaction coordinate has a 30 cm(-)(1) coherent component is discussed in light of possible mechanisms of electron transfer.

Electrochemistry↗

PubMed2000

Structural consequences of the replacement of glycine M203 with aspartic acid in the reaction center from Rhodobacter sphaeroides.

Reaction centers with the double mutation Phe M197 to Arg and Gly M203 to Asp (FM197R/GM203D) have been crystallized from an antenna-deficient strain of Rhodobacter sphaeroides, and the structure has been determined at 2.7 A resolution. Unlike in reaction centers with a single FM197R mutation, the Arg M197 residue in the FM197R/GM203D reaction center adopts a position similar to that of the native Phe residue in the wild-type reaction center. Asp M203 is packed in such a way that the gamma-carboxy group interacts with the backbone carbonyl of Arg M197. The Asp M203 residue takes up part of the volume that is occupied in the wild-type reaction center by a water molecule. This water has been proposed to form a hydrogen bond interaction with the 9-keto carbonyl group of the active branch accessory bacteriochlorophyll, particularly when the primary donor bacteriochlorophylls are oxidized. The GM203D mutation therefore appears to remove the possibility of this hydrogen bond interaction by exclusion of this water molecule, as well as altering the local dielectric environment of the 9-keto carbonyl group. We examine whether the observed structural changes can provide new or alternative explanations for the absorbance and electron-transfer properties of reaction centers with the FM197R and GM203D mutations.

Amino Acid Substitution↗

PubMed2000

X-ray crystal structure of the YM210W mutant reaction centre from Rhodobacter sphaeroides.

The X-ray crystal structure of a reaction centre from Rhodobacter sphaeroides with a mutation of tyrosine M210 to tryptophan (YM210W) has been determined to a resolution of 2.5 A. Structural conservation is very good throughout the body of the protein, with the tryptophan side chain adopting a position in the mutant complex closely resembling that of the tyrosine in the wild-type complex. The spectroscopic properties of the YM210W reaction centre are discussed with reference to the structural data, with particular focus on evidence that the introduction of the bulkier tryptophan in place of the native tyrosine may cause a small tilt of the macrocycle of the B(L) monomeric bacteriochlorophyll.

Light-Harvesting Protein Complexes↗

PubMed2000

Expectancy, attention, and time.

Seven experiments examine the influence of contextual timing manipulations on prospective time judgments. Subjects judged durations of standard vs comparison time intervals in the context of a preceding induction (context) sequence. In some experiments, the rate of the induction sequence was systematically manipulated relative to the range of to-be-judged standard time intervals; in others, the induction sequence was omitted. Time judgments were strongly influenced by the rate of an induction sequence with best performance occurring when the standard time interval ended as expected, given context rate. An expectancy profile, in the form of an inverted U, indicated that time estimation accuracy declined systematically as a standard interval differed from a context rate. A similar expectancy profile emerged when the context rate was based on a harmonic subdivision (one-half) of an expected standard interval. Results are discussed in terms of various stimulus-based models of prospective time judgments, including those which appeal to attentional periodicities and entrainment.

Attention↗

PubMed2000

Reaction centres of purple bacteria.

The bacterial reaction centre is undoubtedly one of the most heavily studied electron transfer proteins and, as this article has tried to describe, it has made some unique contributions to our understanding of biological electron transfer and coupled protonation reactions, and has provided fascinating information in areas that concern basic properties such as protein heterogeneity and protein dynamics. Despite intensive study, much remains to be learned about how this protein catalyses the conversion of solar energy into a form that can be used by the cell. In particular, the dynamic roles played by the protein are still poorly understood. The wide range of time-scales over which the reaction centre catalyses electron transfer, and the relative ease with which electron transfer can be triggered and monitored, will ensure that the reaction centre will continue to be used as a laboratory for testing ideas about the nature of biological electron transfer for many years to come.

Photosynthetic Reaction Center Complex Proteins↗

PubMed2000

Optic disk edema associated with peripapillary serous retinal detachment: an early sign of systemic Bartonella henselae infection.

PURPOSE: To describe optic disk edema associated with peripapillary serous retinal detachment as an early sign of systemic Bartonella henselae infection. METHODS: Multicentered, retrospective case series. RESULTS: Five women and two men presented with optic disk edema producing peripapillary serous retinal detachment. Each patient had a markedly elevated serum anti-B. henselae antibody titer. Patient age ranged from 11 to 44 years, with a mean and median of 26.6 and 28 years, respectively. The time from the onset of systemic symptoms to the onset of visual symptoms varied from 3 days to 1 month. The peripapillary serous retinal detachment resolved within 1 to 3 weeks in each case, producing a macular star in four of seven patients. Initial vision was 20/200 or worse in five of seven patients and improved in four of these five patients to 20/30 or better. CONCLUSIONS: Systemic B. henselae infection should be considered in patients who develop optic disk edema associated with a peripapillary serous retinal detachment, even in the absence of classic neuroretinitis with a macular star.

Adolescent↗

PubMed2000

Individual characteristics and peer relations of psychiatrically hospitalized aggressive youths: implications for treatment.

OBJECTIVE: This study identified individual and peer-relations problems of inpatient youths who are aggressive, and whether youths who are aggressive in two settings have greater treatment needs than youths who are aggressive in one setting only. METHODS: 85 youths aged 10 to 16 years who were consecutively admitted to a psychiatric facility served as participants. Based on ratings by parents and hospital staff, youths were identified as aggressive in the community only, aggressive in the hospital only, aggressive in both settings, or nonaggressive. Dependent measures consisted of youth self-reports and ratings by parents and hospital staff. RESULTS: Youths who demonstrate aggressive behavior in two settings have more nonaggressive behavior problems, more disturbed peer relations, and more hostile thinking than do nonaggressive youths, and some youths, although they may behave aggressively during hospitalization, have similar treatment needs as nonaggressive youths. CONCLUSIONS: Mental health professionals who work with youths in psychiatric settings need to develop treatment plans that directly address the more severe externalizing problems, hostile thinking, and peer problems of aggressive youths over and above that of nonaggressive youths, and should be aware that youths who behave aggressively during hospitalization may not have problems more severe than those of nonaggressive youths.

Adolescent↗

PubMed2000

Racial variation in initial stroke severity.

BACKGROUND AND PURPOSE: Blacks experience greater morbidity and mortality from stroke than do whites. The degree to which this is due to the severity of the initial stroke is not known. The objective of this study is to determine whether there is a racial difference in initial stroke severity. METHODS: A secondary analysis of a prospective cohort of 984 veterans (29.7% black) admitted to any of 9 geographically diverse Veterans Administration Hospitals for acute stroke between April 1995 and March 1997 was performed. Initial stroke severity was ascertained by using the modified Canadian Neurological Scale (CNS) applied retrospectively to medical record data. Stroke severity, unadjusted and adjusted for covariates, was compared between black and white patients. RESULTS: Blacks had greater initial stroke severity than did whites (mean CNS score 7.96 versus 8.32, respectively; P=0.039), with a 0.5-point difference on the scale corresponding to a single-level decrement in either speech or strength of half of an extremity. This difference persisted with adjustment for other important predictors of stroke severity (P=0. 035). However, there was no significant racial difference in severity when CNS scores were collapsed into a priori clinically relevant categories. CONCLUSIONS: Compared with whites, blacks show greater severity of stroke at hospital admission. It remains uncertain whether the relatively small but significant difference at presentation fully explains the striking racial differences in morbidity and mortality from stroke.

Aged↗

PubMed1999

Structural details of an interaction between cardiolipin and an integral membrane protein.

Anionic lipids play a variety of key roles in biomembrane function, including providing the immediate environment for the integral membrane proteins that catalyze photosynthetic and respiratory energy transduction. Little is known about the molecular basis of these lipid-protein interactions. In this study, x-ray crystallography has been used to examine the structural details of an interaction between cardiolipin and the photoreaction center, a key light-driven electron transfer protein complex found in the cytoplasmic membrane of photosynthetic bacteria. X-ray diffraction data collected over the resolution range 30.0-2.1 A show that binding of the lipid to the protein involves a combination of ionic interactions between the protein and the lipid headgroup and van der Waals interactions between the lipid tails and the electroneutral intramembrane surface of the protein. In the headgroup region, ionic interactions involve polar groups of a number of residues, the protein backbone, and bound water molecules. The lipid tails sit along largely hydrophobic grooves in the irregular surface of the protein. In addition to providing new information on the immediate lipid environment of a key integral membrane protein, this study provides the first, to our knowledge, high-resolution x-ray crystal structure for cardiolipin. The possible significance of this interaction between an integral membrane protein and cardiolipin is considered.

Binding Sites↗

PubMed1999

Primary charge separation routes in the BChl:BPhe heterodimer reaction centers of Rhodobacter sphaeroides.

Energy transfer and the primary charge separation process are studied as a function of excitation wavelength in membrane-bound reaction centers of Rhodobacter sphaeroides in which the excitonically coupled bacteriochlorophyll homodimer is converted to a bacteriochlorophyll-bacteriopheophytin heterodimer, denoted D [Bylina, E. J., and Youvan, D. C. (1988) Proc. Natl. Acad. Sci. U.S. A. 85, 7226]. In the HM202L heterodimer reaction center, excitation of D using 880 nm excitation light results in a 43 ps decay of the excited heterodimer, D. The decay of D results for about 30% in the formation of the charge separated state D+QA- and for about 70% in a decay directly to the ground state. Upon excitation of the monomeric bacteriochlorophylls using 798 nm excitation light, approximately 60% of the excitation energy is transferred downhill to D, forming D. Clear evidence is obtained that the other 40% of the excitations results in the formation of D+QA- via the pathway BA --> BA+HA- --> D+HA- --> D+QA-. In the membrane-bound "reversed" heterodimer reaction center HL173L, the simplest interpretation of the transient absorption spectra following B excitation is that charge separation occurs solely via the slow D-driven route. However, since a bleach at 812 nm is associated with the spectrum of D in the HL173L reaction center, it cannot be excluded that a state including BB is involved in the charge separation process in this complex.

Bacteriochlorophylls↗

PubMed1999

Multiple pathways for ultrafast transduction of light energy in the photosynthetic reaction center of Rhodobacter sphaeroides.

A pathway of electron transfer is described that operates in the wild-type reaction center (RC) of the photosynthetic bacterium Rhodobacter sphaeroides. The pathway does not involve the excited state of the special pair dimer of bacteriochlorophylls (P*), but instead is driven by the excited state of the monomeric bacteriochlorophyll (BA*) present in the active branch of pigments along which electron transfer occurs. Pump-probe experiments were performed at 77 K on membrane-bound RCs by using different excitation wavelengths, to investigate the formation of the charge separated state P+HA-. In experiments in which P or BA was selectively excited at 880 nm or 796 nm, respectively, the formation of P+HA- was associated with similar time constants of 1.5 ps and 1. 7 ps. However, the spectral changes associated with the two time constants are very different. Global analysis of the transient spectra shows that a mixture of P+BA- and P* is formed in parallel from BA* on a subpicosecond time scale. In contrast, excitation of the inactive branch monomeric bacteriochlorophyll (BB) and the high exciton component of P (P+) resulted in electron transfer only after relaxation to P*. The multiple pathways for primary electron transfer in the bacterial RC are discussed with regard to the mechanism of charge separation in the RC of photosystem II from higher plants.

Bacteriochlorophylls↗