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Biomedical subjects

A J Bell

Publications and source records attributed to A J Bell.

At least 19 recordsLinked to original sources
PubMed2001

Stabilization of alpha-helix structure by polar side-chain interactions: complex salt bridges, cation-pi interactions, and C-H em leader O H-bonds.

It is generally understood that helical proteins are stabilized by a combination of hydrophobic and packing interactions, together with H-bonds and electrostatic interactions. Here we show that polar side-chain interactions on the surface can play an important role in helix formation and stability. We review studies on model helical peptides that reveal the effect of weak interactions between side chains on helix stability, focusing on some nonclassical side-chain-side-chain interactions: complex salt bridges, cation-pi, and C-H em leader O H-bonding interactions. Each of these can be shown to contribute to helix stability, and thus must be included in a comprehensive catalogue of helix stabilizing effects. The issue of the structure of the unfolded states of helical peptides is also discussed, in the light of recent experiments showing that these contain substantial amounts of polyproline II conformation.

Amino Acid Sequence↗
PubMed2001

Fragmentation and reactions of two isomeric O-alkyl S-(2-dialkylamino)ethyl methylphosphonothiolates studied by electrospray ionization/ion trap mass spectrometry.

An initial investigation into the electrospray ionization ion trap mass spectrometry (ESI/ITMS) of simple organophosphorus compounds [1] demonstrated that detailed structural information could be obtained by sequential fragmentation of the ions using collision induced dissociation (CID). Several novel fragmentations/rearrangements were observed and it was apparent that the full potential of this approach could not be exploited until a more detailed understanding of the ion fragmentations was obtained. Such an understanding will only result from a detailed study of a wide range of compounds. The present paper describes the investigation of two isomeric organophosphates of particular relevance to chemical warfare convention (CWC) considerations.

Chemical Warfare Agents↗
PubMed2001

Interactions between HMG boxes.

Many proteins consist of subdomains that can fold and function independently. We investigate here the interaction between the two high mobility group (HMG) box subdomains of the nuclear protein rHMG1. An HMG box is a conserved amino acid sequence of approximately 80 amino acids rich in basic, aromatic and proline side chains that is active in binding DNA in a sequence or structure-specific manner. In the case of HMG1, each box can bind structural DNA substrates including four-way junctions (4WJs) and branched or kinked DNA duplexes. Since proteins containing up to six HMG boxes are known, the question arises whether linking subdomains together influences the folding or function of individual boxes. In an effort to understand interactions between individual DNA-binding domains in HMG1, we created new fusion proteins: one is an inversion of the order of the AB di-domain in HMG1 (BA); in the second, we added a third A domain C-terminal to the AB di-domain (ABA). Pairs of boxes, AB or BA, behave similarly and are functionally active. By contrast, the ABA triple subdomain construct is partially unfolded and is less active than individual boxes or di-domains. Thus, long-range inter-domain effects can influence the activity of HMG boxes.

Amino Acid Sequence↗
PubMed2000

Characteristics and outcomes of older patients presenting to the emergency department after a fall: a retrospective analysis.

OBJECTIVES: To study older patients presenting to the emergency department after a fall--factors associated with the fall, injuries sustained and outcome. DESIGN: A retrospective analysis using the Emergency Department Information System (EDIS), the Trauma Registry and the patient information database (CCIS), in addition to the patient's emergency and inpatient medical records. SETTING: Emergency department of a major inner city teaching hospital, 1 June-30 November 1997. PATIENTS: All patients over 65 years presenting to the emergency department (ED) after a fall, for whom complete medical records were available. RESULTS: Of 803 patients over 65 years presenting to the ED after a fall, complete records were available for 733 (91.3%) (283 men and 450 women). Extrinsic (accidental) causes were implicated in more than a third of falls (313 patients [42.7%]). A high proportion of the patients were living at home (520; 70.9%) and walking unaided (389; 53.1%). Although absolute numbers of women increased with age, men were as likely as women to present after a fall. Many patients had fallen before--39% of the men (111/283) and 24% of the women (110/450). In 78 patients (10.6%), alcohol misuse may have been a direct cause of the fall. The overall injury rate was 70.5% (517/733 patients), the most common injury being an isolated fracture (269/517 patients; 52.0%). In all, 419 patients (57.2%) were admitted to hospital, 48% (200/419) with a fracture and 52% (219/419) for investigation of the medical cause of the fall. The median length of hospital stay was 6 days (mean, 10.4 days; range, 1-129 days); 35% (146/419) of patients were in hospital for more than 10 days. CONCLUSION: Older patients presenting to the ED after a fall had high injury rates, high admission rates and often prolonged hospitalisation. About a third had fallen before. Patients at risk can be identified in the ED and referred to falls prevention programs.

Accidental Falls↗
PubMed1999

Levels and loops: the future of artificial intelligence and neuroscience.

In discussing artificial intelligence and neuroscience, I will focus on two themes. The first is the universality of cycles (or loops): sets of variables that affect each other in such a way that any feed-forward account of causality and control, while informative, is misleading. The second theme is based around the observation that a computer is an intrinsically dualistic entity, with its physical set-up designed so as not to interfere with its logical set-up, which executes the computation. The brain is different. When analysed empirically at several different levels (cellular, molecular), it appears that there is no satisfactory way to separate a physical brain model (or algorithm, or representation), from a physical implementational substrate. When program and implementation are inseparable and thus interfere with each other, a dualistic point-of-view is impossible. Forced by empiricism into a monistic perspective, the brain-mind appears as neither embodied by or embedded in physical reality, but rather as identical to physical reality. This perspective has implications for the future of science and society. I will approach these from a negative point-of-view, by critiquing some of our millennial culture's popular projected futures.

Artificial Intelligence↗
PubMed1998

Analysis of fMRI data by blind separation into independent spatial components.

Current analytical techniques applied to functional magnetic resonance imaging (fMRI) data require a priori knowledge or specific assumptions about the time courses of processes contributing to the measured signals. Here we describe a new method for analyzing fMRI data based on the independent component analysis (ICA) algorithm of Bell and Sejnowski ([1995]: Neural Comput 7:1129-1159). We decomposed eight fMRI data sets from 4 normal subjects performing Stroop color-naming, the Brown and Peterson work/number task, and control tasks into spatially independent components. Each component consisted of voxel values at fixed three-dimensional locations (a component "map"), and a unique associated time course of activation. Given data from 144 time points collected during a 6-min trial, ICA extracted an equal number of spatially independent components. In all eight trials, ICA derived one and only one component with a time course closely matching the time course of 40-sec alternations between experimental and control tasks. The regions of maximum activity in these consistently task-related components generally overlapped active regions detected by standard correlational analysis, but included frontal regions not detected by correlation. Time courses of other ICA components were transiently task-related, quasiperiodic, or slowly varying. By utilizing higher-order statistics to enforce successively stricter criteria for spatial independence between component maps, both the ICA algorithm and a related fourth-order decomposition technique (Comon [1994]: Signal Processing 36:11-20) were superior to principal component analysis (PCA) in determining the spatial and temporal extent of task-related activation. For each subject, the time courses and active regions of the task-related ICA components were consistent across trials and were robust to the addition of simulated noise. Simulated movement artifact and simulated task-related activations added to actual fMRI data were clearly separated by the algorithm. ICA can be used to distinguish between nontask-related signal components, movements, and other artifacts, as well as consistently or transiently task-related fMRI activations, based on only weak assumptions about their spatial distributions and without a priori assumptions about their time courses. ICA appears to be a highly promising method for the analysis of fMRI data from normal and clinical populations, especially for uncovering unpredictable transient patterns of brain activity associated with performance of psychomotor tasks.

Algorithms↗
PubMed1997

Blind separation of auditory event-related brain responses into independent components.

Averaged event-related potential (ERP) data recorded from the human scalp reveal electroencephalographic (EEG) activity that is reliably time-locked and phase-locked to experimental events. We report here the application of a method based on information theory that decomposes one or more ERPs recorded at multiple scalp sensors into a sum of components with fixed scalp distributions and sparsely activated, maximally independent time courses. Independent component analysis (ICA) decomposes ERP data into a number of components equal to the number of sensors. The derived components have distinct but not necessarily orthogonal scalp projections. Unlike dipole-fitting methods, the algorithm does not model the locations of their generators in the head. Unlike methods that remove second-order correlations, such as principal component analysis (PCA), ICA also minimizes higher-order dependencies. Applied to detected-and undetected-target ERPs from an auditory vigilance experiment, the algorithm derived ten components that decomposed each of the major response peaks into one or more ICA components with relatively simple scalp distributions. Three of these components were active only when the subject detected the targets, three other components only when the target went undetected, and one in both cases. Three additional components accounted for the steady-state brain response to a 39-Hz background click train. Major features of the decomposition proved robust across sessions and changes in sensor number and placement. This method of ERP analysis can be used to compare responses from multiple stimuli, task conditions, and subject states.

Algorithms↗
PubMed1997

The "independent components" of natural scenes are edge filters.

It has previously been suggested that neurons with line and edge selectivities found in primary visual cortex of cats and monkeys form a sparse, distributed representation of natural scenes, and it has been reasoned that such responses should emerge from an unsupervised learning algorithm that attempts to find a factorial code of independent visual features. We show here that a new unsupervised learning algorithm based on information maximization, a nonlinear "infomax" network, when applied to an ensemble of natural scenes produces sets of visual filters that are localized and oriented. Some of these filters are Gabor-like and resemble those produced by the sparseness-maximization network. In addition, the outputs of these filters are as independent as possible, since this infomax network performs Independent Components Analysis or ICA, for sparse (super-gaussian) component distributions. We compare the resulting ICA filters and their associated basis functions, with other decorrelating filters produced by Principal Components Analysis (PCA) and zero-phase whitening filters (ZCA). The ICA filters have more sparsely distributed (kurtotic) outputs on natural scenes. They also resemble the receptive fields of simple cells in visual cortex, which suggests that these neurons form a natural, information-theoretic coordinate system for natural images.

Algorithms↗
PubMed1996

Response of B-cell lymphoma to a combination of bispecific antibodies and saporin.

Observations are described using a combination of two bispecific F(ab')2 antibodies (BsAb) to deliver the ribosome-inactivating protein, saporin, in the treatment of low-grade, end-stage, B-cell lymphoma. Two BsAb were used, each having one arm directed at saporin and one at the CD22 on target B cells. The BsAb, however, recognized different, non-overlapping epitopes on each molecule, a strategy which permits high-avidity double attachment of saporin to the target. The BsAb and saporin were pre-mixed at a molar ratio of 3:1 24 h before treatment and infused intravenously over a period of 1 h. Five patients have been treated, mostly with weekly doses of between 2 and 4 mg of saporin for a period of up to 6 weeks. Toxicity was minimal. Three complained of weakness and myalgia for 1 to 2 days after treatment, without objective neurological deficit or rise in serum creatine kinase. One patient produced an anti-mouse Fab' and an anti-saporin response. All patients showed a rapid and beneficial response to treatment. When present, circulating tumor cells were cleared (4/4 patients), ascitic and pleural effusions were eliminated (2/2 patients) and one patient with splenomegaly showed a marked reduction in tumor bulk. Malignant lymph nodes showed significant, but partial, shrinkage in all patients and finally marrow responded well with tumor clearance in biopsy material and impressive resolution of pancytopenia in some patients. While these responses were mainly short-lived, with tumor progression once the treatment was stopped, their speed and magnitude, and the relative lack of associated toxicity warrants further study of this treatment to determine maximum tolerated doses and therapeutic utility.

Aged↗
PubMed1996

Positive serology to Legionella longbeachae in patients with adult respiratory distress syndrome.

In an observational study we measured the Legionella longbeachae antibody titre rise in patients mechanically ventilated for more than eight days during a two-month period. The patients were divided into two groups on the basis of the presence or absence of the adult respiratory distress syndrome (ARDS). In nine patients with ARDS all showed an antibody rise consistent with recent infection with Legionella longbeachae with a rise in titre (six patients) or a high titre after eight to ten days of ventilation (three patients). Three patients without ARDS did not show a rise in titre. Culture of the environment, ventilator circuits, humidifiers and humidification water did not reveal an environmental source of Legionella longbeachae in the Intensive Care Unit. Legionella longbeachae may be implicated as a pathogenic organism in ARDS, or as a secondary nosocomial infection. Alternatively the antibody titre rise may represent an epiphenomenon and may not be related to Legionella longbeachae infection.

Adult↗
PubMed1995

Treatment of B-cell lymphomas with combination of bispecific antibodies and saporin.

We report the use of a bispecific F(ab')2 antibody to target the ribosome-inactivating protein saporin to the surface antigen CD22 in the treatment of low-grade, end-stage, B-cell lymphoma. Four patients were treated. Toxic effects were minimal (grade I), with mild fever, weakness, and myalgia for 1-2 days after treatment. One patient showed an antibody response to mouse Fab' and saporin. All patients showed rapid and beneficial responses to treatment with improvements in most disease sites and in peripheral blood cytopenia. The responses were short-lived (less than 28 days) but further study of this targeting system is warranted.

Antibodies, Bispecific↗
PubMed1995

Double-blind, placebo-controlled investigation of the effect of combined phototherapy/low intensity laser therapy upon experimental ischaemic pain in humans.

BACKGROUND AND OBJECTIVE: This study assessed the putative analgesic effect of combined monochromatic light/laser irradiation at low intensity (660-950 nm; 31.9 J/cm2; pulsed at 16 or 73 Hz). STUDY DESIGN/MATERIALS AND METHODS: The investigation was completed under double-blind conditions using a standardised form of the submaximal effort tourniquet technique. Healthy male volunteers naive to the experimental conditions (n = 45) attended on two occasions for the purposes of pain induction, the first during which baseline data were obtained and on a second occasion during which they were randomly allocated to one of two treatments or a placebo condition. For the treatment conditions, irradiation was applied to the ipsilateral Erb's point at the parameters stated; for the placebo condition, sham "irradiation" was delivered using a dummy unit. Pain was measured using computerised visual analogue scales and McGill Pain Questionnaires (MPQ) to assess "current pain intensity" and "worst pain experienced," respectively. RESULTS: Analysis of variance and appropriate post hoc tests demonstrated only a weak (but significant) hypoalgesic effect compared to placebo (P < 0.05) in the treatment group irradiated at 16Hz for the sensory component of the MPQ; other comparisons were found to be nonsignificant. CONCLUSIONS: These results do not provide convincing evidence for the hypoalgesic potential of combined monochromatic light/laser irradiation, at least at the parameters used here, and thus indicate the necessity of additional work to investigate this modality further in order to assess the potential benefit, if any, of such treatment in the clinical setting.

Analgesia↗
PubMed1995

An information-maximization approach to blind separation and blind deconvolution.

We derive a new self-organizing learning algorithm that maximizes the information transferred in a network of nonlinear units. The algorithm does not assume any knowledge of the input distributions, and is defined here for the zero-noise limit. Under these conditions, information maximization has extra properties not found in the linear case (Linsker 1989). The nonlinearities in the transfer function are able to pick up higher-order moments of the input distributions and perform something akin to true redundancy reduction between units in the output representation. This enables the network to separate statistically independent components in the inputs: a higher-order generalization of principal components analysis. We apply the network to the source separation (or cocktail party) problem, successfully separating unknown mixtures of up to 10 speakers. We also show that a variant on the network architecture is able to perform blind deconvolution (cancellation of unknown echoes and reverberation in a speech signal). Finally, we derive dependencies of information transfer on time delays. We suggest that information maximization provides a unifying framework for problems in "blind" signal processing.

Algorithms↗
PubMed1994

Identification of the poly-L-proline-binding site on human profilin.

Profilin is a ubiquitous protein that has been implicated in the signaling pathway leading to cytoskeletal rearrangement in cells. An unusual property of profilin is its high binding affinity for poly-L-proline (PLP). This binding property is conserved in the profilins from diverse species with little sequence homology. We have monitored the binding of PLP to profilin by fluorescence and nuclear magnetic resonance spectroscopies. NMR spectroscopy has identified several residues whose amide nitrogen and amide hydrogen chemical shifts are significantly perturbed by binding of PLP. The affected residues are located at various locations throughout profilin's primary structure; however, mapping the location of the affected residues onto the recently determined three-dimensional solution structure of human profilin indicates that the effects of PLP binding are highly localized. Poly-L-proline binds profilin at the hydrophobic interface between profilin's NH2- and COOH-terminal helices and the upper face of its antiparallel beta-sheet. In contrast, residues located on the opposite side of the profilin structure are unaffected. The extent of the potential interaction surface of the PLP-profilin complex suggests that as few as 6 contiguous prolines would be sufficient for binding profilin. Examination of sequence data bases indicates that stretches of prolines of this length and longer occur in numerous regulatory proteins, suggesting that the ability of profilin to bind polyproline may be an important component of its signaling capabilities.

Amino Acid Sequence↗