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Biomedical subjects

L R Williams

Publications and source records attributed to L R Williams.

At least 19 recordsLinked to original sources
PubMed2000

Splicing before import - an intein in a mitochondrially targeted preprotein folds and is catalytically active in the cytoplasm in vivo.

Nuclear-encoded mitochondrial proteins are cytoplasmically synthesized and imported into the organelle. The intein-containing RecA protein of Mycobacterium tuberculosis, with or without the CoxIVp mitochondrial targeting signal (MTS), was used to determine where a protein targeted to mitochondria folds and becomes catalytically active. Analysis of fractions from Saccharomyces cerevisiae cells expressing RecA without the MTS revealed that RecA and intein proteins remained cytoplasmic. With the MTS, most of RecA was directed to mitochondria, while most of the intein remained in the cytoplasm. The intein therefore folds into a catalytically active state in the cytoplasm prior to RecA import into mitochondria.

Base Sequence↗
PubMed2000

Sensitivity of testicular germ cells to toxicant-induced apoptosis in gld mice that express a nonfunctional form of Fas ligand.

Germ cell apoptosis in testis is essential for functional spermatogenesis. Recent evidence suggests that the Fas signaling system is critical for the regulation of testicular germ cell apoptosis. To further evaluate the Fas signaling system in testis, we examined the incidence of germ cell apoptosis in gld mice that lack a functional Fas-signaling pathway. gld mice have a small, but significant, increase in testis weight and numbers of spermatid heads per testis compared with wild-type mice. In addition, gld mice have a small increase in the spontaneous incidence of germ cell apoptosis, as indicated by characteristic DNA fragmentation via the terminal deoxynucleotidyl-transferase-mediated deoxy-UTP nick end labeling assay. To test the role of the Fas system in toxicant-induced germ cell apoptosis, mice were exposed to either a Sertoli cell- or germ cell-specific toxicant [mono-(2-ethylhexyl)phthalate (MEHP; 1 g/kg) or 5 Gy radiation, respectively]. These two exposure paradigms induced extensive increases in germ cell apoptosis in wild-type mice. However, exposure of gld mice to MEHP caused only a minimal increase in germ cell apoptosis, whereas they were as sensitive as wild-type mice to radiation exposure. These data indicate that the Fas signaling pathway is 1) involved in regulating the numbers of germ cells in the testis, 2) crucial for the initiation of germ cell apoptosis after MEHP-induced Sertoli cell injury, and 3) differentially active in the cell-specific regulation of germ cell apoptosis that occurs as a consequence of Sertoli cell vs. germ cell injury.

Animals↗
PubMed2000

Response amendment in fencing: differences between elite and novice subjects.

Reaction time (RT), movement time (MT), total response time (RMT), and accuracy of 3 elite and 3 novice fencers were studied under a dual response paradigm requiring a full lunge. Electromyographic activity (EMG) from selected arm and leg muscles was used to compare response profiles of the two groups. Although the elite subjects had slower MTs, their faster RTs resulted in significantly shorter total response times. The EMG analysis showed that in comparison to the novice subjects, onset of muscle activity was significantly faster for the elite group in five of the six muscles studied. In addition, the elite subjects showed more coherent muscle synergies and more consistent patterns of muscle coordination. Although the requirement to change targets (signalled by the arrival of a second stimulus) led to slightly more target misses for the elite group, the overall frequency was low, which indicates that it did not pose difficulty for either group. The present findings show that measures of response timing and neuromuscular coordination differentiate skill level in the fencing lunge and draw attention to practical implications for skill assessment and training.

Achievement↗
PubMed2000

Coincidence timing of a soccer pass: effects of stimulus velocity and movement distance.

The effect of stimulus velocity and movement extent on coincidence timing and spatial accuracy of a soccer pass was investigated. A Bassin anticipation timer provided light stimulus velocities of 1.79 or 2.68 m/sec. (designated as "Low" and "High", respectively), and subjects were required to kick a stationary soccer ball so that it struck a target in coincidence with the arrival of the light stimulus at the end of the runway. Two kick types were used. The "Short" condition began with the subject 70 cm from the ball and required a single forward step with the nonkicking leg before making the kick. The "Long" condition began 140 cm from the ball and required two steps before the kick. Twenty male subjects were given 16 trials under each of the four combinations of stimulus velocity and kick type. The expectation that the faster stimulus velocity would be associated with lower coincidence timing scores for both absolute error (AE) and variable error (VE) and with late responding for constant error (CEO) was upheld with the exception that for the Long Kick-High Velocity condition, AE was highest. The index of preprogramming (IP) was used to test the hypothesis that a two-stage control process would characterise coincidence anticipation performance involving whole-body movements. Results showed that the preparatory phase of responding produced zero-order IPs signifying reliance on feedback control. Also, while the striking phase produced high IP and suggested reliance on preprogrammed control, the possibility that the High Velocity conditions may have limited the responses was recognised. As a consequence, the role of open-loop processes remained equivocal. The findings are, however, in agreement with the view that the sensorimotor and movement-execution phases of responding require a process that is characterised by adaptability to regulatory features of the environment via closed loop mechanisms involving perception-action coupling.

Adult↗
PubMed1999

Novel, highly lipophilic antioxidants readily diffuse across the blood-brain barrier and access intracellular sites.

In an accompanying article, an in vitro assay for permeability predicts that membrane-protective, antioxidant 2,4-diamino-pyrrolo[2, 3-d]pyrimidines should have improved blood-brain barrier (BBB) permeation over previously described lipophilic antioxidants. Using a first-pass extraction method and brain/plasma quantification, we show here that two of the pyrrolopyrimidines, one of which is markedly less permeable, readily partition into rat brain. The efficiency of extraction was dependent on serum protein binding, and in situ efflux confirms the in vitro data showing that PNU-87663 is retained in brain longer than PNU-89843. By exploiting inherent fluorescence properties of PNU-87663, its distribution within brain and within cells in culture was demonstrated using confocal scanning laser microscopy. PNU-87663 rapidly partitioned into the cell membrane and equilibrates with cytoplasmic compartments via passive diffusion. Although partitioning of PNU-87663 favors intracytoplasmic lipid storage droplets, the compound was readily exchangeable as shown by efflux of compound from cells to buffer when protein was present. The results demonstrated that pyrrolopyrimidines were well suited for quickly accessing target cells within the central nervous system as well as in other target tissues.

Animals↗
PubMed1998

Clonal production of tea tree oil high in terpinen-4-ol for use in formulations for the treatment of thrush.

A programme of evaluation and selection of superior trees has led to the vegetative propagation of highly productive clones which produce tea tree oil high in terpinen-4-ol. These will soon provide commercial quantities of a particularly active oil of consistent quality for use in formulations for therapeutic use and in particular for vaginal thrush.

Anti-Infective Agents, Local↗
PubMed1997

Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex.

Glial cell line-derived neurotrophic factor (GDNF), a recently described and cloned member of the transforming growth factor (TGF)-beta superfamily, has been shown to have marked trophic activity on several populations of central neurons. Survival-promoting and injury protectant activity in vitro and in vivo, using several paradigms, has been demonstrated for ventral mesencephalic dopaminergic neurons and spinal cord motoneurons. In view of a proposed commonality of mechanisms, involving intracellular free radical generation, depolarization-induced Ca2+ influx, and mitochondrial respiratory enzyme injury, between such GDNF-responsive paradigms and those of ischemia-induced injury, we tested the effects of GDNF on the extent of neural degeneration induced by transient middle cerebral artery (MCA) occlusion. We now report that intracerebroventricular and intraparenchymal administration of GDNF potently protects the cerebral hemispheres from damage induced by MCA occlusion. In addition, the increase in nitric oxide that accompanies MCA occlusion and subsequent reperfusion is blocked almost completely by GDNF. Thus, this protein may play an important role in the treatment of cerebrovascular occlusive disease.

Age Factors↗
PubMed1997

Stochastic completion fields; a neural model of illusory contour shape and salience.

We describe an algorithm- and representation-level theory of illusory contour shape and salience. Unlike previous theories, our model is derived from a single assumption: that the prior probability distribution of boundary completion shape can be modeled by a random walk in a lattice whose points are positions and orientations in the image plane (i.e., the space that one can reasonably assume is represented by neurons of the mammalian visual cortex). Our model does not employ numerical relaxation or other explicit minimization, but instead relies on the fact that the probability that a particle following a random walk will pass through a given position and orientation on a path joining two boundary fragments can be computed directly as the product of two vector-field convolutions. We show that for the random walk we define, the maximum likelihood paths are curves of least energy, that is, on average, random walks follow paths commonly assumed to model the shape of illusory contours. A computer model is demonstrated on numerous illusory contour stimuli from the literature.

Algorithms↗
PubMed1997

Regional distribution of iron, transferrin, ferritin, and oxidatively-modified proteins in young and aged Fischer 344 rat brains.

Iron dysregulation in the brain is thought to contribute to the oxidative damage seen in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. A role for iron in the oxidative stress thought to contribute to normal ageing is less certain. To better characterize the role of iron in normal ageing, the concentrations of iron, transferrin, ferritin, and protein carbonyl groups are measured in nine separate regions of Fischer 344 rats. The largest (approximately 30%) age-related increases in brain iron concentration are seen in the temporal cortex, medial septum, and cerebellum. Ferritin concentration in these same brain regions increases 50 to 250% with age, while protein carbonyl concentration is only -27 to +4%, of young rats. These results indicate that an increase in the major iron-binding protein ferritin compensates for any age-related increase in iron concentration, and suggest that the increased ferritin is cytoprotective, serving to prevent the accumulation of protein carbonyl groups (a principal product of metal-catalysed oxidation of proteins).

Aging↗
PubMed1997

Identification of superoxide dismutase activity in Borrelia burgdorferi.

Infective and noninfective strains of Borrelia burgdorferi, along with Borrelia afzelii and Borrelia garinii, possessed a single iron-containing superoxide dismutase (SOD). None of the Lyme disease spirochetes tested possessed catalase or peroxidase activities. The borrelial SOD was not inducible by growth with increased oxygen concentrations and thus appeared to be produced constitutively.

Borrelia burgdorferi Group↗
PubMed1996

Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures.

We have investigated the neuroprotective actions of neurotrophins in a model of ischaemia using slice cultures. Ischaemia was induced in organotypic hippocampal cultures by simultaneous oxygen and glucose deprivation. Cell death was assessed 24 h later by propidium iodide fluorescence. Pre- but not post-ischaemic addition of brain-derived neurotrophic factor (BDNF) produced a concentration-dependent reduction in neuronal damage. Neurotrophin-3 was not neuroprotective. These data suggest that BDNF may form part of an endogenous neuroprotective mechanism.

Animals↗
PubMed1996

Evidence for DNA fragmentation in the CNS of aged Fischer-344 rats.

The aged central nervous system (CNS) is characterized by a loss of neurons. Apoptosis has been reported to be responsible for neuronal death during development and may also be involved in some age-related neurodegenerative diseases of the CNS. No evidence is currently available as to whether apoptosis is also responsible for the loss of neurons associated with physiological aging. In this study, we have found fragmented DNA, a characteristic trait of cells undergoing apoptosis, in the hippocampus and, to a minor extent, in the frontal cortex and basal forebrain of aged (24-month-old) Fisher-344 rats, but not in the cerebellum. These data represent important evidence to support the idea that apoptosis may be associated with the neuronal death observed during normal aging.

Aging↗
PubMed1996

Cyclophosphamide is neuroprotective in a gerbil model of transient severe focal cerebral ischemia: correlation with effects of tirilazad mesylate (U-74006F).

Using a gerbil model of severe, temporary focal ischemia (3 h unilateral carotid occlusion), preliminary experiments identified an involvement of neutrophils in the reperfusion injury to the ischemic hemisphere. The present experiments were designed to (1) quantitate the temporal accumulation of neutrophils in the gerbil model, (2) determine if cyclophosphamide-induced neutropenia provided cytoprotection to the ischemic hemisphere, and (3) attempt to correlate the cytoprotective efficacy of tirilazad mesylate with possible effects on postischemic neutrophil accumulation. Following 3 h of unilateral carotid occlusion, animals were collected at increasing times of reperfusion and the CA1 region of the hippocampus and the lateral cortex were assessed for postischemic neuronal damage using a semiquantitative index (N.D.I.) of 0 (no damage) to 4 (>75% neuronal loss). The extent of neutrophil accumulation was determined by counting intensely cytochrome oxidase-positive cells. Minimal neuronal death was evident after 2 h of reperfusion, mean N.D.I. = 0.36. However, between 2 and 4 h of reperfusion, neuronal death did not increase. By 6 h of reperfusion, the neuronal death began to proceed at an accelerated rate, N.D.I. = 0.78. By 12 h, the N.D.I. reached 3.20. The accelerated neuronal death coincided with parenchymal invasion of neutrophils. Cyclophosphamide administration delayed neuronal death in the hippocampus, but exhibited a more sustained protective effect in the lateral cortex. Administration of tirilazad mesylate also resulted in a significant reduction in neutrophil accumulation and significant neuronal protection in both brain areas. Thus, in this gerbil model of transient, but prolonged focal cerebral ischemia, neutrophils appear to play an active role in the reperfusion injury to brain tissue. Our experiments confirm the previously demonstrated neuroprotective efficacy of tirilazad mesylate in this model and provide evidence for a similar protective effect of cyclophosphamide. Although other effects of this antioxidant are also thought to contribute to the overall efficacy, the data are consistent with the hypothesis that one mechanism by which tirilazad acts involves limiting the ability of neutrophils to participate in the reperfusion phase of ischemic cerebral injury.

Animals↗
PubMed1996

Glial cell line-derived neurotrophic factor sustains axotomized basal forebrain cholinergic neurons in vivo: dose-response comparison to nerve growth factor and brain-derived neurotrophic factor.

Glial cell line-derived neurotrophic factor (GDNF) was infused continuously for 2 weeks into the ventricles of male Wistar rats that had received a unilateral knife transection of the fimbria/fornix. In vehicle-treated, control animals, there was a 70% loss of choline acetyltransferase (ChAT)-positive and a 60% loss of p75-positive neurons in the septum/diagonal band ipsilateral to the axotomy as identified by immunohistochemistry, with no loss in ChAT biochemical activity. GDNF treatment at 10 micrograms/day completely prevented the loss of p75-positive neurons, significantly reduced the loss of ChAT-positive neurons to 40% of normal, and stimulated ChAT biochemical activity to 40% more than normal in an axotomy-dependent manner. GDNF is 1 order of magnitude less potent than NGF but, unlike NGF, had little or no effect on normal, uninjured neurons. GDNF was 1 order of magnitude more potent than BDNF, and BDNF had no effect on ChAT biochemical activity. GDNF and NGF inhibited weight gain, whereas BDNF induced significant weight loss and death at the dosage of 100 micrograms/day.

Animals↗
PubMed1995

Painful keratoderma and photophobia: hallmarks of tyrosinemia type II.

Tyrosinemia type II (Richner-Hanhart syndrome), which is caused by a deficiency of hepatic tyrosine aminotransferase, results in elevated plasma and urinary tyrosine concentrations. We describe a young boy who was seen at 6 months of age with red eyes, photophobia, and eye pain that were not suspected to be caused by tyrosinemia II until painful plantar keratoderma developed at 2 1/2 years of age. Treatment with a diet low in tyrosine and phenylalanine reversed the manifestations of the disease.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

A proposed blood circulation model for Reference Man.

As part of the revision of the Reference Man model of the International Commission on Radiological Protection (ICRP), we have reviewed and reanalyzed available data on blood flow and in previous publications have proposed reference values for total and regional blood volumes, total cardiac output, and the distribution of cardiac output. In this paper we unify these proposed features of the revised Reference Man within the framework of a dynamic blood circulation model and show how the model can be used to predict the distribution of decays of short-lived radionuclides after injection or absorption into blood. The total blood volume is partitioned into the blood contents of 24 separate organs or tissues, right heart chambers, left heart chambers, pulmonary circulation, arterial outflow to the systemic tissues (aorta and large arteries), and venous return from the systemic tissues (large veins). As a compromise between physical reality and computational simplicity, the circulation of blood is viewed as a system of first-order transfers between blood pools, but outflow from any given pool is delayed during the first pass of material through the circulation with the delay time depending on the mean transit time across the pool. The model can be used to predict the movement and gradual dispersal of a bolus of material in the circulation after intravascular injection. In contrast to the treatment of the circulation in ICRP Publication 53, Radiation Dose to Patients from Radiopharmaceuticals, the present model allows consideration of incomplete, tissue-dependent extraction of material during passage through the circulation and return of material from tissues to plasma.

Adult↗
PubMed1995

Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment.

Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.

Aging↗