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Biomedical subjects

T A Jones

Publications and source records attributed to T A Jones.

At least 19 recordsLinked to original sources
PubMed2006

Abnormalities in skilled reaching movements are improved by peripheral anesthetization of the less-affected forelimb after sensorimotor cortical infarcts in rats.

Unilateral damage to sensorimotor cortical (SMC) regions can profoundly impair skilled reaching function in the contralesional forelimb. Such damage also results in impairments and compensatory changes in the less-affected/ipsilesional forelimb, but these effects remain poorly understood. Furthermore, anesthetization of the ipsilesional hand in humans with cerebral infarcts has been reported to produce transient functional improvements in the paretic hand [Floel A, Nagorsen U, Werhahn KJ, Ravindran S, Birbaumer N, Knecht S, et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann Neurol 2004;56:206-12; Voller B, Floel A, Werhahn KJ, Ravindran S, Wu CW, Cohen LG. Contralateral hand anesthesia transiently improves poststroke sensory deficits. Ann Neurol 2006;59:385-8]. One aim of this study was to sensitively assay the bilateral effects of unilateral ischemic SMC damage on performance of a unimanual skilled reaching task (the single pellet retrieval task) that rats had acquired pre-operatively with each forelimb. The second aim was to determine whether partially recovered contralesional reaching function is influenced by anesthetization of the ipsilesional forelimb. Unilateral SMC lesions were found to result in transient ipsilesional impairments in reaching success and significant ipsilesional abnormalities in reaching movements compared with sham-operates. There were major contralesional reaching impairments which improved during a 4 week training period, but movements remained significantly abnormal. Anesthetization of the ipsilesional forelimb with lidocaine at this time attenuated the contralesional movement abnormalities. These findings indicate that unilateral ischemic SMC lesions impair skilled reaching behavior in both forelimbs. Furthermore, after partial recovery in the contralesional forelimb, additional improvements can be induced by transient anesthetization of the ipsilesional forelimb. This is consistent with the effects of unilateral anesthetization in humans which have been attributed to the modulation of competitive interhemispheric interactions. The present findings suggest that such interactions are also likely to influence skilled reaching function in rats.

Anesthesia↗
PubMed2006

Application of the use of high-throughput technologies to the determination of protein structures of bacterial and viral pathogens.

The Structural Proteomics In Europe (SPINE) programme is aimed at the development and implementation of high-throughput technologies for the efficient structure determination of proteins of biomedical importance, such as those of bacterial and viral pathogens linked to human health. Despite the challenging nature of some of these targets, 175 novel pathogen protein structures (approximately 220 including complexes) have been determined to date. Here the impact of several technologies on the structural determination of proteins from human pathogens is illustrated with selected examples, including the parallel expression of multiple constructs, the use of standardized refolding protocols and optimized crystallization screens.

Animals↗
PubMed2005

Environmental and management factors affecting the welfare of chickens on commercial farms in the United Kingdom and Denmark stocked at five densities.

Data from a large commercial-scale experiment in which 10 major broiler producer companies stocked whole houses of birds at 30, 34, 38, 42, and 46 kg/m2 were analyzed to identify 1) temperature and humidity profiles achieved throughout the growth cycle, 2) management practices and equipment that contributed to observed variation in environmental conditions, and 3) the extent to which environmental variables affected bird welfare. The study involved a total of 2.7 million birds in 114 houses on commercial farms with measurement of a wide range of environmental and bird variables. Much of the variation in broiler health and welfare was associated with the percentage of time a company could maintain house temperature and RH within limits recommended by the breeder company. RH in the first week of life was particularly important to later health, suggesting that better control of humidity might lead to improved welfare. Key management factors affecting bird welfare were those relating to good ventilation and air control such as the type of ventilation, type of drinker, numbers of stockmen, and litter type. Controlling the environment, particularly temperature, humidity, and air and litter quality, is crucial to broiler chicken welfare. This does not mean that stocking density is unimportant, but lowering stocking density on its own, without regard to the environment the birds experience, is not sufficient. Genuine improvements in bird welfare will come from setting standards that combine stocking density, safeguards on the environment, and the genetic makeup of the birds.

Animal Husbandry↗
PubMed2005

Training the "less-affected" forelimb after unilateral cortical infarcts interferes with functional recovery of the impaired forelimb in rats.

PURPOSE: Unilateral lesions of the sensorimotor cortex (SMC) in adult rats cause major behavioral changes in the ipsilesional, "less-affected" forelimb. An increase in function and reliance on this forelimb can aid compensation for contralesional impairments, but may also promote disuse and reduced functionality of the impaired forelimb. We hypothesized that training focused on the ipsilesional forelimb following a unilateral SMC lesion would reduce the efficacy of later motor rehabilitative training of the impaired forelimb. METHODS: Rats with ischemic SMC lesions were trained on a skilled reaching task with the ipsilesional forelimb (PriorT) or received control procedures (Cont) for 10 days. Both groups were then trained with the impaired forelimb on the same reaching task for 10 days. RESULTS: In comparison with Cont, PriorT rats had little improvement on the reaching task with the impaired forelimb and had a more enduring disuse of the impaired forelimb for postural support behaviors. Lesion sizes were similar between groups. CONCLUSIONS: Behavioral experience with the less-affected forelimb early after unilateral SMC lesions has the potential to increase disuse and dysfunction of the impaired forelimb, consistent with a training-induced exacerbation of learned non-use. These findings are suggestive of competitive processes in experience-dependent neural restructuring after brain damage.

Animals↗
PubMed2004

Evidence for macular gravity receptor modulation of hypothalamic, limbic and autonomic nuclei.

Mice lacking normal vestibular gravity reception show altered homeostatic, circadian and autonomic responses to hypergravity (+G) exposure. Using c-Fos as a marker of neuronal activation, the current study identifies CNS nuclei that may be critical for initiating and integrating such responses to changes in vestibular signaling. This experiment utilized the mutant C57BL/6JEi-het mouse (het), which lacks macular otoconia and thus gravity receptor function. Following 2 h of 2G (2x Earth's gravity) exposure (via centrifugation) the neuronal responses of the het mice were compared with wildtype mice similarly exposed to 2G, as well as het and wildtype 1G controls. Wildtype mice exposed to 2G demonstrated robust c-Fos expression in multiple autonomic, hypothalamic and limbic nuclei, including: the lateral septum, bed nucleus of the stria terminalis, amygdala, paraventricular hypothalamus, dorsomedial hypothalamus, arcuate, suprachiasmatic hypothalamus, intergeniculate leaflet, dorsal raphe, parabrachial and locus coeruleus. The het mice exposed to 2G demonstrated little to null c-Fos expression in these nuclei with a few exceptions and, in general, a similar pattern of c-Fos to 1G controls. Data from this study further support the existence of a complex and extensive influence of the neurovestibular system on homeostatic, circadian and possibly autonomic regulatory systems.

Animals↗
PubMed2004

Behavioral and neuroplastic effects of focal endothelin-1 induced sensorimotor cortex lesions.

Previous studies have established the usefulness of endothelin-1 (ET-1) for the production of focal cerebral ischemia. The present study assessed the behavioral effects of focal ET-1-induced lesions of the sensorimotor cortex (SMC) in adult rats as well as cellular and structural changes in the contralateral homotopic motor cortex at early (2 days) and later (14 days) post-lesion time points. ET-1 lesions resulted in somatosensory and postural-motor impairments in the contralateral (to the lesion) forelimb as assessed on a battery of sensitive measures of sensorimotor function. The lesions also resulted in the development of a hyper-reliance on the ipsilateral forelimb for postural-support behaviors. In comparison to sham-operated rats, in layer V of the motor cortex opposite the lesions, there were time- and laminar-dependent increases in the surface density of dendritic processes immunoreactive for microtubule-associated protein 2, in the optical density of N-methyl-D-asparate receptor (NMDA) subunit 1 immunoreactivity, and in the numerical density of cells immunolabeled for Fos, the protein product of the immediate early gene c-fos. These findings corroborate and extend previous findings of the effects of electrolytic lesions of the SMC. It is likely that compensatory forelimb behavioral changes and transcallosal degeneration play important roles in these changes in the cortex opposite the lesion, similar to previously reported effects of electrolytic SMC lesions.

Animals↗
PubMed2003

Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes.

AIM: These analyses were undertaken to evaluate the efficacy of the insulin sensitizer rosiglitazone (RSG) when added to the therapy of obese type 2 diabetes mellitus patients (T2DM) taking near-maximal doses (2.5 g/day) of metformin (MET). In obese, insulin-resistant patients with T2DM who are inadequately controlled on MET, the addition of an agent that reduces insulin resistance may be a more rational and innovative approach than the addition of an insulin secretagogue. METHODS: Data were pooled from two double-blind studies of RSG added to 2.5 g/day MET, involving a total of 550 T2DM patients. Patients were categorized as non-overweight, overweight and obese according to their baseline BMI using WHO criteria (<25 kgm(-2), 25-30 kgm(-2), >30 kgm(-2) respectively). RESULTS: RSG improved glycaemia (HbA1c) and fasting plasma glucose (FPG) to a clinically significant extent in all three subgroups but the effect was most pronounced in the obese patients. Improvements in HOMA estimates of insulin resistance and beta-cell function were also greatest in the obese patients (4 mg: -16% and +19%; 8 mg: -37% and + 33% respectively), as were reductions in fasting insulin. The profile of adverse events was not demonstrably different in obese patients from the non-obese. CONCLUSIONS: In obese type 2 diabetic patients inadequately controlled on MET alone, addition of rosiglitazone improves glycaemic control, insulin sensitivity and beta-cell function to a clinically important extent.

Adult↗
PubMed2001

Primordial rhythmic bursting in embryonic cochlear ganglion cells.

This study examined the nature of spontaneous discharge patterns in cochlear ganglion cells in embryonic day 13 (E13) to early E17 chicken embryos (stages 39-43). Neural recordings were made with glass micropipettes. No sound-driven activity was seen for the youngest embryos (maximum intensity 107 dB sound pressure level). Ganglion cells were labeled with biotinylated dextran amine in four embryos. In two animals, primary afferents projected to hair cells in the middle region along the length of the basilar papilla in which, in one cell, the terminals occupied a neural transverse position and, in the other, a more abneural location. Statoacoustic ganglion cells showing no spontaneous activity were seen for the first time in the chicken. The proportion of "silent" cells was largest at the youngest stages (stage 39, 67%). In active cells, mean spontaneous discharge rates [9.4 +/- 10.4 spikes (Sp)/sec; n = 44] were lower than rates for older embryos (19 +/- 17 Sp/sec) (Jones and Jones, 2000). Embryos at stages 39-41 evidenced even lower rates (4.2 +/- 5.0 Sp/sec). The most salient feature of spontaneous activity for stages 39-43 was a bursting discharge pattern in >75% of active neurons (33 of 44). Moreover, in 55% of these cells, there was a clear, slow, rhythmic bursting pattern. The proportion of cells showing rhythmic bursting was greatest at the youngest stages (39-42) and decreased to <30% at stage 43. Rate of bursting ranged from 1 to 54 bursts per minute. The presence of rhythmic bursting in cochlear ganglion cells at E13-E17 provides an explanation for the existence of such patterns in central auditory relays. The bursting patterns may serve as a patterning signal for central synaptic refinements in the auditory system during development.

Acoustic Stimulation↗
PubMed2001

Computational identification of noncoding RNAs in E. coli by comparative genomics.

Some genes produce noncoding transcripts that function directly as structural, regulatory, or even catalytic RNAs [1, 2]. Unlike protein-coding genes, which can be detected as open reading frames with distinctive statistical biases, noncoding RNA (ncRNA) gene sequences have no obvious inherent statistical biases [3]. Thus, genome sequence analyses reveal novel protein-coding genes, but any novel ncRNA genes remain invisible. Here, we describe a computational comparative genomic screen for ncRNA genes. The key idea is to distinguish conserved RNA secondary structures from a background of other conserved sequences using probabilistic models of expected mutational patterns in pairwise sequence alignments. We report the first whole-genome screen for ncRNA genes done with this method, in which we applied it to the "intergenic" spacers of Escherichia coli using comparative sequence data from four related bacteria. Starting from >23,000 conserved interspecies pairwise alignments, the screen predicted 275 candidate structural RNA loci. A sample of 49 candidate loci was assayed experimentally. At least 11 loci expressed small, apparently noncoding RNA transcripts of unknown function. Our computational approach may be used to discover structural ncRNA genes in any genome for which appropriate comparative genome sequence data are available.

Animals↗
PubMed2001

Molray--a web interface between O and the POV-Ray ray tracer.

A publicly available web-based interface is presented for producing high-quality ray-traced images and movies from the molecular-modelling program O [Jones et al. (1991), Acta Cryst. A47, 110-119]. The interface allows the user to select O-plot files and set parameters to create standard input files for the popular ray-tracing renderer POV-Ray, which can then produce publication-quality still images or simple movies. To ensure ease of use, we have made this service available to the O user community via the World Wide Web. The public Molray server is available at http://xray.bmc.uu.se/molray.

Internet↗
PubMed2001

Binding site differences revealed by crystal structures of Plasmodium falciparum and bovine acyl-CoA binding protein.

Acyl-CoA binding protein (ACBP) maintains a pool of fatty acyl-CoA molecules in the cell and plays a role in fatty acid metabolism. The biochemical properties of Plasmodium falciparum ACBP are described together with the 2.0 A resolution crystal structures of a P. falciparum ACBP-acyl-CoA complex and of bovine ACBP in two crystal forms. Overall, the bovine ACBP crystal structures are similar to the NMR structures published previously; however, the bovine and parasite ACBP structures are less similar. The parasite ACBP is shown to have a different ligand-binding pocket, leading to an acyl-CoA binding specificity different from that of bovine ACBP. Several non-conservative differences in residues that interact with the ligand were identified between the mammalian and parasite ACBPs. These, together with measured binding-specificity differences, suggest that there is a potential for the design of molecules that might selectively block the acyl-CoA binding site.

Amino Acid Sequence↗
PubMed2001

Engineering of a glycosidase Family 7 cellobiohydrolase to more alkaline pH optimum: the pH behaviour of Trichoderma reesei Cel7A and its E223S/ A224H/L225V/T226A/D262G mutant.

The crystal structures of Family 7 glycohydrolases suggest that a histidine residue near the acid/base catalyst could account for the higher pH optimum of the Humicola insolens endoglucanase Cel7B, than the corresponding Trichoderma reesei enzymes. Modelling studies indicated that introduction of histidine at the homologous position in T. reesei Cel7A (Ala(224)) required additional changes to accommodate the bulkier histidine side chain. X-ray crystallography of the catalytic domain of the E223S/A224H/L225V/T226A/D262G mutant reveals that major differences from the wild-type are confined to the mutations themselves. The introduced histidine residue is in plane with its counterpart in H. insolens Cel7B, but is 1.0 A (=0.1 nm) closer to the acid/base Glu(217) residue, with a 3.1 A contact between N(epsilon2) and O(epsilon1). The pH variation of k(cat)/K(m) for 3,4-dinitrophenyl lactoside hydrolysis was accurately bell-shaped for both wild-type and mutant, with pK(1) shifting from 2.22+/-0.03 in the wild-type to 3.19+/-0.03 in the mutant, and pK(2) shifting from 5.99+/-0.02 to 6.78+/-0.02. With this poor substrate, the ionizations probably represent those of the free enzyme. The relative k(cat) for 2-chloro-4-nitrophenyl lactoside showed similar behaviour. The shift in the mutant pH optimum was associated with lower k(cat)/K(m) values for both lactosides and cellobiosides, and a marginally lower stability. However, k(cat) values for cellobiosides are higher for the mutant. This we attribute to reduced non-productive binding in the +1 and +2 subsites; inhibition by cellobiose is certainly relieved in the mutant. The weaker binding of cellobiose is due to the loss of two water-mediated hydrogen bonds.

Alkalies↗
PubMed2001

The X-ray crystal structure of the Trichoderma reesei family 12 endoglucanase 3, Cel12A, at 1.9 A resolution.

We present the three-dimensional structure of Trichoderma reesei endoglucanase 3 (Cel12A), a small, 218 amino acid residue (24.5 kDa), neutral pI, glycoside hydrolase family 12 cellulase that lacks a cellulose-binding module. The structure has been determined using X-ray crystallography and refined to 1.9 A resolution. The asymmetric unit consists of six non-crystallographic symmetry-related molecules that were exploited to improve initial multiple isomorphous replacement phasing, and subsequent structure refinement. The enzyme contains one disulfide bridge and is glycosylated at Asp164 by a single N-acetyl glucosamine residue. The protein has the expected fold for a glycoside hydrolase clan-C family 12 enzyme. It contains two beta-sheets, of six and nine strands, packed on top of one another, and one alpha-helix. The concave surface of the nine-stranded beta-sheet forms a large substrate-binding groove in which the active-site residues are located. In the active site, we find a carboxylic acid trio, similar to that of glycoside hydrolase families 7 and 16. The strictly conserved Asp99 hydrogen bonds to the nucleophile, the invariant Glu116. The binding crevice is lined with both aromatic and polar amino acid side-chains which may play a role in substrate binding. The structure of the fungal family 12 enzyme presented here allows a complete structural characterization of the glycoside hydrolase-C clan.

Amino Acid Sequence↗
PubMed2001

Structural basis for enantiomer binding and separation of a common beta-blocker: crystal structure of cellobiohydrolase Cel7A with bound (S)-propranolol at 1.9 A resolution.

Cellobiohydrolase Cel7A (previously called CBH 1), the major cellulase produced by the mould fungus Trichoderma reesei, has been successfully exploited as a chiral selector for separation of stereo-isomers of some important pharmaceutical compounds, e.g. adrenergic beta-blockers. Previous investigations, including experiments with catalytically deficient mutants of Cel7A, point unanimously to the active site as being responsible for discrimination of enantiomers. In this work the structural basis for enantioselectivity of basic drugs by Cel7A has been studied by X-ray crystallography. The catalytic domain of Cel7A was co-crystallised with the (S)-enantiomer of a common beta-blocker, propranolol, at pH 7, and the structure of the complex was determined and refined at 1. 9 A resolution. Indeed, (S)-propranolol binds at the active site, in glucosyl-binding subsites -1/+1. The catalytic residues Glu212 and Glu217 make tight salt links with the secondary amino group of (S)-propranolol. The oxygen atom attached to the chiral centre of (S)-propranolol forms hydrogen bonds to the nucleophile Glu212 O(epsilon1) and to Gln175 N(epsilon2), whereas the aromatic naphthyl moiety stacks with the indole ring of Trp376 in site +1. The bidentate charge interaction with the catalytic glutamate residues is apparently crucial, since no enantioselectivity has been obtained with the catalytically deficient mutants E212Q and E217Q. Activity inhibition experiments with wild-type Cel7A were performed in conditions close to those used for crystallisation. Competitive inhibition constants for (R)- and (S)-propranolol were determined at 220 microM and 44 microM, respectively, corresponding to binding free energies of 20 kJ/mol and 24 kJ/mol, respectively. The K(i) value for (R)-propranolol was 57-fold lower than the highest concentration, 12.5 mM, used in co-crystallisation experiments. Still several attempts to obtain a complex with the (R)-enantiomer have failed. By using cellobiose as a selective competing ligand, the retention of the enantiomers of propranolol on the chiral stationary phase (CSP) based on Cel7A mutant D214N were resolved into enantioselective and non- selective binding. The enantioselective binding was weaker for both enantiomers on D214N-CSP than on wild-type-CSP.

Adrenergic beta-Antagonists↗
PubMed2001

Compound gravity receptor polarization vectors evidenced by linear vestibular evoked potentials.

The utricle and saccule are gravity receptor organs of the vestibular system. These receptors rely on a high-density otoconial membrane to detect linear acceleration and the position of the cranium relative to Earth's gravitational vector. The linear vestibular evoked potential (VsEP) has been shown to be an effective non-invasive functional test specifically for otoconial gravity receptors (Jones et al., 1999). Moreover, there is some evidence that the VsEP can be used to independently test utricular and saccular function (Taylor et al., 1997; Jones et al., 1998). Here we characterize compound macular polarization vectors for the utricle and saccule in hatchling chickens. Pulsed linear acceleration stimuli were presented in two axes, the dorsoventral (DV, +/- Z axis) to isolate the saccule, and the interaural (IA, +/- Y axis) to isolate the utricle. Traditional signal averaging was used to resolve responses recorded from the surface of the skull. Latency and amplitude of eighth nerve components of the linear VsEP were measured. Gravity receptor responses exhibited clear preferences for one stimulus direction in each axis. With respect to each utricular macula, lateral translation in the IA axis produced maximum ipsilateral response amplitudes with substantially greater amplitude intensity (AI) slopes than medially directed movement. Downward caudal motions in the DV axis produced substantially larger response amplitudes and AI slopes. The results show that the macula lagena does not contribute to the VsEP compound polarization vectors of the sacculus and utricle. The findings suggest further that preferred compound vectors for the utricle depend on the pars externa (i.e. lateral hair cell field) whereas for the saccule they depend on pars interna (i.e. superior hair cell fields). These data provide evidence that maculae saccule and utricle can be selectively evaluated using the linear VsEP.

Afferent Pathways↗
PubMed2001

The relationship between tail biting in pigs, docking procedure and other management practices.

The tail length (docked, tipped or undocked) and tail status (bitten or unbitten) of 27,870 pigs from 450 units was recorded at six UK abattoirs. A farm survey of the final finishing stage was used to investigate the relationship between management practice and tail biting. This showed that docking was the most important factor influencing the probability of being not bitten, with 2.4% of docked and 8.5% of long-tailed pigs being tail-bitten. The following factors reduced the probability of long-tailed pigs being tail-bitten; light straw provision, use of natural ventilation or artificially controlled natural ventilation (ACNV), mixed sex grouping, meal or liquid feeding, and use of double or multi-space feeders. Docked and long-tailed pigs provided with light straw and natural ventilation/ACNV had levels of tail biting of 1.2% and 4.3% respectively; 3.9% of docked pigs with artificial ventilation and no straw were tail-bitten. Long-tailed pigs fed via double or multi-space feeders also had 3.9% of tails bitten.

Animal Husbandry↗
PubMed2001

Bouveret's syndrome presenting as upper gastrointestinal hemorrhage without hematemesis.

A 74-year-old woman with a recent diagnosis of peptic ulcer disease diagnosed by endoscopy after presentation with an episode of upper gastrointestinal bleeding returned 6 1/2 weeks later with a 5-day history of nausea and vomiting without associated symptoms. An ultrasound was nondiagnostic except for a large gallstone and a poorly visualized gallbladder. Repeat endoscopy revealed a hard mass that was presumed to have formed secondarily to an ulcer-induced stricture, and a 6-cm filling defect just proximal to the duodenal bulb was seen on a preoperative upper gastrointestinal series. At laparotomy the mass was actually a large gallstone and two smaller stones, which had eroded into and become impacted in the duodenal bulb creating a gastric outlet obstruction. The stones were extracted via a duodenotomy, and the remaining portion of the gallbladder was removed with repair of the cholecystoduodenal fistula. The patient was discharged home after an uncomplicated postoperative course. Gastric outlet obstruction by a duodenal gallstone is a condition known as Bouveret's syndrome, which is a rare complication of gallstone disease. Upper gastrointestinal hemorrhage is an especially rare form of presentation.

Aged↗