The Gene Ontology (GO) Consortium (GOC, http://www.geneontology.org) is a community-based bioinformatics resource that classifies gene product function through the use of structured, controlled vocabularies. Over the past year, the GOC has implemented several processes to increase the quantity, quality and specificity of GO annotations. First, the number of manual, literature-based annotations has grown at an increasing rate. Second, as a result of a new ‘phylogenetic annotation’ process, manually reviewed, homology-based annotations are becoming available for a broad range of species. Third, the quality of GO annotations has been improved through a streamlined process for, and automated quality checks of, GO annotations deposited by different annotation groups. Fourth, the consistency and correctness of the ontology itself has increased by using automated reasoning tools. Finally, the GO has been expanded not only to cover new areas of biology through focused interaction with experts, but also to capture greater specificity in all areas of the ontology using tools for adding new combinatorial terms. The GOC works closely with other ontology developers to support integrated use of terminologies. The GOC supports its user community through the use of e-mail lists, social media and web-based resources.

In the brain, pressure-induced myogenic constriction of cerebral arteriolar muscle contributes to autoregulation of cerebral blood flow (CBF). This study examined the role of 20-HETE in autoregulation of CBF in anesthetized rats. The expression of P-450 4A protein and mRNA was localized in isolated cerebral arteriolar muscle of rat by immunocytochemistry and in situ hybridization. The results of reverse transcriptase-polymerase chain reaction studies revealed that rat cerebral microvessels express cytochrome P-450 4A1, 4A2, 4A3, and 4A8 isoforms, some of which catalyze the formation of 20-HETE from arachidonic acid. Cerebral arterial microsomes incubated with [(14)C]arachidonic acid produced 20-HETE. An elevation in transmural pressure from 20 to 140 mm Hg increased 20-HETE concentration by 6-fold in cerebral arteries as measured by gas chromatography/mass spectrometry. In vivo, inhibition of vascular 20-HETE formation with N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS), or its vasoconstrictor actions using 15-HETE or 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), attenuated autoregulation of CBF to elevations of arterial pressure. In vitro application of DDMS, 15-HETE, or 20-HEDE eliminated pressure-induced constriction of rat middle cerebral arteries, and 20-HEDE and 15-HETE blocked the vasoconstriction action of 20-HETE. Taken together, these data suggest an important role for 20-HETE in the autoregulation of CBF.

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UKbased ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.

Previously, we found heightened expression of inhibitory neurochemicals and depressed expression of excitatory neurochemicals with a sudden drop in metabolic activity around postnatal day (P) 12 in rat brainstem respiratory nuclei, suggesting that this period is a critical window during which respiratory control or regulation may be distinctly different. To test this hypothesis, the hypoxic ventilatory responses (HVR) to 10% oxygen were tested in rats every day from P0 to P21. Our data indicate that (1) during normoxia (N), breathing frequency (f ) increased with age, peaking at P13, followed by a gradual decline, whereas both tidal volume (V T ) and minute ventilation (V E ) significantly increased in the second postnatal week, followed by a progressive increase in V T and a relative plateau inV E ; (2) during 5 min of hypoxia (H), V E exhibited a biphasic response from P3 onward. Significantly, the ratio ofV E(H) toV E(N) was generally > 1 during development, except for P13-16, when it was < 1 after the first 1-2 min, with the lowest value at P13; (3) the H : N ratio for f , V T andV E during the first 30 s and the last minute of hypoxia all showed a distinct dip at P13, after which the V T andV E values rose again, while the f values declined through P21; and (4) the H : N ratios for f , V T andV E averaged over 5 min of hypoxia all exhibited a sudden fall at P13. The f ratio remained low thereafter, while those for V T andV E increased again with age until P21. Thus, hypoxic ventilatory response is influenced by both f and V T before P13, but predominantly by V T after P13. The striking changes in normoxic ventilation as well as HVR at or around P13, together with our previous neurochemical and metabolic data, strongly suggests that the end of the second postnatal week is a critical period of development for brainstem respiratory nuclei in the rat.

The purpose of the present study was to determine the effect on breathing in the awake state of carotid body denervation (CBD) over 1-2 wk after denervation. Studies were completed on adult goats repeatedly before and 1) for 15 days after bilateral CBD (n = 8), 2) for 7 days after unilateral CBD (n = 5), and 3) for 15 days after sham CBD (n = 3). Absence of ventilatory stimulation when NaCN was injected directly into a common carotid artery confirmed CBD. There was a significant (P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. The maximum PaCO2 increase (8 Torr for unilateral and 11 Torr for bilateral) occurred approximately 4 days after CBD. This maximum was transient because by 7 (unilateral) to 15 (bilateral) days after CBD, PaCO2 was only 3-4 Torr above control. CO2 sensitivity was attenuated from control by 60% on day 4 after bilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO2 sensitivity returned to control temporally similar to the return of PaCO2 during the breathing of room air. During mild and moderate treadmill exercise 1-8 days after bilateral CBD, PaCO2 was unchanged from its elevated level at rest, but, 10-15 days after CBD, PaCO2 decreased slightly from rest during exercise. These data indicate that 1) carotid afferents are an important determinant of rest and exercise breathing and ventilatory CO2 sensitivity, and 2) apparent plasticity within the ventilatory control system eventually provides compensation for chronic loss of these afferents.

Purpose-To characterize structural and functional injuries following a single dose of whole-thorax irradiation that might be survivable after a nuclear attack/accident.Methods-Rats were exposed to 5 or 10 Gy of X-rays to the whole thorax with other organs shielded. Non-invasive measurements of breathing rate and arterial oxygen saturation, and invasive evaluations of bronchoalveolar lavage fluid, (for total protein, Clara cell secretory protein), vascular reactivity and histology were conducted for at least 6 time points up to 52 wks after irradiation.Results-Irradiation with 10 Gy resulted in increased breathing rate, a reduction in oxygen saturation, an increase in bronchoalveolar lavage fluid protein and attenuation of vascular reactivity between 4-12 wks after irradiation. These changes were not observed with the lower dose of 5 Gy. Histological examination revealed perivascular edema at 4-8 wks after exposure to both doses, and mild fibrosis beyond 20 wks after 10 Gy.Conclusions-Single-dose exposure of rat thorax to 10 but not 5 Gy X-irradiation resulted in a decrease in oxygen uptake and vasoreactivity and an increase in respiratory rate, which paralleled early pulmonary vascular pathology. Vascular edema resolved and was replaced by mild fibrosis beyond 20 wks after exposure, while lung function recovered.

Liu Q, Fehring C, Lowry TF, Wong-Riley MTT. Postnatal development of metabolic rate during normoxia and acute hypoxia in rats: implication for a sensitive period. J Appl Physiol 106: 1212-1222, 2009. First published December 31, 2008 doi:10.1152/japplphysiol.90949.2008.-Previously, we reported that the hypoxic ventilatory response (HVR) in rats was weakest at postnatal day (P) P13, concomitant with neurochemical changes in respiratory nuclei. A major determinant of minute ventilation (V E) is reportedly the metabolic rate [O2 consumption (V O2) and CO2 production (V CO2)]. The present study aimed at testing our hypothesis that daily metabolic rates changed in parallel with ventilation during development and that a weak HVR at P13 was attributable mainly to an inadequate metabolic rate in hypoxia. Ventilation and metabolic rates were monitored daily in P0 -P21 rats. We found that 1) ventilation and metabolic rates were not always correlated, and V E/V O2 and V E/V CO2 ratios were not constant during development; 2) metabolic rate and V E/V O2 and V E/V CO2 ratios at P0 -P1 were significantly different from the remaining first postnatal week in normoxia and hypoxia; 3) at P13, metabolic rates and V E/V O2 and V E/V CO2 ratios abruptly increased in normoxia and were compromised in acute hypoxia, unlike more stable trends during the remaining second and third postnatal weeks; and 4) the respiratory quotient (V CO2/V O2) was quite stable in normoxia and fluctuated slightly in hypoxia from P0 to P21. Thus our data revealed heretofore unsuspected metabolic adjustments at P0 -P1 and P13. At P0 -P1, ventilation and metabolic rates were uncorrelated, whereas at P13, they were closely correlated under normoxia and hypoxia. The findings further strengthened the existence of a critical period of respiratory development around P13, when multiple physiological and neurochemical adjustments occur simultaneously. carbon dioxide production; critical period; oxygen consumption; respiratory quotient; ventilation PREVIOUSLY, WE CONDUCTED DETAILED, day-to-day studies of various brain stem respiratory nuclei of the rat and found that neurotransmitters and receptors underwent distinct developmental changes. Significantly, at or around postnatal day (P) 12, the expression of excitatory neurotransmitter glutamate and its N-methyl-D-aspartate receptors dropped precipitously, whereas the expression of inhibitory neurotransmitter ␥-aminobutyric acid (GABA), GABA B receptors, and glycine receptors rose sharply (27,30, 61). Concomitantly, there was a sudden fall in cytochrome oxidase activity (27,28, 61), a sensitive indicator of metabolic capacity and neuronal activity (60). We hypothesized that at and around P12 is a sensitive period in the postnatal development of the rat's respiratory control network, when a transient dominance of inhibitory over excitatory neurotransmission renders the animals less capable of overcoming exogenous respiratory stressors. Our subsequent ventilatory studies revealed striking changes in normoxic ventilation ...

BackgroundThe Pathway Ontology (PW) developed at the Rat Genome Database (RGD), covers all types of biological pathways, including altered and disease pathways and captures the relationships between them within the hierarchical structure of a directed acyclic graph. The ontology allows for the standardized annotation of rat, and of human and mouse genes to pathway terms. It also constitutes a vehicle for easy navigation between gene and ontology report pages, between reports and interactive pathway diagrams, between pathways directly connected within a diagram and between those that are globally related in pathway suites and suite networks. Surveys of the literature and the development of the Pathway and Disease Portals are important sources for the ongoing development of the ontology. User requests and mapping of pathways in other databases to terms in the ontology further contribute to increasing its content. Recently built automated pipelines use the mapped terms to make available the annotations generated by other groups.ResultsThe two released pipelines – the Pathway Interaction Database (PID) Annotation Import Pipeline and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Annotation Import Pipeline, make available over 7,400 and 31,000 pathway gene annotations, respectively. Building the PID pipeline lead to the addition of new terms within the signaling node, also augmented by the release of the RGD “Immune and Inflammatory Disease Portal” at that time. Building the KEGG pipeline lead to a substantial increase in the number of disease pathway terms, such as those within the ‘infectious disease pathway’ parent term category. The ‘drug pathway’ node has also seen increases in the number of terms as well as a restructuring of the node. Literature surveys, disease portal deployments and user requests have contributed and continue to contribute additional new terms across the ontology. Since first presented, the content of PW has increased by over 75%.ConclusionsOngoing development of the Pathway Ontology and the implementation of pipelines promote an enriched provision of pathway data. The ontology is freely available for download and use from the RGD ftp site at ftp://rgd.mcw.edu/pub/ontology/pathway/ or from the National Center for Biomedical Ontology (NCBO) BioPortal website at http://bioportal.bioontology.org/ontologies/PW.