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A J Millar

Publications and source records attributed to A J Millar.

At least 19 recordsLinked to original sources
PubMed2005

Uncovering the design principles of circadian clocks: mathematical analysis of flexibility and evolutionary goals.

In this paper, we present the mathematical details underlying both an approach to the flexibility of regulatory networks and an analytical characterization of evolutionary goals of circadian clock networks. A fundamental problem in cellular regulation is to understand the relation between the form of regulatory networks and their function. Circadian clocks present a particularly interesting instance of this. Recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. We address the question of why they have such a complex structure and argue that it is to provide the flexibility necessary to simultaneously attain multiple key properties of circadian clocks such as robust entrainment and temperature compensation. To do this we address two fundamental problems: (A) to understand the relationships between the key evolutionary aims of the clock and (B) to ascertain how flexible the clock's structure is. To address the first problem we use infinitesimal response curves (IRCs), a tool that we believe will be of general utility in the analysis of regulatory networks. To understand the second problem we introduce the flexibility dimension d, show how to calculate it and then use it to analyse a range of models. We believe our results will generalize to a broad range of regulatory networks.

Animals↗
PubMed2005

The effect of hCG administration five days after insemination on the first service conception rate of anestrous dairy cows.

The aim of this study was to investigate the effect of treating anovulatory anestrous (AA) dairy cows with 1500 IU of hCG IM, 5 d after insemination, on their first service conception rate. A clinical trial was conducted during the 2003/2004 breeding season involving 442 AA dairy cows in six herds. On Day -8, all cows were treated with a progesterone-containing intravaginal device (Cue-Mate). The devices were removed on Day -2, and on Day -1 all cows received an IM injection of 1mg of estradiol benzoate. Cows in the control group (n=220) received no further treatments. Cows in the treatment group (n=222) which had been inseminated on Days 0 or 1 were treated with 1500 IU of hCG IM 5 d after insemination. Blood was collected from 30 cows (15 in each group) on Days 5 and 12 after AI for analysis of plasma P4 concentration. There was no difference in first service conception rates between the control and treatment groups (46.3% versus 43.6%, respectively; P=0.68), despite the fact that plasma P4 concentrations were higher in the treatment group on Day 12 (4.9+/-1.3 ng/mL versus 6.2+/-2.7 ng/mL for control and treatment groups, respectively; P<0.01). In conclusion, 1500 IU of hCG 5 d after insemination did not improve first service conception rate in AA dairy cows.

Anestrus↗
PubMed2005

Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana.

Circadian clocks in all organisms include feedback loops that generate rhythmic expression of key genes. We model the first such loop proposed for the clock of Arabidopsis thaliana, the experimental model species for circadian timing in higher plants. As for many biological systems, there are no experimental values for the parameters in our model, and the data available for parameter fitting is noisy and varied. To tackle this we constructed a cost function, which quantifies the agreement between our model and various key experimental features. We then undertook an efficient global search of parameter space, to test whether the proposed circuit can fit the experimental data. Using this approach we show that circadian clock models can function well with low cooperativity in transcriptional regulation, whereas high cooperativity has been a feature of previous (hand-fitted) clock models in other species. Our optimized solution for the Arabidopsis clock model fits several, but not all, of the key experimental features. We test the predicted effects of well-characterized mutations in the clock circuit and show the phases of the circadian cycle where additional components that are yet to be identified experimentally must be present to complete the circadian feedback loop.

Arabidopsis↗
PubMed2004

Design principles underlying circadian clocks.

A fundamental problem for regulatory networks is to understand the relation between form and function: to uncover the underlying design principles of the network. Circadian clocks present a particularly interesting instance, as recent work has shown that they have complex structures involving multiple interconnected feedback loops with both positive and negative feedback. While several authors have speculated on the reasons for this, a convincing explanation is still lacking. We analyse both the flexibility of clock networks and the relationships between various desirable properties such as robust entrainment, temperature compensation, and stability to environmental variations and parameter fluctuations. We use this to argue that the complexity provides the flexibility necessary to simultaneously attain multiple key properties of circadian clocks. As part of our analysis we show how to quantify the key evolutionary aims using infinitesimal response curves, a tool that we believe will be of general utility in the analysis of regulatory networks. Our results suggest that regulatory and signalling networks might be much less flexible and of lower dimension than their apparent complexity would suggest.

Animals↗
PubMed2004

The wild-type circadian period of Neurospora is encoded in the residual network of the null frq mutants.

We model theoretically the response of the widely studied circadian oscillator of Neurospora crassa to inactivation of the frq gene. The resulting organism has been termed "arrhythmic" under constant conditions. Under entrainment to periodic temperature cycles Roenneberg, Merrow and coworkers have shown that the phase angle at which spore formation occurs depends on the entrainment period, curiously even in the null frq mutants (frq9 and frq10). We show that such a response does not imply the presence of a self-sustained free-running oscillator. We derive a simple candidate model (a damped harmonic oscillator) for the null frq mutants that successfully reproduces the observed phase angle response. An endogenous period of 21 h for the damped harmonic oscillator coincides with the endogenous period of wild-type Neurospora. This suggests that the (noise driven) "residual system" present in the mutants may have a significant timekeeping role in the wild-type organism. Our model (with no change of parameters) was then used to investigate spore formation patterns under constant conditions and reproduces the corresponding experimental data of Aronson et al. (Proc. Natl. Acad. Sci. USA 91 (1994) 7683.)

Biological Clocks↗
PubMed2001

Watching the hands of the Arabidopsis biological clock.

Oligonucleotide and cDNA microarrays have been used to analyse the mRNA levels of 8,000 genes in Arabidopsis thaliana throughout the day/night cycle. Genes involved in signal transduction and in various metabolic pathways were found to be coordinately regulated by circadian rhythms and/or by light.

Arabidopsis↗
PubMed2001

Extended hepatic resection with transplantation back-up for an "unresectable" tumour.

Liver transplantation (LT) for malignancy has had disappointing long-term results due to tumour recurrence. Ex-vivo dissection and auto-transplantation have had poor results when the tumor was obstructing bile ducts. Advances in liver surgery have made extensive liver resection safer, but cases of "unresectable" tumours due to site and size still present. A 10-year-old boy was referred with jaundice due to a 6 x 8-cm central (segment 4) tumour shown on biopsy to be a fibrolamellar hepatocellular carcinoma. Ultrasound (US) and Computed Tomography also showed dilatation of intrahepatic bile ducts in both lobes. Angiography showed a large tumour mass supplied by the left branch of the hepatic artery, a low take-off of a right branch of the hepatic artery, and a very displaced but patent portal vein. The initial surgical consensus was that the tumour was unresectable. The patient was listed for LT with the plan of first attempting resection with a liver graft-in-waiting. An extended left hepatectomy was performed under total vascular exclusion with resection of the tumour, which had extended from segment 4 into surrounding segments 1, 3, 5, and 8. Intraoperative US assisted in planning the resection. The right hepatic vein, artery, and the right branch of the portal vein could be preserved and a Roux loop was anastomosed to a markedly dilated segment 6 and 7 intrahepatic duct for bile drainage. Vascular exclusion time was 30 min. The patient made a good recovery without major complications. Jaundice and bile-duct dilatation resolved. On follow up at 5 years there was no recurrence. The liver graft-in-waiting gave the surgical team confidence to proceed with an extensive resection beyond a "point of no return" and allowed good clearance of the disease and avoidance of LT with all the long-term consequences of immunosuppression. This mandates that extensive hepatic surgery in children should be carried out in centres that have a facility for LT should the need arise.

Carcinoma, Hepatocellular↗
PubMed2001

An unusual complication of retrosternal colon interposition successfully managed by median sternotomy and revision retrosternal pull-through.

An unusual complication of a retro-sternal colonic interposition is described where the redundant retro-sternal section of the graft underwent mesentericoaxial volvulus and infarction 3.5 years after the initial procedure. Access to the graft was obtained via a median sternotomy. At a second procedure the residual distal colon was used to reconstitute the interposition graft via the retro-sternal route without a repeat sternotomy with an excellent outcome. Graft redundancy is an avoidable complication of colon interposition provided certain technical steps in the operation are adhered to. Median sternotomy afforded safe access to the retro-sternal problem with good healing and long-term outcome.

Child, Preschool↗
PubMed2001

Detection of caustic oesophageal injury with technetium 99m-labelled sucralfate.

BACKGROUND/PURPOSE: Radiolabelled sucralfate has been used to show the extent and severity of reflux oesophagitis, peptic ulceration, and inflammatory bowel disease. Endoscopy under general anaesthetic has been the preferred method to assess the injury after caustic ingestion. The aim of this study was to assess whether sucralfate has an affinity for the chemically injured oesophageal mucosa and, if so, to assess the accuracy of radiolabeled sucralfate as an indicator of presence and extent of oesophageal injury. METHODS: A prospective study was conducted of 22 patients with mean age of 30 months (range, 13 to 90) admitted consecutively with a history of caustic ingestion between January 1998 and January 2000. A sucralfate-labelled scan followed by endoscopic assessment of upper gastrointestinal tract with documentation of extent and grade of injury was performed in all patients within 24 hours of admission except the first 6 who underwent scan after the endoscopy. The sucralfate was labelled by the direct stannous reduction method. Oesophageal transit was studied by recording 120 images (64 x 64 matrix size) at 1 image per second while the child swallowed 5 mL of labelled sucralfate containing 2 to 3 MBq Technetium 99m. Retention of radiolabelled oesophageal activity was considered abnormal. RESULTS: The caustic substances ingested were household cleaners in 18, potassium permanganate in 3, and pool chlorine in 1. There were 11 scans that showed residual activity in the oesophagus, which correlated exactly with endoscopic findings. The other 11 patients had normal oesophageal mucosa, but 2 were found to be falsely positive on scanning. In 2 cases repeat sucralfate scan results correlated well with the healing process assessed endoscopically. CONCLUSIONS: The results indicate that technetium 99m sucralfate swallow is an accurate technique for assessing oesophageal injury after ingestion of caustic substances. In addition, it may be used to document healing.

Burns, Chemical↗
PubMed2001

Circadian clock-regulated expression of phytochrome and cryptochrome genes in Arabidopsis.

Many physiological and biochemical processes in plants exhibit endogenous rhythms with a period of about 24 h. Endogenous oscillators called circadian clocks regulate these rhythms. The circadian clocks are synchronized to the periodic environmental changes (e.g. day/night cycles) by specific stimuli; among these, the most important is the light. Photoreceptors, phytochromes, and cryptochromes are involved in setting the clock by transducing the light signal to the central oscillator. In this work, we analyzed the spatial, temporal, and long-term light-regulated expression patterns of the Arabidopsis phytochrome (PHYA to PHYE) and cryptochrome (CRY1 and CRY2) promoters fused to the luciferase (LUC(+)) reporter gene. The results revealed new details of the tissue-specific expression and light regulation of the PHYC and CRY1 and 2 promoters. More importantly, the data obtained demonstrate that the activities of the promoter::LUC(+) constructs, with the exception of PHYC::LUC(+), display circadian oscillations under constant conditions. In addition, it is shown by measuring the mRNA abundance of PHY and CRY genes under constant light conditions that the circadian control is also maintained at the level of mRNA accumulation. These observations indicate that the plant circadian clock controls the expression of these photoreceptors, revealing the formation of a new regulatory loop that could modulate gating and resetting of the circadian clock.

Arabidopsis↗
PubMed2001

Conditional circadian regulation of PHYTOCHROME A gene expression.

The phytochrome photoreceptors and the circadian clock control many of the same developmental processes, in all organs and throughout the growth of Arabidopsis plants. Phytochrome A (phyA) provides light input signals to entrain the circadian clock. The clock is known to rhythmically regulate its light input pathway, so we tested rhythmic regulation of phyA, using transgenic plants carrying a PHYA promoter fusion to the luciferase reporter (PHYA:LUC). We provide the first images of LUC activity with subcellular resolution in intact tissue. PHYA transcription and the accumulation of all three PHYA mRNAs were indeed clock controlled. PHYA is expressed throughout the seedling, so we tested whether circadian rhythms were observed in all PHYA-expressing organs and whether the rhythms were autonomously controlled by each organ. In contrast to our previous results using other clock controlled genes, the rhythmic pattern of PHYA expression varied markedly among isolated organs and between isolated organs and intact plants. High-amplitude rhythms were maintained for many days in isolated leaves in darkness, whereas the leaves of intact plants rapidly lost rhythmicity. Wounding the leaves of intact plants had no effect. The rhythmic pattern of PHYA expression is not organ autonomous but depends upon the physical continuity or isolation of the rhythmic tissues, consistent with the presence of a transmitted signal that controls the overt expression of circadian rhythms without necessarily affecting the underlying clock. A circadian system might be present in most, if not all, plant cells, but its effect on intracellular rhythms can be controlled by supracellular signaling.

Arabidopsis↗
PubMed2000

The ELF3 zeitnehmer regulates light signalling to the circadian clock.

The circadian system regulates 24-hour biological rhythms and seasonal rhythms, such as flowering. Long-day flowering plants like Arabidopsis thaliana, measure day length with a rhythm that is not reset at lights-off, whereas short-day plants measure night length on the basis of circadian rhythm of light sensitivity that is set from dusk, early flowering 3 (elf3) mutants of Arabidopsis are aphotoperiodic and exhibit light-conditional arrhythmias. Here we show that the elf3-7 mutant retains oscillator function in the light but blunts circadian gating of CAB gene activation, indicating that deregulated phototransduction may mask rhythmicity. Furthermore, elf3 mutations confer the resetting pattern of short-day photoperiodism, indicating that gating of phototransduction may control resetting. Temperature entrainment can bypass the requirement for normal ELF3 function for the oscillator and partially restore rhythmic CAB expression. Therefore, ELF3 specifically affects light input to the oscillator, similar to its function in gating CAB activation, allowing oscillator progression past a light-sensitive phase in the subjective evening. ELF3 provides experimental demonstration of the zeitnehmer ('time-taker') concept.

Arabidopsis↗
PubMed2000

The surgical management of cricopharyngeal achalasia in children.

OBJECTIVE: The objective of this study was to evaluate the clinical presentation of children with cricopharyngeal achalasia and to document the diagnostic process followed and evaluate the immediate and long-term results of those children treated with a cricopharyngeal myotomy. METHODS: Five children who underwent cricopharyngeal myotomies since 1976 were identified and the hospital records were reviewed in detail. Four patients were followed up to establish the long-term results of surgery. RESULTS: The age of initial presentation ranged from birth to 6 months with a universal delay in establishing the diagnosis ranging from 11 to 138 months. Two children had pre- and post-operative manometry of the upper esophageal sphincter. Post-operative upper esophageal sphincter pressures were reduced to 29 and 47% in relation to pre-operative values. Nissen fundoplications were performed in two patients to control documented gastro esophageal reflux. No post-operative complications were noted and complete symptomatic relief was obtained in all children. The long-term follow up was 2, 10, 12 and 14 years with all children remaining free of symptoms. CONCLUSION: Cricopharyngeal achalasia is an important but relatively seldom diagnosed cause of dysphagia in children. The diagnosis is almost always delayed because the condition is not widely recognised amongst physicians. If the diagnosis and effective treatment is delayed significant morbidity or even mortality, mainly due to pulmonary aspiration, may result. Cricopharyngeal myotomy is a safe and effective operation with excellent results. Symptomatic relief is immediate and complete with no long-term recurrence documented in this series.

Child, Preschool↗