408 research outputs found
Version control of pathway models using XML patches
<p>Background: Computational modelling has become an important tool in understanding biological systems such as signalling pathways. With an increase in size complexity of models comes a need for techniques to manage model versions and their relationship to one another. Model version control for pathway models shares some of the features of software version control but has a number of differences that warrant a specific solution.</p>
<p>Results: We present a model version control method, along with a prototype implementation, based on XML patches. We show its application to the EGF/RAS/RAF pathway.</p>
<p>Conclusion: Our method allows quick and convenient storage of a wide range of model variations and enables a thorough explanation of these variations. Trying to produce these results without such methods results in slow and cumbersome development that is prone to frustration and human error.</p>
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Midline1 and the development of the cranial peripheral nervous system
Genetic abnormalities involving the skull and facial region account for around 1/3 of birth defects. Opitz BBB/G syndrome is one such disorder that gives rise to craniofacial malformations, as well as midline defects that cause gastrointestinal anomalies. Patients with X-linked Opitz BBB/G syndrome have loss of function mutations in the gene Midline 1 (Mid1).
Using a chick model of cranial development, we demonstrate the expression pattern of the chick orthologue of Mid1 and report a novel function for cMid1 in the formation of the cranial ganglia.
In order to study the role of cMid1, we ectopically expressed cMid1 in subpopulations of neural crest cells (NCCās) from rhombomere 4 (r4), normally devoid of the protein. We find that ectopic targeting of cMid1 to r4 NCCs transiently induces the formation of a larger facial ganglion. Subsequent work to down regulate endogenous cMid1 activity in rhombomere 2 demonstrates a reduction in the size of the developing trigeminal ganglia. Current work aimed at elucidating the mechanisms underlying these observations will be presented
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Age-related changes in blood-brain barrier integrity in C57BL/6J mice
The blood-brain barrier (BBB) is formed by the endothelial cells of the brain microvasculature, which control the molecular traffic between the blood and brain to maintain the neural microenvironment
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Changes in the enteric nervous system and surrounding cells during ageing
The enteric nervous system continues to undergo changes throughout life. Changes in both enteric neurons and glial cells in old age have been reported, but our understanding both of the effects of described changes on gastrointestinal function and the causes of age-related changes are poorly understood. We are analysing changes in the enteric nervous system and surrounding cells in the intestine of the C57/Bl6 mouse during ageing, using a multidisciplinary approach. We are focusing on the large intestine and terminal bowel; regions that are implicated in changes that may contribute to the increased incidence of constipation and incontinence in the elderly population. The progression of age-associated changes is studied by analysing tissues from animals at 3, 12, 18 and 24 months of age. Changes in the numbers and phenotypic properties of neurons and nerve fibre density and also changes in Interstitial cells, fibroblast-like cells and enteroendocrine cells are being studied in both tissue sections and whole mount preparations by immunohistochemistry, confocal and electron microscopy. Physiological and pharmacological analysis of tissues is also performed and the combined data from all these types of approach allows us to understand more fully how ageing affects neural and non-neural regulation of gut functions. Our data show that changes in the responses of the distal colon, rectum and internal anal sphincter in vitro occur during ageing, and that these changes are complex, involve several different signalling systems and do not simply relate to changes in cell number. In addition, we are investigating the mechanisms that cause age-related changes in both neurons and non-neural cells in the intestine, using a combination of markers and imaging techniques. Our preliminary data indicate that the different cell types involved in the regulation of gastrointestinal motility may be differentially affected during ageing. A detailed understanding of ageing of the ENS and surrounding cells will provide valuable information to increase our understanding of age-associated gastrointestinal dysfunction
Glucagon-like peptide-1 (GLP-1) increases in plasma and colon tissue prior to estrus and circulating levels change with increasing age in reproductively competent Wistar rats
There is a well-documented association between cyclic changes to food intake and the changing ovarian hormone levels of the reproductive cycle in female mammals. Limited research on appetite-controlling gastrointestinal peptides has taken place in females, simply because regular reproductive changes in steroid hormones present additional experimental factors to account for. This study focussed directly on the roles that gastrointestinal-secreted peptides may have in these reported, naturally occurring, changes to food intake during the rodent estrous cycle and aimed to determine whether peripheral changes occurred in the anorexigenic (appetite-reducing) hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female Wistar rats (32-44 weeks of age). Total forms of each peptide were measured in matched fed and fasted plasma and descending colon tissue samples for each animal during the dark (feeding) phase. PYY concentrations did not significantly change between defined cycle stages, in either plasma or tissue samples. GLP-1 concentrations in fed plasma and descending colon tissue were significantly increased during proestrus, just prior to a significant reduction in fasted stomach contents at estrus, suggesting increased satiety and reduced food intake at this stage of the cycle. Increased proestrus GLP-1 concentrations could contribute to the reported reduction in food intake during estrus and may also have biological importance in providing the optimal nutritional and metabolic environment for gametes at the potential point of conception. Additional analysis of the findings demonstrated significant interactions of ovarian cycle stage and fed/fasted status with age on GLP-1, but not PYY plasma concentrations. Slightly older females had reduced fed plasma GLP-1 suggesting that a relaxation of regulatory control of this incretin hormone may also take place with increasing age in reproductively competent females
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Investigating the effect of photodynamic therapy on nerves using tissue engineered culture models
Introduction: Photodynamic therapy (PDT) shows potential as an effective treatment for prostate cancer. Clinical observations indicate that this approach causes fewer nerve damage related side-effects than conventional treatments. The aim here is to investigate the effect of PDT on nerve tissue using engineered 3-dimensional cell culture models. Initial experiments focussed on establishing photosensitiser localisation in neurones and Schwann cells, then developing a model for simulating nerve PDT in culture
The interconnectedness of ageing:does the convoy principal apply?
This is an excerpt from the content: The convoy principal states that any system is only as functional as its āslowestā unit. As organisms are made up of interconnected networks of physiological systems, it is possible that this principle applies to the biology of ageing. Often biogerontology will focus either on organismal ageing (mechanisms associated with increased longevity of a lower model organism for example), ageing of an individual organ system (such as the cardiovascular/musculoskeletal/immune) or ageing at the cellular level (from telomere length to cellular senescence, with many different cell types being studied) without considering the interconnectedness between the three and importantly, between the separate units of the convoy; the different organ systems. Conceptually, research that aims to identify āanti-ageingā therapies is often deemed to be reaching for a panacea that will arrest or slow down the ageing process as a whole, whereas a more realistic aim is to first identify how we can improve the perfor ..
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Age-related changes to lumbosacral spinal cord motoneurons that modulate bladder and bowel functions in male C57BL/6 mice
Incontinence and sexual dysfunction are often increased in the aged human population. In rats and mice the pattern of micturition and faecal clearance also changes with ageing and is suggestive of bladder and bowel dysfunction
Changes in murine anorectum signaling across the life course
Background: Increasing age is associated with an increase in the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to these conditions is not fully understood. This study examined the effects of increasing age on the function of the murine anorectum.Methods: The effects of increasing age on cholinergic, nitrergic, and purinergic signaling pathways in the murine anorectum were examined using classical organ bath assays to examine tissue function and electrochemical sensing to determine ageārelated changes in nitric oxide and acetylcholine release.Key Results: Nitrergic relaxation increased between 3 and 6 months, peaked at 12 months and declined in the 18 and 24 months groups. These changes were in part explained by an ageārelated decrease in nitric oxide (NO) release. Cholinergic signaling was maintained with age by an increase in acetylcholine (ACh) release and a compensatory decrease in cholinesterase activity. Ageārelated changes in purinergic relaxation were qualitatively similar to nitrergic relaxation although the relaxations were much smaller. Increasing age did not alter the response of the anorectum smooth muscle to exogenously applied ACh, ATP, sodium nitroprusside or KCl. Similarly, there was no change in basal tension developed by the anorectum.Conclusions and Inferences: The decrease in nitrergic signaling with increasing age may contribute to the ageārelated fecal impaction and constipation previously described in this model by partially obstructing defecation
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Ultrastructural analysis of changes in neurons of the mouse internal anal sphincter during ageing
Gastrointestinal disorders, including chronic constipation, faecal impaction and incontinence, are a major cause of morbidity in the elderly
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