| 1. |
- Challis, B G, et al.
(författare)
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Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 101:13, s. 4695-700
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Tidskriftsartikel (refereegranskat)abstract
- Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc(-/-) mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc(-/-) mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc(-/-) and Pomc(+/-) mice. The effects of leptin on food intake and body weight were blunted in obese Pomc(-/-) mice whereas nonobese Pomc(-/-) mice were sensitive to leptin. Surprisingly, we found that Pomc(-/-) mice maintained their acute anorectic response to peptide-YY(3-36) (PYY(3-36)). However, 7 days of PYY(3-36) administration had no effect on cumulative food intake or body weight in wild-type or Pomc(-/-) mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY(3-36) or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
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| 2. |
- Reiser, Philip G.K., et al.
(författare)
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Developing a Logical Model of Yeast Metabolism
- 2001
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- With the completion of the sequencing of genomes of an increasing number of organisms, the focus of biology is moving to determining the role of these genes (functional genomics). To this end it is useful to view the cell as a biochemical machine: it consumes simple molecules to manufacture more complex ones by chaining together biochemical reactions into long sequences referred to as metabolic pathways. Such metabolic pathways are not linear but often intersect to form a complex network. Genes play a fundamental role in this network by synthesising the enzymes that catalyse biochemical reactions. Although developing a complete model of metabolism is of fundamental importance to biology and medicine, the size and complexity of the network has proven beyond the capacity of human reasoning. This paper presents intermediate results in the Robot Scientist research programme that aims to discover the function of genes in the metabolism of the yeast Saccharomyces cerevisiae. Results include: (1) the first logical model of metabolism; (2) a method to predict phenotype by deductive inference; and (3) a method to infer reactions and gene function by abductive inference. We describe the in vivo experimental set-up which will allow these in silico inferences to be automatically tested by a laboratory robot.
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| 3. |
- Arsura, Marcello, et al.
(författare)
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Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis : implications in liver tumor formation.
- 2003
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 22:3, s. 412-425
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Tidskriftsartikel (refereegranskat)abstract
- NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity.
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| 4. |
- Bryant, C.H., et al.
(författare)
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Combining Inductive Logic Programming, Active Learning and Robotics to Discover the Function of Genes
- 2001
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- We aim to partially automate some aspects of scientific work, namely the processes of forming hypotheses, devising trials to discriminate between these competing hypotheses, physically performing these trials and then using the results of these trials to converge upon an accurate hypothesis. We have developed ASE-Progol, an Active Learning system which uses Inductive Logic Programming to construct hypothesised first-order theories and uses a CART-like algorithm to select trials for eliminating ILP derived hypotheses. We have developed a novel form of learning curve, which in contrast to the form of learning curve normally used in Active Learning, allows one to compare the costs incurred by different leaning strategies.We plan to combine ASE-Progol with a standard laboratory robot to create a general automated approach to Functional Genomics. As a first step towards this goal, we are using ASE-Progol to rediscover how genes participate in the aromatic amino acid pathway of Saccharomyces cerevisiae. Our approach involves auxotrophic mutant trials. To date, ASE-Progol has conducted such trials in silico. However we describe how they will be performed automatically in vitro by a standard laboratory robot designed for these sorts of liquid handling tasks, namely the Beckman/Coulter Biomek 2000.Although our work to date has been limited to trials conducted in silico, the results have been encouraging. Parts of the model were removed and the ability of ASE-Progol to efficiently recover the performance of the model was measured. The cost of the chemicals consumed in converging upon a hypothesis with an accuracy in the range 46-88% was reduced if trials were selected by ASE-Progol rather than if they were sampled at random (without replacement). To reach an accuracy in the range 46-80%, ASE-Progol incurs five orders of magnitude less experimental costs than random sampling. ASE-Progol requires less time to converge upon a hypothesis with an accuracy in the range 74-87% than if trials are sampled at random (without replacement) or selected using the naive strategy of always choosing the cheapest trial from the set of candidate trials. For example to reach an accuracy of 80%, ASE-Progol requires 4 days while random sampling requires 6 days and the naive strategy requires 10 days.
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| 5. |
- Kalscheuer, Vera M, et al.
(författare)
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Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation
- 2003
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 35:4, s. 313-315
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Tidskriftsartikel (refereegranskat)abstract
- We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.
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| 6. |
- Munthe, John, et al.
(författare)
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Distribution of atmospheric mercury species in Northern Europe: Final results from the MOE-project
- 2003
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Ingår i: Atmospheric Environment. - 1352-2310 .- 1873-2844. ; 37:Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- The mercury species over Europe (MOE) project was aimed at identifying sources, occurrence and atmospheric behaviour of atmospheric Hg species. Within MOE, emission measurements, ambient air measurements, process and regional-scale modelling and laboratory measurements were conducted. In this work, a summary of some of the main results is given. From the emission measurements, information on stack gas concentrations and emission factors for five coal fired power plants and three waste incinerators are presented. Results from field measurements of mercury species in ambient air at five locations in Northern Europe are presented. Examples from regional-scale atmospheric modelling are also given. The results emphasise the importance of information on Hg species for instance in emission inventories and measurement data from background sites. Furthermore, the importance of considering the role of the global cycling of mercury in future control strategies is emphasised
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| 7. |
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| 8. |
- Oliver, K R, et al.
(författare)
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Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature
- 2002
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 22:5, s. 620-629
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Tidskriftsartikel (refereegranskat)abstract
- Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein-coupled receptor, the calcitonin receptor-like receptor (CRLR), Whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP1 binds calcitonin gene-related peptide With high affinity. whereas CRLR coexpression with RAMP2 or -3 confers, high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral. pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel type,,. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine. and may lead to possible Ways in which future synthetic ligands may be applied to manage these disorders.
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| 13. |
- Tran, K. Q., et al.
(författare)
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A novel particle trap impactor for use with the gas-quenching probe sampling system
- 2004
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Ingår i: Aerosol Science and Technology. - : Informa UK Limited. - 0278-6826 .- 1521-7388. ; 38:10, s. 955-962
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Tidskriftsartikel (refereegranskat)abstract
- A novel particle trap impactor has been developed for use with the gas-quenching probe in order to exclude solid particles from entering into the probe during sampling of gaseous metallic species in fluidized bed combustion conditions. The impactor must be small in size (empty set(impactor)less than or equal toempty set(probe) = 45 mm) but capable of collecting a relatively large amount of particles at elevated temperatures. As the first step, the impactor was designed, constructed, and tested at room temperature for KCl aerosol particles. The impactor with a nozzle of 0.95 mm in diameter, in combination with the orifice-to-jet diameter ratio of 1.5 and the ratio of the jet-to-plate spacing to jet diameter at 1.4 yielded a sharp cutoff curve with a maximum collection efficiency of about 0.9 and a rootStk(50) value of about 0.22. In addition, the collection efficiency of the impactor was compared with the particle removal efficiency of a filter of the same type as the filter previously used with the gas-quenching probe. The difference from the comparison is very small, indicating that the impactor can be used to replace the filter to prevent fly ash particles from entering the gas-quenching probe in fluidized bed combustion conditions.
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