PubMed Health⌕ Search

Biomedical subjects

Daniel Martin

Publications and source records attributed to Daniel Martin.

54 records · Page 3Linked to original sources
PubMed2005

Distinct requirements for the Sprouty domain for functional activity of Spred proteins.

Sprouty and Spred {Sprouty-related EVH1 [Ena/VASP (vasodilator-stimulated phosphoprotein) homology 1] domain} proteins have been identified as antagonists of growth factor signalling pathways. We show here that Spred-1 and Spred-2 appear to have distinct mechanisms whereby they induce their effects, as the Sprouty domain of Spred-1 is not required to block MAPK (mitogen-activated protein kinase) activation, while that of Spred-2 is required. Similarly, deletion of the C-terminal Sprouty domain of Spred-1 does not affect cell-cycle progression of G(0)-synchronized cells through to S-phase following growth factor stimulation, while the Sprouty domain is required for Spred-2 function. We also demonstrate that the inhibitory function of Spred proteins is restricted to the Ras/MAPK pathway, that tyrosine phosphorylation is not required for this function, and that the Sprouty domain mediates heterodimer formation of Spred proteins. Growth-factor-mediated activation of the small GTPases, Ras and Rap1, was able to be regulated by Spred-1 and Spred-2, without affecting receptor activation. Taken together, these results highlight the potential for different functional roles of the Sprouty domain within the Spred family of proteins, suggesting that Spred proteins may use different mechanisms to induce inhibition of the MAPK pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Constitution aims to bring an end to health economy warfare.

A rough new constitution is being drawn up for the NHS in a bid to prevent health economies sliding into bitter 'Bradford-style' warfare in the era of foundations trusts and payment by results. The rules of engagement are part of a package of measures designed to rescue some of the government's flagship reforms amid warnings from audit chiefs on the impact of PbR.

Constitution and Bylaws↗
PubMed2004

Medical management of severe traumatic brain injury.

This article reviews the current guidelines for the management of patients with severe traumatic brain injury from presentation in the accident and emergency department, through transfer, to specialist treatment in a neurocritical care unit.

Brain Injuries↗
PubMed2003

Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival signal against multiple apoptotic insults. In addition, phase II enzymes such as heme oxygenase-1 (HO-1) protect cells against diverse toxins and oxidative stress. In this work, we describe a link between these defense systems at the level of transcriptional regulation of the antioxidant enzyme HO-1. The herb-derived phenol carnosol induced HO-1 expression at both mRNA and protein levels. Luciferase reporter assays indicated that carnosol targeted the mouse ho1 promoter at two enhancer regions comprising the antioxidant response elements (AREs). Moreover, carnosol increased the nuclear levels of Nrf2, a transcription factor governing AREs. Electrophoretic mobility shift assays and luciferase reporter assays with a dominant-negative Nrf2 mutant indicated that carnosol increased the binding of Nrf2 to ARE and induced Nrf2-dependent activation of the ho1 promoter. While investigating the signaling pathways responsible for HO-1 induction, we observed that carnosol activated the ERK, p38, and JNK pathways as well as the survival pathway driven by PI3K. Inhibition of PI3K reduced the increase in Nrf2 protein levels and activation of the ho1 promoter. Expression of active PI3K-CAAX (where A is aliphatic amino acid) was sufficient to activate AREs. The use of dominant-negative mutants of protein kinase Czeta and Akt1, two kinases downstream from PI3K, demonstrated a requirement for active Akt1, but not protein kinase Czeta. Moreover, the long-term antioxidant effect of carnosol was partially blocked by PI3K or HO-1 inhibitors, further demonstrating that carnosol attenuates oxidative stress through a pathway that involves PI3K and HO-1.

Abietanes↗
PubMed2002

Ceramide and reactive oxygen species generated by H2O2 induce caspase-3-independent degradation of Akt/protein kinase B.

This study was designed to elucidate the mechanisms leading to down-regulation of the Akt/protein kinase B (PKB) survival pathway during H2O2-induced cell death. H2O2 produced early activation of Akt/PKB and also DNA damage that was followed by stabilization of p53 levels, formation of reactive oxygen species (ROS), and generation of ceramide through activation of a glutathione-sensitive neutral sphingomyelinase. These events correlated with long term dephosphorylation and subsequent degradation of Akt. A membrane-targeted active Akt version attenuated apoptosis but not necrosis induced by H2O2 and was more resistant to dephosphorylation and proteolysis induced by apoptotic concentrations of H2O2. Proteolysis of Akt was prevented by exogenous addition of glutathione, indicating a role of ROS and ceramide in Akt degradation. However, Akt was degraded similarly in cells transfected with wild type and dominant negative p53 mutant, indicating that degradation of Akt under oxidative injury may be p53-independent. Specific inhibitors of caspase groups I and III prevented proteolysis of Akt/PKB and poly(ADP-ribose) polymerase in cells submitted to apoptotic but not necrotic H2O2 concentrations. Surprisingly, in caspase-3-deficient MCF-7 cells Akt was more sensitive to H2O2-induced degradation than the caspase-3 substrate poly(ADP-ribose) polymerase. Moreover, the Akt/PKB double mutant Akt(D108A,D119A), which is not cleaved by caspase-3, and a triple mutant (D453A,D455A,D456A), which lacks the consensus sequence for caspase-3 cleavage, were also degraded in H2O2-treated cells. Our results suggest that strong oxidants generate intracellular ROS and ceramide which in term lead to down-regulation of Akt by dephosphorylation and caspase-3-independent proteolysis.

Animals↗
PubMed2002

Advances in quantitative proteomics using stable isotope tags.

A great deal of current biological and clinical research is directed at the interpretation of the information contained in the human genome sequence in terms of the structure, function and control of biological systems and processes. Proteomics, the systematic analysis of proteins, is becoming a critical component in this endeavor because proteomic measurements are carried out directly on proteins--the catalysts and effectors of essentially all biological functions. To detect changes in protein profiles that might provide important diagnostic or functional insights, proteomic analyses necessarily have to be quantitative. This article summarizes recent technological advances in quantitative proteomics.

Animals↗
PubMed2002

Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles.

Neurons are often assumed to be the principal sites for replication of the infectious agents causing Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy because they express high levels of normal and pathological prion protein (PrP). However, isolated brain cell types have not been evaluated for either infection or gene expression. Microglia purified from CJD-infected mice showed infectivity comparable to that of starting brain homogenate but expressed approximately 50-fold less PrP. CJD-infected microglia also displayed morphological changes indicative of cellular activation. To determine the molecular pathways of activation, we evaluated pertinent transcripts, including those linked to inflammation. Semiquantitative reverse transcription-PCR showed a >4-fold increase in cathepsin S, an enzyme important in antigen presentation, the cytokine interleukin-1beta, and the chemokine B-lymphocyte chemoattractant. The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by beta-amyloid, a structure comparable to pathological PrP. These microglial studies emphasize migratory hematopoietic cells in the dispersion, and possibly replication, of the CJD agent. The low PrP levels in these highly infectious and activated cells further support the concept that pathological PrP is the result of infection rather than the infectious agent itself. Because microglia develop a specific pattern of responses to the CJD agent, microglial markers may be exploited in the diagnosis of these spongiform encephalopathies.

Amyloid beta-Peptides↗
PubMedDate not supplied

Changes in subjective vs objective burn scar assessment over time: does the patient agree with what we think?

It is not known whether objective measurements of burn scar quality reflect, or even bear any relationship to, the patient's opinion of their scar. The purpose of this study was to determine whether any correlation exists between the rehabilitation therapist's rating of the scar using the Vancouver Scar Scale (VSS) and the patient's subjective opinion of their scar. A total of 37 scars in 20 adult patients (mean age, 34 +/- 13 years; 30% female; mean %TBSA burn, 16 +/- 11%) were evaluated at 3.1 +/- 1.9 months after injury (early assessment). Patients were asked to rate their own scar (question 1) and to rate how they perceive other people view the scar (question 2). A visual analog scale (VAS) was used to score the answers to both questions. A burn occupational therapist who was blinded to the VAS scores performed a VSS rating of the scar. These evaluations were repeated 1.5 years after injury (late assessment). At the early assessment, there was no correlation between the VSS score and VAS scores for question 1 (r =.291) or question 2 (r =.371). At the late assessment, there was significant improvement in the VSS score and the VAS score for question 2. Also, a significant correlation developed between the VSS score and the VAS score for question 1 (r =.646, P =.003) but not between the VSS score and VAS score for question 2 (r =.099). The VSS measurement of the scar bears no relationship to the patient's opinion of their scar early after a burn injury. As the scar improves over time, the patient's opinion of their scar appears to improve and shows better correlation with the VSS rating. Conversely, the patient's impression of what others think of the scar continues to bear no relationship to the VSS rating, suggesting that scar acceptance by the patient is incomplete despite objective improvement in the quality of the scar. Although the VSS was never intended to measure a patient's opinion of their scar, these preliminary findings emphasize the necessity of including a patient-centered subjective component to routine scar monitoring and assessment.

Adult↗