PubMed Health⌕ Search

Biomedical subjects

M J Lees

Publications and source records attributed to M J Lees.

11 recordsLinked to original sources
PubMed2002

Effect of ARA9 on dioxin receptor mediated transcription.

The dioxin (Aryl hydrocarbon) receptor (DR) is a unique bHLH transcription factor which is activated by binding of planar aromatic hydrocarbons typified by dioxin (TCDD). The active receptor is key to metabolism of aryl hydrocarbon xenobiotics by being a potent inducer of CYP1A1 gene activity. Chlorinated dioxins are inert to metabolism and initiate multifarious toxicities, including potent tumour promotion. These ill-effects are mediated by the activated DR and we are studying the mechanisms by which the ligand binding domain of the DR controls activity of the protein. The DR ligand binding domain resides within a PAS (Per/Arnt/Sim homology) region which is contiguous with the bHLH. The latent bHLH/PAS dioxin receptor (DR) is found in the cytoplasm of most mammalian cell types in a complex with heat shock protein 90, a novel immunophilin like protein termed ARA9/XAP2/AIP, and the co-chaperone p23. Here we use antisense ARA9 constructs to reveal that in the absence of ARA9, the DR is unable to form a transcriptionally active complex. Co-expression of antisense ARA9 with a form of the DR which is constitutively targeted to the nucleus leads to dramatically decreased levels of the nuclear DR protein, implying that ARA9 may function beyond its currently proposed role in cytoplasmic retention of the latent DR.

Animals↗
PubMed2001

Flow pattern dynamics in convecting liquid helium.

We present experimental data which correlate thermal measurements and flow visualization in convecting liquid 4He. For a small range R(C) R1, generating thermal oscillations as in earlier reports. At higher R values the time dependence becomes aperiodic with the surprising appearance of spiral-defect chaos at an aspect ratio smaller than has previously been reported.

Journal Article↗
PubMed1999

Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt.

The dioxin receptor is a ligand-activated transcription factor belonging to an emerging class of basic helix-loop-helix/PAS proteins which show interaction with the molecular chaperone hsp90 in their latent states and require heterodimerization with a general cofactor, Arnt, to form active DNA binding complexes. Upon binding of polycyclic aromatic hydrocarbons typified by dioxin, the dioxin receptor translocates from the cytoplasm to the nucleus to allow interaction with Arnt. Here we have bypassed the nuclear translocation step by creating a cell line which expresses a constitutively nuclear dioxin receptor, which we find remains in a latent form, demonstrating that ligand has functional roles beyond initiating nuclear import of the receptor. Treatment of the nuclear receptor with dioxin induces dimerization with Arnt to form an active transcription factor complex, while in stark contrast, treatment with the hsp90 ligand geldanamycin results in rapid degradation of the receptor. Inhibition of degradation by a proteasome inhibitor allowed geldanamycin to transform the nuclear dioxin receptor to a heterodimer with Arnt (DR-Arnt). Our results indicate that unchaperoned dioxin receptor is extremely labile and is consistent with a concerted nuclear mechanism for receptor activation whereby hsp90 is released from the ligand-bound dioxin receptor concomitant with Arnt dimerization. Strikingly, artificial transformation of the receptor by geldanamycin provided a DR-Arnt complex capable of binding DNA but incapable of stimulating transcription. Limited proteolysis of DR-Arnt heterodimers indicated different conformations for dioxin versus geldanamycin-transformed receptors. Our studies of intracellular dioxin receptor transformation indicate that ligand plays multiple mechanistic roles during receptor activation, being important for nuclear translocation, transformation to an Arnt heterodimer, and maintenance of a structural integrity key for transcriptional activation.

Adrenal Glands↗
PubMed1991

Experimental cutaneous free flap transfers in the horse.

Equine limb wounds often heal slowly by epithelialization, and large scars are a frequent end result. In some ways, they resemble the wound associated with human tibial injuries. The literature indicates that previous investigators have failed to transfer free skin flaps successfully in the horse. In this paper, we review our experimental work with the deep circumflex iliac flap in the horse. Dissections of 20 cadavers confirmed the anatomical consistency of the flap. Four flaps survived well when elevated as island flaps, but five orthotopic and nine heterotopic free flap transfers all failed. The cause of failure is still unknown, but our experiments suggested that the horse must be highly susceptible to ischemic reperfusion injury.

Animals↗
PubMed1990

Identification of a free skin flap from the region vascularized by the deep circumflex iliac artery of horses.

Areas of skin vascularized by large axial vessels potentially suitable for microvascular anastomosis were investigated in 10 horse cadavers. Eleven such areas were dissected, and the skin over the flank region vascularized by the deep circumflex iliac artery was most suitable. The anatomy of this area was further defined, using angiography and latex injection studies on 10 cadavers.

Animals↗
PubMedDate not supplied

Transfer of deep circumflex iliac flaps to the tarsus by microvascular anastomosis in the horse.

Eighteen deep circumflex iliac flaps were elevated in healthy adult horses. Four flaps survived well when elevated as islands, but five orthotopic flaps and nine heterotopic flaps transferred to the tarsus and face failed. Technical reasons could explain the failure of the orthotopic flaps, but not the heterotopic flaps. Failure of the heterotopic flaps was apparently caused by the no-reflow phenomenon.

Anastomosis, Surgical↗