Biomedical subjects

Andrew McCarthy

Publications and source records attributed to Andrew McCarthy.

6 recordsLinked to original sources

PubMed2006

Structure of C3b reveals conformational changes that underlie complement activity.

Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity. Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-A resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 A away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the alpha-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.

Binding Sites↗

PubMed2006

Antithrombin Nagasaki (Ser 116 to Pro): a rare antithrombin variant with abnormal heparin binding presenting during pregnancy.

Quantitative antithrombin deficiency constitutes an important risk factor for venous thromboembolism, stillbirth, and other complications of pregnancy. Studies suggest, however, that individuals heterozygous for missense mutations involving the heparin-binding site of antithrombin do not have a significantly increased thrombotic risk. Owing to the rarity of such mutations, it remains unclear whether any specific heparin-binding site defects might be associated with thrombotic potential. We report here the case of a pregnant woman with an exceptionally rare Type II heparin-binding site antithrombin variant. This case highlights the difficult issues that are associated with the management of Type II antithrombin deficiency during pregnancy.

Adult↗

PubMed2005

Successful spontaneous pregnancy following surgical removal of a post uterine artery embolized necrotic fibroid capsule: a case report.

Uterine artery embolization has been shown to be an effective treatment in controlling symptomatic uterine fibroids. Reports suggest that significant complications associated with the procedure are rare. However, data pertaining to preservation of fertility after embolization are scarce, and some authors do not advocate this procedure for women considering future pregnancy. We present a case of a post-embolization uterine cavity abnormality which was repaired surgically, followed by successful pregnancy outcome.

Adult↗

PubMed2005

Automation of macromolecular crystallography beamlines.

The production of three-dimensional crystallographic structural information of macromolecules can now be thought of as a pipeline which is being streamlined at every stage from protein cloning, expression and purification, through crystallisation to data collection and structure solution. Synchrotron X-ray beamlines are a key section of this pipeline as it is at these that the X-ray diffraction data that ultimately leads to the elucidation of macromolecular structures are collected. The burgeoning number of macromolecular crystallography (MX) beamlines available worldwide may be enhanced significantly with the automation of both their operation and of the experiments carried out on them. This paper reviews the current situation and provides a glimpse of how a MX beamline may look in the not too distant future.

Crystallography, X-Ray↗

PubMed2004

Suspect identification by facial features.

Often during criminal investigations, witnesses must examine photographs of known offenders, colloquially called 'mug shots'. As witnesses view increasing numbers of mug shots that are presented in an arbitrary order, they become more likely to identify the wrong suspect. An alternative is a subjective feature-based mug shot retrieval system in which witnesses first complete a questionnaire about the appearance of the suspect, and then examine photographs in order of decreasing resemblance to their description. In the first experiment, this approach is found to be more efficient and more accurate than searching an album. The next three experiments show that it makes little difference if the witness has seen the suspect in person or only seen a photograph. In the last two experiments, it is shown that the feature-based retrieval system is effective even when the witness has seen the suspect in realistic natural settings. The results show that the main conclusions drawn from previous studies, where witnesses searched for faces seen only in photographs, also apply when witnesses are searching for a face that they saw live in naturalistic settings. Additionally, it is shown that is it better to have two raters than one create the database, but that more than two raters yield rapidly diminishing returns for the extra cost.

Adolescent↗

PubMed2004

Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes.

Members of the serum paraoxonase (PON) family have been identified in mammals and other vertebrates, and in invertebrates. PONs exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein (HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis. We describe the first crystal structure of a PON family member, a variant of PON1 obtained by directed evolution, at a resolution of 2.2 A. PON1 is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding. The three-dimensional structure and directed evolution studies permit a detailed description of PON1's active site and catalytic mechanism, which are reminiscent of secreted phospholipase A2, and of the routes by which PON family members diverged toward different substrate and reaction selectivities.

Amino Acid Sequence↗