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Anthony Williams

Publications and source records attributed to Anthony Williams.

10 recordsLinked to original sources
PubMed2005

The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex.

Major histocompatibility complex (MHC) class I complexes present peptides from both self and foreign intracellular proteins on the surface of most nucleated cells. The assembled heterotrimeric complexes consist of a polymorphic glycosylated heavy chain, non-polymorphic beta(2) microglobulin, and a peptide of typically nine amino acids in length. Assembly of the class I complexes occurs in the endoplasmic reticulum and is assisted by a number of chaperone molecules. A multimolecular unit termed the peptide-loading complex (PLC) is integral to this process. The PLC contains a peptide transporter (transporter associated with antigen processing), a thiooxido-reductase (ERp57), a glycoprotein chaperone (calreticulin), and tapasin, a class I-specific chaperone. We suggest that class I assembly involves a process of optimization where the peptide cargo of the complex is edited by the PLC. Furthermore, this selective peptide loading is biased toward peptides that have a longer off-rate from the assembled complex. We suggest that tapasin is the key chaperone that directs this action of the PLC with secondary contributions from calreticulin and possibly ERp57. We provide a framework model for how this may operate at the molecular level and draw parallels with the proposed mechanism of action of human leukocyte antigen-DM for MHC class II complex optimization.

Animals↗
PubMed2004

Tapasin enhances MHC class I peptide presentation according to peptide half-life.

Understanding how peptides are selected for presentation by MHC class I is crucial to vaccination strategies based on cytotoxic T lymphocyte priming. We have studied this selection of the MHC class I peptide repertoire in terms of the presentation of a series of individual peptides with a wide range of binding to MHC class I. This series was expressed as minigenes, and the presentation of each peptide variant was determined with the same MHC class I peptide-specific antibody. In wild-type cells, the hierarchy of presentation followed peptide half-life. This hierarchy broke down in cells lacking tapasin but not in cells lacking calreticulin or in cells lacking transporter associated with antigen processing-associated ERp57. We demonstrate a key role for tapasin in shaping the MHC class I peptide repertoire, as enhancement of presentation in the presence of tapasin correlated with peptide half-life.

Amino Acid Sequence↗
PubMed2004

Randomised controlled trial of support from volunteer counsellors for mothers considering breast feeding.

OBJECTIVE: To investigate whether offering volunteer support from counsellors in breast feeding would result in more women breast feeding. DESIGN: Randomised controlled trial. SETTING: 32 general practices in London and south Essex. PARTICIPANTS: 720 women considering breast feeding. MAIN OUTCOME MEASURES: Primary outcome was prevalence of any breast feeding at six weeks. Secondary outcomes were the proportion of women giving any breast feeds, or bottle feeds at four months, duration of any breast feeding, time to introduction of bottle feeds, and satisfaction with breast feeding. RESULTS: Offering support in breast feeding did not significantly increase the prevalence of any breast feeding to six weeks (65% (218/336) in the intervention group and 63% (213/336) in the control group; relative risk 1.02, 95% confidence interval 0.84 to 1.24). Survival analysis up to four months confirmed that neither duration of breast feeding nor time to introduction of formula feeds differed significantly between control and intervention groups. Not all women in the intervention group contacted counsellors postnatally, but 73% (123/179) of those who did rated them as very helpful. More women in the intervention group than in the control group said that their most helpful advice came from counsellors rather than from other sources. CONCLUSIONS: Women valued the support of a counsellor in breast feeding, but the intervention did not significantly increase breastfeeding rates, perhaps because some women did not ask for help.

Adolescent↗
PubMed2003

The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat.

Physical activity can induce neuroplastic adaptations and improve outcomes after cerebral injury. To determine if these outcomes are dependent on the type and timing of physical rehabilitation and the particular outcome/endpoint being tested, we evaluated the effect of voluntary exercise exposure beginning 24 h after cerebral ischemic injury on behavioral, physiological, and histological outcomes. In an observer-blinded fashion, Sprague-Dawley (300 g) male rats were allocated to three groups [sham-exercise (SHAM), stroke-exercise (SE), stroke-no exercise (SNE)] before a 1-h right middle cerebral artery occlusion (MCAo). Running wheels were used for voluntary exercise. A significant difference was found at 1 week post-infarction between the SNE and SE, with SNE showing worst neurological scores and higher number of foot faults. In addition, nearly 20% more of the SE animals regained their pre-MCAo weight by 7 days. These differences were not as evident at 2 weeks. No differences were found between the three groups in the paw preference test, wheel activity, and body temperature, as well as between SNE and SE with regards to infarct or hemispheric volumes, body weight, synaptophysin staining, and electroencephalography (EEG) testing. Within-group comparisons showed no relationships between infarct volume and foot faults, neurological scores, or exercise level. We conclude that (1) unlike behavioral outcomes, physiological and histological outcomes may not be influenced by the introduction of voluntary exercise once lesion maturation has occurred at 24 h, and (2) repetitive outcomes testing can obscure findings in rat models of cerebral ischemic injury.

Animals↗
PubMed2003

DX-88 and HAE: a developmental perspective.

An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.

Acute Disease↗
PubMed2002

Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia.

We previously developed a murine model of acute promyelocytic leukemia (APL) by using human cathepsin G gene regulatory elements to direct the expression of promyelocytic leukemia (PML)/retinoic acid receptor alpha (RAR alpha) and RAR alpha/PML fusion cDNAs to the early myeloid compartment of transgenic mice. To study the efficacy of noncytotoxic therapy in this animal model, cohorts of naive immunocompetent mice were inoculated with primary murine APL cells from a frozen tumor bank. Arsenic trioxide and liposomally encapsulated all-trans-retinoic acid (Lipo ATRA), alone or in combination, were administered for 21 days by i.p. injection using doses that yielded plasma levels similar to those observed in human APL patients treated with these agents. Lipo ATRA was highly effective in inducing durable molecular remissions in immunocompetent mice [C57BL/6 x C3H F(1) (B6C3HF1)]; arsenic therapy was much less effective, and did not clearly synergize with Lipo ATRA to increase the remission rate in immunocompetent mice. The survival of Lipo ATRA-treated severe combined immunodeficient (SCID) animals (lacking functional T and B cells) was inferior to that of immunocompetent B6C3HF1 recipients (40% vs. 88% survival at 1 y, P < 0.001). These data suggest that adaptive immunity cooperates with pharmacologic therapy to induce or maintain remissions in murine APL. It also implies that immunosuppressive anti-leukemia therapies could paradoxically blunt effective anti-leukemia immune responses that are important for clearing small numbers of residual tumor cells after chemotherapy-mediated cytoreduction.

Animals↗
PubMed2002

Targetting out of the workforce nurses: a promising local recruitment strategy.

A successful pilot program to attract and orient 'out of the workforce' nurses to a hospital outreach acute and post acute care service is described. Three new staff members attended a one-month education program prior to commencing supervised clinical activity. Survey and focus group methods were used to evaluate the initiative. Principal lessons learned were that preceptoring and preceptor support is central to a positive outcome for new and existing staff. We also learned that a tendency to underestimate the complexity of the post acute care nursing role in the initial advertising was unhelpful.

Australia↗
PubMedDate not supplied

Generation and selection of novel estrogen receptor ligands using the de novo structure-based design tool, SkelGen.

A de novo design approach to generating novel estrogen receptor (ER) ligands is described. The SkelGen program was used to generate ligands in the active sites of seven crystal structures of ERalpha. Seventeen high-scoring, diverse structures were selected from the SkelGen output and synthesized without introducing any modifications to the structures. Five ligands, four of which are novel, showed < or = 25 microM affinity, with the best compound displaying an IC50 of 340 nM. SkelGen can, therefore, be a powerful tool for designing active molecules.

Binding, Competitive↗
PubMedDate not supplied

Exhaustive de novo design of low-molecular-weight fragments against the ATP-binding site of DNA-gyrase.

We present a de novo design approach to generating small fragments in the DNA-gyrase ATP-binding site using the computational drug design platform SkelGen. We have generated an exhaustive number of structural possibilities, which were subsequently filtered for site complementarity and synthetic tractability. A number of known active fragments are found, but most of the species created are potentially novel and could be valuable for further elaboration and development into lead-like structures.

Adenosine Triphosphate↗