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Andrew Williams

Publications and source records attributed to Andrew Williams.

10 recordsLinked to original sources
PubMed2025

Transcriptional benchmark dose modeling of ultraviolet radiation-induced genomic activation in mouse skin.

The in vivo transcriptional response of mouse skin to ultraviolet radiation (UV-R) exposure reveals key genomic alterations associated with UV-R-induced damage but it does not provide precise dose thresholds for these effects. These initial findings provided the impetus to advance dose-response characterization by integrating benchmark dose (BMD) modeling with transcriptomic data, aiming to identify biologically relevant points of departure for gene and pathway activation. To accomplish this, mice were exposed to five erythemally weighted UV-R doses (0-40 mJ/cm2) emitted from a UV-emitting tanning device, across six post-exposure timepoints (0-96 h). Four analytical methods were used to estimate BMDs, with the lowest consistent response dose (LCRD) approach yielding the most sensitive estimates (1.21-3.44 mJ/cm2). Transcriptomic responses revealed activation of shared pathways related to DNA damage and cancer, oxidative stress and metabolism, inflammation and immunity, and hormonal disruption. Notably, the majority of LCRD BMD estimates (1.21-3.44 mJ/cm2) were lower than the International Electrotechnical Commission standard actinic exposure limit (3 mJ/cm2 (erythemally weighted)) for broadband UV-R (200-400 nm) for unprotected skin and the eye for an 8 h period. These findings suggest that transcriptomic BMD modeling can detect early biological responses to UV-R at doses lower than current exposure limits.

Animals↗
PubMed2003

Reaction of imidazole with toluene-4-sulfonate salts of substituted phenyl N-methylpyridinium-4-carboxylate esters: special base catalysis by imidazole.

The reaction of imidazole in aqueous solution with toluene-4-sulfonate salts of substituted phenyl N-methylpyridinium-4-carboxylate esters obeys the rate law: k(obs) - k(background) = k2[Im] + k3[Im]2 where [Im] is the imidazole concentration present as free base. The parameters k2 and k3 fit Brønsted type free energy correlations against the pKa of the leaving phenol with betaLg values of -0.65 and -0.42 respectively. The imidazolysis is insensitive to catalysis by general bases and yet k3 for the 3-cyanophenyl ester possesses a deuterium oxide solvent isotope effect of 4.43 consistent with rate limiting proton transfer. A special catalytic function is proposed for decomposition of the tetrahedral addition intermediate (T+/-) via k3 whereby the catalytic imidazole interacts electrophilically with the leaving phenolate ion and removes a proton from the nitrogen in the rate limiting step with subsequent non-rate limiting ArO-C bond fission. This is consistent with the change in effective charge on the leaving oxygen in the transition structure of k3 which is more positive (-0.42) than that expected (-0.60) for the equilibrium formation of the zwitterion intermediate. The catalytic function at the leaving oxygen is likely to be an electrophilic role of the NH as a hydrogen bond donor. In the k2 step the deuterium oxide solvent isotope effect of 1.51 for the 3-cyanophenyl ester and the betaLg of -0.65 are consistent with rate limiting expulsion of the phenolate ion from the T+/- intermediate. The absence of general base catalysis of imidazolysis rules out the established mechanism for aminolysis of esters where T+/- is stabilised by a standard rate limiting proton transfer. The kinetically equivalent term for k3 where T- reacts with the imidazolium ion as an acid catalyst would require this step to be rate limiting and involve proton transfer not consistent with departure of the good aryl oxide leaving group.

Journal Article↗
PubMed2003

The base-catalysed cyclisation of phenyl N-(2-hydroxybenzyl)-N-methylcarbamates is concerted.

The kinetics of the cyclisation in aqueous solution of phenyl-(2-hydroxybenzyl)-N-methylcarbamates to 3-methyl- 3,4-dihydrobenzo[e][1,3]oxazin-2-ones and phenolate ions fit the rate law: kobs = kc/(1 + [H3O+]/Ka) The values of kc and pKa fit Brønsted equations against the pKa's of the corresponding free phenols but the system does not conform to the reactivity-selectivity hypothesis. The values of the Brønsted parameters beta Y and beta X vary as a function of Y and X according to the equations: beta X = -0.179pKaHY + 0.87 beta Y = -0.179pKaHX + 2.30 The magnitude and sign of the Cordes-Thornton cross-interaction coefficient pXY (-0.179) rule out a stepwise mechanism involving a tetrahedral intermediate and is consistent with a concerted displacement mechanism. A similar concerted mechanism is proposed for the base-catalysed cyclisation of phenyl-N-(2-hydroxyphenyl)-N-methylcarbamate esters to benzoxazol-2-ones.

Journal Article↗
PubMed2003

Spinal cord infarction following central-line insertion.

Hemothorax is a recognized complication of central line insertion into the jugular or subclavian vein. We describe a case of hemothorax consequent upon acute dialysis catheter insertion, which resulted in spinal cord infarction and quadriplegia. We postulate that the extensive mediastinal shift induced after insertion of the catheter resulted in stretching of the veins draining the cord with a resultant drop in perfusion pressure and infarction. This case highlights a hitherto unreported complication of this procedure.

Catheterization, Central Venous↗
PubMed2002

Effect of MRI on clinical outcome of recurrent fistula-in-ano.

Recurrent fistula-in-ano is usually due to sepsis missed at surgery, which can be identified by MRI. We aimed to establish the therapeutic effect of MRI in patients with fistula-in-ano. We did MRI in 71 patients with recurrent fistula, with further surgery done at the discretion of the surgeon. Surgery and MRI agreed in 40 patients, five (13%) of whom had further recurrence, compared with 16 (52%) of 31 in whom surgery and MRI disagreed (p=0.0005). Further recurrence in all 16 was at the site predicted by MRI. For surgeons who always acted on MRI, further recurrences arose in four of 25 (16%) operations versus eight of 14 (57%) operations for those who ignored imaging (p=0.008). Surgery guided by MRI reduces further recurrence of fistula-in-ano by 75% and should be done in all patients with recurrent fistula.

Adolescent↗
PubMed2002

Characterization of a unique human single-chain antibody isolated by phage-display selection on membrane-bound mosquito midgut antigens.

The insect midgut is the primary site for food digestion, as well as for vector-borne pathogen infection into the invertebrate host. Accordingly, antigens of this critical insect organ are targets for anti-vector vaccines, insecticidal toxins, and transmission-blocking vaccines. We used midgut proteins of the African malaria vector mosquito Anopheles gambiae to select single-chain human antibody fragments (scFv) from a high-diversity, phage-displayed library. Using a phage-display selection method on western-blotted antigens, we selected an unusual truncated scFv clone, consisting of a heavy-chain only, which binds to An. gambiae midgut tissue. This clone binds a spectrum of mosquito antigens from the midgut and other mosquito tissues, as well as various mammalian glycoproteins, but binding was reduced when these glycoproteins were enzymatically deglycosylated. We also observed that this clone preferentially binds the lumenal midgut surface. Furthermore, antigen binding by our selected scFv was limited by competition with increasing concentrations of certain soluble carbohydrates, most dramatically by galactose and N-acetyl glucosamine. Our results show that the cognate epitope of this scFv is a carbohydrate moiety. This paper describes a phage-display selection of antibody fragments on mosquito midgut tissue and it also describes a method for phage-display selection on membrane-immobilized heterogeneous antigens. These selection methods resulted in the isolation of a novel, truncated, carbohydrate-binding human antibody fragment from a naive phage-display library.

Amino Acid Sequence↗
PubMed2002

Allergic rhinitis.

Most nurses will come into contact with sufferers of allergic rhinitis, a highly prevalent disease. This Factfile examines diagnosis and management.

Humans↗
PubMed2002

Immunotherapy.

Immunotherapy is effective and safe when carried out by properly trained and equipped health professionals on patients who have been carefully selected and screened. Access to these treatments is limited because, although allergy has a high profile with the public, this has yet to translate into adequate service availability.

Humans↗