An investigation of transition probabilities in the spectrum of the hydroxyl radical

Imperial Users onl

Tribute to John Pickering

I knew John Pickering from the time that I was a second-year law student- just a few years ago, it seems-when he and Sally Katzen recruited me to join what was then the small firm of Wilmer, Cutler & Pickering. We remained friends thereafter, sharing among other interests an avid loyalty to the University of Michigan

A Unified Total Synthesis of the Actinoallolides, a Family of Potent Anti-Trypanosomal Macrolides.

Trypanosoma protozoan parasites are the causative agents of Chagas disease and sleeping sickness, two neglected tropical diseases where there is an urgent need for improved treatments and the evaluation of promising drug leads like the actinoallolides. Enabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks, an efficient first total synthesis of the potent anti-trypanosomal macrolide (+)-actinoallolide A has been achieved in 17 steps and 8 % overall yield. Our convergent route features an adventurous ring-closing metathesis to form the requisite trisubstituted (8E)-alkene in the 12-membered macrolactone, followed by the controlled installation of the labile transannular hemiacetal. Late-stage diversification then provides ready access to the congeneric (+)-actinoallolides B-E

Total synthesis of the actinoallolides and a designed photoaffinity probe for target identification.

The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against trypanosomes, the causative agents of the neglected tropical diseases human African trypanosomiasis (sleeping sickness) and Chagas disease, while exhibiting no cytotoxicity against human cell lines. Herein, we give a full account of our strategy evolution towards the synthesis of this structurally unique class of 12-membered macrolides, which culminated in the first total synthesis of (+)-actinoallolide A in 20 steps and 8% overall yield. Subsequent late-stage diversification then provided ready access to the congeneric (+)-actinoallolides B-E. Enabled by this flexible and efficient endgame sequence, we also describe the design and synthesis of a photoaffinity probe based on actinoallolide A to investigate its biological mode of action. This will allow ongoing labelling studies to identify their protein binding target(s)

Radiocarbon Ecology of the Land Snail Helix Melanostoma in Northeastern Libya

Terrestrial gastropods are problematical for radiocarbon (14C) measurement because they tend to incorporate carbon from ancient sources as a result of their dietary behavior. The 14C ecology of the pulmonate land snail, Helix melanostoma in Cyrenaica, northeastern Libya, was investigated as part of a wider study on the potential of using terrestrial mollusk shell for 14C dating of archaeological deposits. H. melanostoma was selected out of the species available in the region as it has the most predictable 14C ecology and also had a ubiquitous presence within the local archaeology. The ecological observations indicate that H. melanostoma has a very homogenous 14C ecology with consistent variations in F14C across sample sites controlled by availability of dietary vegetation. The majority of dated specimens from nonurbanized sample locations have only a small old carbon effect, weighted mean of 476±48 14C yr, with between ~1% and 9% of dietary F14C from non-organic carbonate sources. Observed instabilities in the 14C ecology can all be attributed to the results of intense human activity not present before the Roman Period. Therefore, H. melanostoma and species with similar ecological behavior are suitable for 14C dating of archaeological and geological deposits with the use of a suitable offset

Toward the total synthesis of patellazole B: synthesis of an advanced C1-C25 fragment corresponding to the macrocyclic skeleton.

The patellazoles are a family of complex marine macrolides that exhibit potent cytotoxicity against cancer cell lines. However, despite extensive characterisation efforts, their full stereochemical assignment has remained elusive. We report our approach towards the synthesis-enabled structural elucidation of patellazole B (4), a 24-membered macrolide with 16 stereocentres and a signature thiazole-containing side chain. Our plan hinges upon isolating the unknown stereocentres into a single C20-C25 fragment to facilitate the flexible assembly of various possible diastereomers of an advanced C1-C25 fragment. Towards this end, a highly convergent and modular synthesis of one candidate diastereomer 37, corresponding to the patellazole B macrocyclic skeleton, has been achieved based on the strategic application of stereocontrolled aldol methodology, combined with Suzuki and Heck cross-coupling reactions

Visual Behaviours (ViBes) in Cerebral Visual Impairment: Validating a Descriptive Tool to Support Diagnosis and Monitoring

Introduction: Cerebral visual impairment (CVI) is the most common cause of visual impairment in children in the UK. Diagnosis is based on identification of visual behaviours (ViBes) relating to visual dysfunction. Examination techniques and inventories have been developed to elicit these in children with a developmental age of two years or more. The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis. The aim of the study was to develop a matrix of visual behaviours seen in pre-verbal and pre-motor children with visual impairment and establish its content validity and inter-rater reliability. Methods ViBe content validation: Visual behaviour descriptors relating to visual function were collated and categorised by expert consensus of vision professionals into a matrix composed of three functions (attention, field/fixation, motor response) and five levels (0 = no awareness; 1 = visual awareness; 2 = visual attention; 3 = visual detection; 4 = visual understanding). ViBe inter-rater reliability: The participants (two orthoptists, an optometrist, an ophthalmologist and two qualified teachers of the visually impaired) used the ViBe matrix to independently score each of 17 short video clips of children demonstrating visual behaviours seen in CVI. Results: The ViBe matrix will be presented. Cohen’s kappa for the matrix was 0.67, demonstrating moderate-to-strong inter-rater reliability. Conclusion: The development of standardised descriptors can support clinicians and teachers in identifying areas of concern for children with complex needs. In addition, the ViBe matrix could be utilised in research, clinical and diagnostic reports to clearly communicate the areas of visual dysfunction and track progress resulting from interventions. Key Points • The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis. • The ViBe matrix offers descriptors relating to visual behaviours and has demonstrated acceptable inter-rater reliability. • The tool may support the identification and diagnosis of cerebral visual impairment in a population of children who cannot access standard testing

In-school eyecare in special education settings has measurable benefits for children’s vision and behaviour

ObjectivesTo determine whether implementation of comprehensive in-school eyecare results in measurable benefits for children and young people in terms of visual status, classroom behaviours and how well their visual needs are met.DesignSchool-based observational study.Participants & methods200 pupils [mean age 10 years 9 months, 70% male, majority moderate (40%) or severe (35%) learning difficulty] of a special education school in the UK. A sector-agreed in-school eyecare framework including full eye examination and cycloplegic refraction, dispensing of spectacles (as appropriate) and written reporting of outcomes to parents/teachers was applied. Classroom behaviours were observed and recorded prior to, and after, the in-school eyecare. Surveys were employed to obtain visual histories from parents/teachers. School records and statutory documents were reviewed for diagnostic and learning disability classifications. Visual function and ocular health were profiled at baseline and significant visual deficits identified. Where such deficits were previously unrecognised, untreated or not compensated for (e.g. correction of refractive error, enlargement of educational material) they were recorded as 'unmet visual need'. At follow-up, 2-5 months after initial (baseline) measures, eye examinations, parent/teacher surveys and behaviour observations were repeated. Follow-up measures were used to determine if measurable improvements were evident in visual function, ocular health, the level of unmet need and classroom behaviour following implementation of in-school eyecare.Results199 participants completed baseline and follow-up measures. 122 (61%) participants presented with at least one significant visual or ocular health deficit and 90 (45%) participants had at least one unmet visual need. Younger pupils and those with no previous history of eyecare were more likely to demonstrate unmet visual needs at baseline (OR 1.12 95% CI 1.03 to 1.21) p = 0.012; (OR 4.44 95% CI 1.38 to 14.29 p = 0.007 respectively). On follow-up, the number of pupils with unmet visual needs dropped significantly to 36 (18%) (McNemar's test p0.05). Where significant refractive deficits were corrected at follow-up, near visual acuity improved significantly (Wilcoxon signed rank p = 0.013), however, poor spectacle compliance was a persistent cause of unmet visual need. Off-task behaviour reduced significantly after actions to address unmet visual needs were communicated to parents and teachers (Wilcoxon signed rank p = 0.035).ConclusionsThe present study demonstrates for the first time measurable visual and behaviour benefits to children in special education settings when they receive comprehensive in-school eye examinations, on-site spectacle dispensing and jargon-free reporting of outcomes to teachers and parents