Clinical Genetics in Britain: Origins and development

Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2010.©The Trustee of the Wellcome Trust, London, 2010.All volumes are freely available online at: www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Annotated and edited transcript of a Witness Seminar held on 23 September 2008. Introduction by Professor Sir John Bell, Uiversity of Oxford.Clinical genetics has become a major medical specialty in Britain since its beginnings with Lionel Penrose’s work on mental handicap and phenylketonuria (PKU) and John Fraser Robert’s first genetic clinic in 1946. Subsequent advances in diagnosis and prediction have had key impacts on families with inherited disorders and prospective parents concerned about their unborn children. The Witness Seminar focused on the beginnings of British clinical genetics in London, Oxford, Liverpool and Manchester, the development of subspecialties, such as dysmorphology, and also the roles of the Royal College of Physicians, the Clinical Genetics Society and the Department of Health in the establishment of clinical genetics as a specialty in 1980. Specialist non-medical genetic counsellors, initially from the fields of nursing and social work, progressively became a more significant part of genetic services, while lay societies also developed an important influence on services. Prenatal diagnosis became possible with the introduction of new genetic tools in regional centres to identify fetal anomalies and chromosomal disorders. This volume complements the 2001 Witness Seminar on genetic testing which emphasizes laboratory aspects of medical genetics, with limited coverage of clinical genetics. Participants include: Ms Chris Barnes, Dr Caroline Berry, Professor Martin Bobrow (chair), Professor Sir John Burn, Dr Ian Lister Cheese, Professor Angus Clarke, Dr Clare Davison, Professor Joy Delhanty, Dr Nick Dennis, Professor Dian Donnai, Professor Alan Emery, Professor George Fraser, Mrs Margaret Fraser Roberts, Professor Peter Harper, Dr Hilary Harris, Professor Rodney Harris, Professor Shirley Hodgson, Dr Alan Johnston, Mrs Ann Kershaw, Mrs Lauren Kerzin-Storrar, Professor Michael Laurence, Professor Ursula Mittwoch, Professor Michael Modell, Professor Marcus Pembrey, Professor Sue Povey, Professor Heather Skirton, Professor Sir David Weatherall. Harper P A, Reynolds L A, Tansey E M. (eds) (2010) Clinical genetics in Britain: Origins and development. Wellcome Witnesses to Twentieth Century Medicine, vol. 39. London: The Wellcome Trust Centre for the History of Medicine at UCL.The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

The challenges of extending climate risk insurance to fisheries

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordNatural Environment Research Council (NERC)Centre for Environment, Fisheries and Aquaculture Science (Cefas)Willis Research NetworkCommonwealth Marine Economies Programme, UK Foreign and Commonwealth Offic

Early Stage Biomineralization in the Periostracum of the ‘Living Fossil’ Bivalve Neotrigonia

A detailed investigation of the shell formation of the palaeoheterodont ‘living fossil’ Neotrigonia concentrated on the timing and manufacture of the calcified ‘bosses’ which stud the outside of all trigonioid bivalves (extant and fossil) has been conducted. Electron microscopy and optical microscopy revealed that Neotrigonia spp. have a spiral-shaped periostracal groove. The periostracum itself is secreted by the basal cell, as a thin dark pellicle, becoming progressively transformed into a thin dark layer by additions of secretions from the internal outer mantle fold. Later, intense secretion of the internal surface of the outer mantle fold forms a translucent layer, which becomes transformed by tanning into a dark layer. The initiation of calcified bosses occurred at a very early stage of periostracum formation, deep within the periostracal groove immediately below the initialmost dark layer. At this stage, they consist of a series of polycyclically twinned crystals. The bosses grow as the periostracum traverse through the periostracal groove, in coordination with the thickening of the dark periostracal layer and until, upon reaching the mantle edge, they impinge upon each other and become transformed into large prisms separated by dark periostracal walls. In conclusion, the initial bosses and the external part of the prismatic layer are fully intraperiostracal. With later growth, the prisms transform into fibrous aggregates, although the details of the process are unknown. This reinforces the relationships with other groups that have the ability to form intraperiostracal calcifications, for example the unionoids with which the trigonioids form the clade Paleoheterodonta. The presence of similar structures in anomalodesmatans and other euheterodonts raises the question of whether this indicates a relationship or represents a convergence. The identification of very early calcification within an organic sheet has interesting implications for our understanding of how shells may have evolved.Coordinated Research Projects CGL2010-20748-C02-01 (AGC, EMH) and 02 (CS) (DGI, Spanish MICINN); the Research Group RNM363 (Consejería de Economía, Investigación, Ciencia y Empleo, Junta de Andalucía); and the FP7 COST Action TD0903 of the European Community

Kaposi’s sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs

Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose high translational demands on the host during replication. We explore the possibility that KSHV manipulates ribosome biogenesis producing specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic replication. We demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and the KSHV ORF11 protein, with small ribosomal subunit precursor complexes during lytic replication. BUD23 depletion resulted in significantly reduced viral gene expression, culminating in dramatic reduction of infectious virion production. Ribosome profiling demonstrated BUD23 is essential for reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the downstream coding sequence. Results provide mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes facilitating efficient translation of viral mRNAs

High benthic methane flux in low sulfate oceans: Evidence from carbon isotopes in Late Cretaceous Antarctic bivalves

The shell material of marine benthic bivalves provides a sensitive archive of water chemistry immediately above the sediment–water interface, which in turn is affected by sedimentary geochemistry and redox reactions. Sulfate has a major controlling effect on sedimentary carbon cycling, particularly the processes of methane production and oxidation, with lower concentrations of sulfate likely resulting in an increase in sedimentary methane production. Whilst it is accepted that ocean sulfate varied markedly across the Phanerozoic, evidence of changes in methane production in sediments has so far been lacking. There is potential for the oxidation products of sedimentary methane to be preserved and detected in marine fossils. Here we present the results of high resolution carbonate isotope records from two taxa of well-preserved shallow-infaunal bivalve (Lahillia and Cucullaea) collected from the marine shelf succession across the Cretaceous–Paleogene (K–Pg) boundary in Seymour Island, Antarctica. The succession has pre-existing subtle indications of more abundant methane, and the time period is characterized by much lower marine sulfate concentrations than modern. These shell carbonate–carbon isotope records vary widely: at one extreme, shells have typical average values and small ranges compatible with a contemporaneous marine dissolved inorganic carbon (DIC) source and modern-style sedimentary carbon cycling. At the other, the shells have large-amplitude annual cycles of carbon isotopic variability of up to 23.8‰ within a single year of growth and shell carbonate δ13δ13C compositions as negative as −34‰. Shells with these increased ranges and unusually negative values are found at discrete intervals and across both bivalve taxa. The contribution of methane required to explain the most negative carbonate–carbon isotopic values in the bivalve shells is extremely high (between 30 to 85% of bottom-water DIC based on mass balance calculations). Records of organic-carbon isotopes from the same succession remained between −26.1 and −21.7‰ throughout, suggesting that methane influence was restricted to bottom-waters. A lack of authigenic carbonate in the section indicates that methane oxidation progressed aerobically and may have provided a significant driver for transient bottom water de-oxygenation. Where methane addition is indicated, the seasonal sensitivity precludes control by methane hydrates. We argue that these data represent the increased importance and sensitivity of methanogenesis in the sediments, enabled by lower ocean sulfate concentrations during the Late Cretaceous. The tendency towards a more dynamic role for marine methane production and oxidation is likely to apply to other times of low marine sulfate in Earth's history

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Dissolution dominating calcification process in polar pteropods close to the point of aragonite undersaturation

Thecosome pteropods are abundant upper-ocean zooplankton that build aragonite shells. Ocean acidification results in the lowering of aragonite saturation levels in the surface layers, and several incubation studies have shown that rates of calcification in these organisms decrease as a result. This study provides a weight-specific net calcification rate function for thecosome pteropods that includes both rates of dissolution and calcification over a range of plausible future aragonite saturation states (Omega_Ar). We measured gross dissolution in the pteropod Limacina helicina antarctica in the Scotia Sea (Southern Ocean) by incubating living specimens across a range of aragonite saturation states for a maximum of 14 days. Specimens started dissolving almost immediately upon exposure to undersaturated conditions (Omega_Ar,0.8), losing 1.4% of shell mass per day. The observed rate of gross dissolution was different from that predicted by rate law kinetics of aragonite dissolution, in being higher at Var levels slightly above 1 and lower at Omega_Ar levels of between 1 and 0.8. This indicates that shell mass is affected by even transitional levels of saturation, but there is, nevertheless, some partial means of protection for shells when in undersaturated conditions. A function for gross dissolution against Var derived from the present observations was compared to a function for gross calcification derived by a different study, and showed that dissolution became the dominating process even at Omega_Ar levels close to 1, with net shell growth ceasing at an Omega_Ar of 1.03. Gross dissolution increasingly dominated net change in shell mass as saturation levels decreased below 1. As well as influencing their viability, such dissolution of pteropod shells in the surface layers will result in slower sinking velocities and decreased carbon and carbonate fluxes to the deep ocean

Role of silicon in the development of complex crystal shapes in coccolithophores

The development of calcification by the coccolithophores had a profound impact on ocean carbon cycling, but the evolutionary steps leading to the formation of these complex biomineralized structures are not clear. Heterococcoliths consisting of intricately shaped calcite crystals are formed intracellularly by the diploid life cycle phase. Holococcoliths consisting of simple rhombic crystals can be produced by the haploid life cycle stage but are thought to be formed extracellularly, representing an independent evolutionary origin of calcification. We use advanced microscopy techniques to determine the nature of coccolith formation and complex crystal formation in coccolithophore life cycle stages. We find that holococcoliths are formed in intracellular compartments in a similar manner to heterococcoliths. However, we show that silicon is not required for holococcolith formation and that the requirement for silicon in certain coccolithophore species relates specifically to the process of crystal morphogenesis in heterococcoliths. We therefore propose an evolutionary scheme in which the lower complexity holococcoliths represent an ancestral form of calcification in coccolithophores. The subsequent recruitment of a silicon-dependent mechanism for crystal morphogenesis in the diploid life cycle stage led to the emergence of the intricately shaped heterococcoliths, enabling the formation of the elaborate coccospheres that underpin the ecological success of coccolithophores

Are Differences in Disability-Free Life Expectancy by Gender, Race, and Education Widening at Older Ages?

To examine change from 1991 to 2001 in disability-free life expectancy in the age range 60-90 by gender, race, and education in the United States. Mortality is estimated over two 10-year follow-up periods for persons in the National Health Interview Surveys of 1986/1987 and 1996/1997. Vital status is ascertained through the National Death Index. Disability prevalence is estimated from the National Health and Nutrition Examination Surveys of 1988-1994 and 1999-2002. Disability is defined as ability to perform four activities of daily living without difficulty. Disability-free life expectancy increased only among white men. Disabled life expectancy increased for all groups-black and white men and women. Racial differences in disability-free life expectancy widened among men; gender differences were reduced among whites. Expansion of socioeconomic differentials in disability-free life at older ages occurred among white men and women and black women. The 1990s was a period where the increased years of life between ages 60 and 90 were concentrated in disabled years for most population groups

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle