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"Williams, H."
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Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms
Abstract
Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign—an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii) 600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)]; subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly 50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the specific primary hypertension subgroups are feasible.
Journal Article
Evaluating Presence-Absence Models in Ecology: The Need to Account for Prevalence
1. Models for predicting the distribution of organisms from environmental data are widespread in ecology and conservation biology. Their performance is invariably evaluated from the percentage success at predicting occurrence at test locations. 2. Using logistic regression with real data from 34 families of aquatic invertebrates in 180 Himalayan streams, we illustrate how this widespread measure of predictive accuracy is affected systematically by the prevalence (i.e. the frequency of occurrence) of the target organism. Many evaluations of presence-absence models by ecologists are inherently misleading. 3. With the same invertebrate models, we examined alternative performance measures used in remote sensing and medical diagnostics. We particularly explored receiver-operating characteristic (ROC) plots, from which were derived (i) the area under each curve (AUC), considered an effective indicator of model performance independent of the threshold probability at which the presence of the target organism is accepted, and (ii) optimized probability thresholds that maximize the percentage of true absences and presences that are correctly identified. We also evaluated Cohen's kappa, a measure of the proportion of all possible cases of presence or absence that are predicted correctly after accounting for chance effects. 4. AUC measures from ROC plots were independent of prevalence, but highly significantly correlated with the much more easily computed kappa. Moreover, when applied in predictive mode to test data, models with thresholds optimized by ROC erroneously overestimated true occurrence among scarcer organisms, often those of greatest conservation interest. We advocate caution in using ROC methods to optimize thresholds required for real prediction. 5. Our strongest recommendation is that ecologists reduce their reliance on prediction success as a performance measure in presence-absence modelling. Cohen's kappa provides a simple, effective, standardized and appropriate statistic for evaluating or comparing presence-absence models, even those based on different statistical algorithms. None of the performance measures we examined tests the statistical significance of predictive accuracy, and we identify this as a priority area for research and development.
Journal Article
(Re)constructing memory : school textbooks and the imagination of the nation
This book examines the shifting portrayal of the nation in school textbooks in 14 countries during periods of rapid political, social, and economic change. Drawing on a range of analytic strategies, the authors examine history and civics textbooks, and the teaching of such texts, along with other prominent curricular materials--children's readers, a required text penned by the head of state, a holocaust curriculum, etc. The authors analyze the uses of history and pedagogy in building, reinforcing and/or redefining the nation and state especially in the light of challenges to its legitimacy. The primary focus is on countries in developing or transitional contexts. Issues include the teaching of democratic civics in a multiethnic state with little history of democratic governance; shifts in teaching about the Khmer Rouge in post-conflict Cambodia; children's readers used to define national space in former republics of the Soviet Union; the development of Holocaust education in a context where citizens were both victims and perpetuators of violence; the creation of a national past in Turkmenistan; and so forth.
Book
Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage
The hollow cavities of coordination cages can provide an environment for enzyme-like catalytic reactions of small-molecule guests. Here, we report a new example (catalysis of the Kemp elimination reaction of benzisoxazole with hydroxide to form 2-cyanophenolate) in the cavity of a water-soluble M
8
L
12
coordination cage, with two features of particular interest. First, the rate enhancement is among the largest observed to date: at pD 8.5, the value of
k
cat
/
k
uncat
is 2 × 10
5
, due to the accumulation of a high concentration of partially desolvated hydroxide ions around the bound guest arising from ion-pairing with the 16+ cage. Second, the catalysis is based on two orthogonal interactions: (1) hydrophobic binding of benzisoxazole in the cavity and (2) polar binding of hydroxide ions to sites on the cage surface, both of which were established by competition experiments.
The Kemp elimination has been catalysed in the cavity of a coordination cage with a rate enhancement (
k
cat
/
k
uncat
) of 200,000 at pD 8.5. The catalysis requires two orthogonal interactions to bring together the components: hydrophobic binding of benzisoxazole, and accumulation of hydroxide ions at the cationic cage surface by ion-pairing.
Journal Article
Unusual biology across a group comprising more than 15% of domain Bacteria
More than 15% of the bacterial domain consists of a radiation of phyla about which very little is known; here, metagenomics is used to reconstruct 8 complete and 789 draft genomes from more than 35 of these phyla, revealing a shared evolutionary history, metabolic limitations, and unusual ribosome compositions.
Knowing unknown bacteria
More than 15% of all bacteria are members of a radiation of phyla about which very little is known, and from which no members have been cultivated. Jillian Banfield and colleagues have used metagenomics to reconstruct 8 complete and 789 draft genomes from more than 35 of these phyla obtained from groundwater samples from an aquifer adjacent to the Colorado River. The data reveal a shared evolutionary history that leads the authors to group these phyla under the name candidate phyla radiation (CPR) as a subdivision within domain Bacteria. Characteristics of the CPR bacteria include small genomes lacking many biosynthetic pathways, self-splicing introns and proteins encoded within their rRNA genes, as well as an unusual ribosome composition, lacking proteins previously considered universal in all bacteria. CPR bacteria are likely to be obligate fermenters dependent on other organisms for survival.
A prominent feature of the bacterial domain is a radiation of major lineages that are defined as candidate phyla because they lack isolated representatives. Bacteria from these phyla occur in diverse environments
1
and are thought to mediate carbon and hydrogen cycles
2
. Genomic analyses of a few representatives suggested that metabolic limitations have prevented their cultivation
2
,
3
,
4
,
5
,
6
. Here we reconstructed 8 complete and 789 draft genomes from bacteria representing >35 phyla and documented features that consistently distinguish these organisms from other bacteria. We infer that this group, which may comprise >15% of the bacterial domain, has shared evolutionary history, and describe it as the candidate phyla radiation (CPR). All CPR genomes are small and most lack numerous biosynthetic pathways. Owing to divergent 16S ribosomal RNA (rRNA) gene sequences, 50–100% of organisms sampled from specific phyla would evade detection in typical cultivation-independent surveys. CPR organisms often have self-splicing introns and proteins encoded within their rRNA genes, a feature rarely reported in bacteria. Furthermore, they have unusual ribosome compositions. All are missing a ribosomal protein often absent in symbionts, and specific lineages are missing ribosomal proteins and biogenesis factors considered universal in bacteria. This implies different ribosome structures and biogenesis mechanisms, and underlines unusual biology across a large part of the bacterial domain.
Journal Article
Shared decision-making around anal cancer screening among black bisexual and gay men in the USA
Shared decision-making is a strategy to achieve health equity by strengthening patient-provider relationships and improve health outcomes. There is a paucity of research examining these factors among patients who identify as sexual or gender minorities and racial/ethnic minorities. Through intrapersonal, interpersonal and societal lenses, this project evaluates the relationship between intersectionality and shared decision-making around anal cancer screening in Black gay and bisexual men, given their disproportionate rates of anal cancer. Thirty semi-structured, one-on-one interviews and two focus groups were conducted during 2016-2017. Participants were asked open-ended questions regarding intersectionality, relationships with healthcare providers and making shared decisions about anal cancer screening. Forty-five individuals participated - 30 in individual interviews and 15 in focus groups. All participants identified as Black and male; 13 identified as bisexual and 32 as gay. Analysis revealed that the interaction of internalised racism, biphobia/homophobia, provider bias and medical apartheid led to reduced healthcare engagement and discomfort with discussing sexual practices, potentially hindering patients from engaging in shared decision-making. Non-judgemental healthcare settings and provider relationships in which patients communicate openly about each aspect of their identity will promote effective shared decision-making about anal cancer screening, and thus potentially impact downstream anal cancer rates.
Journal Article