Bayesian molecular dating: opening up the black box Bromham, Lindell; Duchêne, Sebastián; Hua, Xia ...
Biological reviews of the Cambridge Philosophical Society,
20/May , Volume:
93, Issue:
2
Journal Article
Peer reviewed
Open access
ABSTRACT
Molecular dating analyses allow evolutionary timescales to be estimated from genetic data, offering an unprecedented capacity for investigating the evolutionary past of all species. These ...methods require us to make assumptions about the relationship between genetic change and evolutionary time, often referred to as a ‘molecular clock’. Although initially regarded with scepticism, molecular dating has now been adopted in many areas of biology. This broad uptake has been due partly to the development of Bayesian methods that allow complex aspects of molecular evolution, such as variation in rates of change across lineages, to be taken into account. But in order to do this, Bayesian dating methods rely on a range of assumptions about the evolutionary process, which vary in their degree of biological realism and empirical support. These assumptions can have substantial impacts on the estimates produced by molecular dating analyses. The aim of this review is to open the ‘black box’ of Bayesian molecular dating and have a look at the machinery inside. We explain the components of these dating methods, the important decisions that researchers must make in their analyses, and the factors that need to be considered when interpreting results. We illustrate the effects that the choices of different models and priors can have on the outcome of the analysis, and suggest ways to explore these impacts. We describe some major research directions that may improve the reliability of Bayesian dating. The goal of our review is to help researchers to make informed choices when using Bayesian phylogenetic methods to estimate evolutionary rates and timescales.
A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We ...evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.
This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.
Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 0·6% of 4440 in the ChAdOx1 nCoV-19 group vs71 1·6% of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three 0·2% of 1367 vs 30 2·2% of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 0·5% of 5807 vs 101 1·7% of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.
ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.
UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses ...given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.
We present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005).
Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4–74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3–85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio GMR 0·66 95% CI 0·59–0·74). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% 95% CI 60·3–91·2 at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% 33·0–69·9 at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18–55 years (GMR 2·32 2·01–2·68).
The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.
UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D’Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
Imposing an external periodic electrostatic potential to the electrons confined in a quantum well makes it possible to engineer synthetic two-dimensional band structures, with electronic properties ...different from those in the host semiconductor. Here we report the fabrication and study of a tunable triangular artificial lattice on a GaAs/AlGaAs heterostructure where it is possible to transform from the original GaAs band structure and a circular Fermi surface to a new band structure with multiple artificial Fermi surfaces simply by altering a gate bias. For weak electrostatic modulation magnetotransport measurements reveal multiple quantum oscillations and commensurability oscillations due to the electron scattering from the artificial lattice. Increasing the strength of the modulation reveals new commensurability oscillations of the electrons from the artificial Fermi surface scattering from the triangular artificial lattice. These results show that low disorder gate-tunable lateral superlattices can be used to form artificial two-dimensional crystals with designer electronic properties.
Self-assembled quantum dots comprise a versatile system with which to study quantum effects in the solid state. Many devices have been developed that demonstrate controlled charging of a quantum dot, ...Rabi oscillations, coherent spin control and electrically injected non-classical photon emission. Often referred to as 'artificial atoms', quantum dots have discrete energy levels, making them a viable candidate for encoding qubits. However, unlike single atoms, no two quantum dots are alike. This is a complication for quantum-information applications that require qubits initialized in the same state and interactions between remote systems mediated by indistinguishable photons. We report that truly remote, independent, quantum dots can be tuned to the same energy using large applied electric fields. This allows two-photon interference of their emission under coincidence gating and opens up the possibility of transferring quantum information between remote solid-state sources.
Electrically defined semiconductor quantum dots are attractive systems for spin manipulation and quantum information processing. Heavy-holes in both Si and GaAs are promising candidates for ...all-electrical spin manipulation, owing to the weak hyperfine interaction and strong spin-orbit interaction. However, it has only recently become possible to make stable quantum dots in these systems, mainly due to difficulties in device fabrication and stability. Here, we present electrical transport measurements on holes in a gate-defined double quantum dot in a GaAs/Al x Ga1–x As heterostructure. We observe clear Pauli spin blockade and demonstrate that the lifting of this spin blockade by an external magnetic field is highly anisotropic. Numerical calculations of heavy-hole transport through a double quantum dot in the presence of strong spin-orbit coupling show quantitative agreement with experimental results and suggest that the observed anisotropy can be explained by both the anisotropic effective hole g-factor and the surface Dresselhaus spin-orbit interaction.
Recognizing an object takes just a fraction of a second, less than the blink of an eye. Applying multivariate pattern analysis, or "brain decoding", methods to magnetoencephalography (MEG) data has ...allowed researchers to characterize, in high temporal resolution, the emerging representation of object categories that underlie our capacity for rapid recognition. Shortly after stimulus onset, object exemplars cluster by category in a high-dimensional activation space in the brain. In this emerging activation space, the decodability of exemplar category varies over time, reflecting the brain's transformation of visual inputs into coherent category representations. How do these emerging representations relate to categorization behavior? Recently it has been proposed that the distance of an exemplar representation from a categorical boundary in an activation space is critical for perceptual decision-making, and that reaction times should therefore correlate with distance from the boundary. The predictions of this distance hypothesis have been born out in human inferior temporal cortex (IT), an area of the brain crucial for the representation of object categories. When viewed in the context of a time varying neural signal, the optimal time to "read out" category information is when category representations in the brain are most decodable. Here, we show that the distance from a decision boundary through activation space, as measured using MEG decoding methods, correlates with reaction times for visual categorization during the period of peak decodability. Our results suggest that the brain begins to read out information about exemplar category at the optimal time for use in choice behaviour, and support the hypothesis that the structure of the representation for objects in the visual system is partially constitutive of the decision process in recognition.
Summary Background Malignant pleural mesothelioma incidence continues to rise, with few available evidence-based therapeutic options. Results of previous non-randomised studies suggested that ...video-assisted thoracoscopic partial pleurectomy (VAT-PP) might improve symptom control and survival. We aimed to compare efficacy in terms of overall survival, and cost, of VAT-PP and talc pleurodesis in patients with malignant pleural mesothelioma. Methods We undertook an open-label, parallel-group, randomised, controlled trial in patients aged 18 years or older with any subtype of confirmed or suspected mesothelioma with pleural effusion, recruited from 12 hospitals in the UK. Eligible patients were randomly assigned (1:1) to either VAT-PP or talc pleurodesis by computer-generated random numbers, stratified by European Organisation for Research and Treatment of Cancer risk category (high vs low). The primary outcome was overall survival at 1 year, analysed by intention to treat (all patients randomly assigned to a treatment group with a final diagnosis of mesothelioma). This trial is registered with ClinicalTrials.gov , number NCT00821860. Findings Between Oct 24, 2003, and Jan 24, 2012, we randomly assigned 196 patients, of whom 175 (88 assigned to talc pleurodesis, 87 assigned to VAT-PP) had confirmed mesothelioma. Overall survival at 1 year was 52% (95% CI 41–62) in the VAT-PP group and 57% (46–66) in the talc pleurodesis group (hazard ratio 1·04 95% CI 0·76–1·42; p=0·81). Surgical complications were significantly more common after VAT-PP than after talc pleurodesis, occurring in 24 (31%) of 78 patients who completed VAT-PP versus ten (14%) of 73 patients who completed talc pleurodesis (p=0·019), as were respiratory complications (19 24% vs 11 15%; p=0·22) and air-leak beyond 10 days (five 6% vs one 1%; p=0·21), although not significantly so. Median hospital stay was longer at 7 days (IQR 5–11) in patients who received VAT-PP compared with 3 days (2–5) for those who received talc pleurodesis (p<0·0001). Interpretation VAT-PP is not recommended to improve overall survival in patients with pleural effusion due to malignant pleural mesothelioma, and talc pleurodesis might be preferable considering the fewer complications and shorter hospital stay associated with this treatment. Funding BUPA Foundation.
Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current ...lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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•TGF-β is an osteocyte-intrinsic regulator of perilacunar/canalicular remodeling (PLR)•Osteocytes actively maintain bone quality through regulated control of PLR•Osteocytic PLR is the cellular mechanism by which TGF-β controls bone quality•Defects in PLR cause severe bone fragility, even when bone mass is normal
Resistance to fracture requires healthy bone mass and quality. However, the cellular mechanisms regulating bone quality are unclear. Dole et al. show that osteocyte-intrinsic TGF-β signaling maintains bone quality through perilacunar/canalicular remodeling. Thus, osteocytes mediate perilacunar/canalicular remodeling and osteoclast-directed remodeling to cooperatively maintain bone quality and mass and prevent fragility.
Many bacterial pathogens rely on a conserved membrane histidine sensor kinase, QseC, to respond to host adrenergic signaling molecules and bacterial signals in order to promote the expression of ...virulence factors. Using a high-throughput screen, we identified a small molecule, LED209, that inhibits the binding of signals to QseC, preventing its autophosphorylation and consequently inhibiting QseC-mediated activation of virulence gene expression. LED209 is not toxic and does not inhibit pathogen growth; however, this compound markedly inhibits the virulence of several pathogens in vitro and in vivo in animals. Inhibition of signaling offers a strategy for the development of broad-spectrum antimicrobial drugs.
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