Temporal and phylogenetic evolution of the sauropod dinosaur body plan

The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to date, there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here, we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton : body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass (CoM) in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad CoM shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic–Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and CoM position are not strongly correlated with inferred feeding habits. Instead the craniad CoM positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous

Temporal and phylogenetic evolution of the sauropod dinosaur body plan

The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to-date there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton:body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad centre-of-mass shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic–Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and center-of-mass position are not strongly correlated with inferred feeding habits. Instead the craniad center-of-mass positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous

A ‘quiet revolution’? The impact of Training Schools on initial teacher training partnerships

This paper discusses the impact on initial teacher training of a new policy initiative in England: the introduction of Training Schools. First, the Training School project is set in context by exploring the evolution of a partnership approach to initial teacher training in England. Ways in which Training Schools represent a break with established practice are considered together with their implications for the dominant mode of partnership led by higher education institutions (HEIs). The capacity of Training Schools to achieve their own policy objectives is examined, especially their efficacy as a strategy for managing innovation and the dissemination of innovation. The paper ends by focusing on a particular Training School project which has adopted an unusual approach to its work and enquires whether this alternative approach could offer a more profitable way forward. During the course of the paper, five different models of partnership are considered: collaborative, complementary, HEI-led, school-led and partnership within a partnership

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482

Rossby wave dynamics of the North Pacific extra-tropical response to El Niño: importance of the basic state in coupled GCMs

The extra-tropical response to El Nino in a "low" horizontal resolution coupled climate model, typical of the Intergovernmental Panel on Climate Change fourth assessment report simulations, is shown to have serious systematic errors. A high resolution configuration of the same model has a much improved response that is similar to observations. The errors in the low resolution model are traced to an incorrect representation of the atmospheric teleconnection mechanism that controls the extra-tropical sea surface temperatures (SSTs) during El Nino. This is due to an unrealistic atmospheric mean state, which changes the propagation characteristics of Rossby waves. These erroneous upper tropospheric circulation anomalies then induce erroneous surface circulation features over the North Pacific. The associated surface wind speed and direction errors create erroneous surface flux and upwelling anomalies which finally lead to the incorrect extra-tropical SST response to El Nino in the low resolution model. This highlights the sensitivity of the climate response to a single link in a chain of complex climatic processes. The correct representation of these processes in the high resolution model indicates the importance of horizontal resolution in resolving such processes

Networks link antigenic and receptor-binding sites of influenza hemagglutinin: Mechanistic insight into fitter strain propagation

Influenza viral passaging through pre-vaccinated mice shows that emergent antigenic site mutations on the viral hemagglutinin (HA) impact host receptor-binding affinity and, therefore, the evolution of fitter influenza strains. To understand this phenomenon, we computed the Significant Interactions Network (SIN) for each residue and mapped the networks of antigenic site residues on a representative H1N1 HA. Specific antigenic site residues are ‘linked’ to receptor-binding site (RBS) residues via their SIN and mutations within “RBS-linked” antigenic residues can significantly influence receptor-binding affinity by impacting the SIN of key RBS residues. In contrast, other antigenic site residues do not have such “RBS-links” and do not impact receptor-binding affinity upon mutation. Thus, a potential mechanism emerges for how immunologic pressure on RBS-linked antigenic residues can contribute to evolution of fitter influenza strains by modulating the host receptor-binding affinity

Rule-based knowledge aggregation for large-scale protein sequence analysis of influenza A viruses

Background: The explosive growth of biological data provides opportunities for new statistical and comparative analyses of large information sets, such as alignments comprising tens of thousands of sequences. In such studies, sequence annotations frequently play an essential role, and reliable results depend on metadata quality. However, the semantic heterogeneity and annotation inconsistencies in biological databases greatly increase the complexity of aggregating and cleaning metadata. Manual curation of datasets, traditionally favoured by life scientists, is impractical for studies involving thousands of records. In this study, we investigate quality issues that affect major public databases, and quantify the effectiveness of an automated metadata extraction approach that combines structural and semantic rules. We applied this approach to more than 90,000 influenza A records, to annotate sequences with protein name, virus subtype, isolate, host, geographic origin, and year of isolation. Results: Over 40,000 annotated Influenza A protein sequences were collected by combining information from more than 90,000 documents from NCBI public databases. Metadata values were automatically extracted, aggregated and reconciled from several document fields by applying user-defined structural rules. For each property, values were recovered from ≥88.8% of records, with accuracy exceeding 96% in most cases. Because of semantic heterogeneity, each property required up to six different structural rules to be combined. Significant quality differences between databases were found: GenBank documents yield values more reliably than documents extracted from GenPept. Using a simple set of semantic rules and a reasoner, we reconstructed relationships between sequences from the same isolate, thus identifying 7640 isolates. Validation of isolate metadata against a simple ontology highlighted more than 400 inconsistencies, leading to over 3,000 property value corrections. Conclusion: To overcome the quality issues inherent in public databases, automated knowledge aggregation with embedded intelligence is needed for large-scale analyses. Our results show that user-controlled intuitive approaches, based on combination of simple rules, can reliably automate various curation tasks, reducing the need for manual corrections to approximately 5% of the records. Emerging semantic technologies possess desirable features to support today's knowledge aggregation tasks, with a potential to bring immediate benefits to this field

Dizziness reported by elderly patients in family practice: prevalence, incidence, and clinical characteristics

Background: Although dizziness in elderly patients is very common in family practice, most prevalence studies on dizziness are community-based and include a study population that is not representative of family practice. The aim of this study was to investigate the prevalence and incidence of dizziness reported by elderly patients in family practice, to describe their final diagnoses as recorded by the family physician, and to compare the clinical characteristics of dizzy patients with those of non-dizzy patients. Methods: Data were obtained from the Second Dutch National Survey of General Practice, a prospective registration study which took place over a 12-month period in 2001. We developed a search strategy consisting of 15 truncated search terms (based on Dutch synonyms for dizziness), and identified all patients aged 65 or older who visited their family physician because of dizziness (N=3,990). We used the mid-time population as denominator to calculate the prevalence and incidence, and for group comparisons we used the Student's t and Chi-square test, and logistic regression analysis. Results: The one-year prevalence of dizziness in family practice in patients aged 65 or older was 8.3%, it was higher in women than in men, and it increased with age. In patients aged 85 or older the prevalence was similar for men and women. The incidence of dizziness was 47.1 per 1000 person-years. For 39% of the dizzy patients the family physicians did not specify a diagnosis, and recorded a symptom diagnosis as the final diagnosis. Living alone, lower level of education, pre-existing cerebrovascular disease, and pre-existing hypertension were independently associated with dizziness. Conclusions: Dizziness in family practice patients increases with age. It is more common in women than in men, but this gender difference disappears in the very old. Because a large proportion of dizzy elderly patients in family practice remains undiagnosed, it would be worthwhile to carry out more diagnostic research on dizziness in a family practice setting