A Features Analysis Tool For Assessing And Improving Computational Models In Structural Biology

The protein-folding problem is to predict, from a protein's amino acid sequence, its folded 3D conformation. State of the art computational models are complex collaboratively maintained prediction software. Like other complex software, they become brittle without support for testing and refactoring. Features analysis, a language of `scientific unit testing', is the visual and quantitative comparison of distributions of features (local geometric measures) sampled from ensembles of native and predicted conformations. To support features analysis I develop a features analysis tool--a modular database framework for extracting and managing sampled feature instance and an exploratory data analysis framework for rapidly comparing feature distributions. In supporting features analysis, the tool supports the creation, tuning, and assessment of computational models, improving protein prediction and design. I demonstrate the features analysis tool through 6 case studies with the Rosetta molecular modeling suite. The first three demonstrate the tool usage mechanics through constructing and checking models. The first evaluates bond angle restraint models when used with the Backrub local sampling heuristic. The second identifies and resolves energy function derivative discontinuities that frustrate gradient-based minimization. The third constructs a model for disulfide bonds. The second three demonstrate using the tool to evaluate and improve how models represent molecular structure. I focus on modeling H-bonds because of their geometric specificity and environmental dependence lead to complex feature distributions. The fourth case study develops a novel functional form for Sp2 acceptor H-bonds. The fifth fits parameters for a refined H-bond model. The sixth combines the refined model with an electrostatics model and harmonizes them with the rest of the energy function. Next, to facilitate assessing model improvements, I develop recovery tests that measure predictive accuracy by asking models to recover native conformations that have been partially randomized. Finally, to demonstrate that the features analysis and recovery test tools support improving protein prediction and design, I evaluated the refined H-bond model and electrostatics model with additional corrections from the Rosetta community. Based on positive results, I recommend a new standard energy function, which has been accepted by the Rosetta community as the largest systematic improvement in nearly a decade.Doctor of Philosoph

Genetic evidence further elucidates the history and extent of badger introductions from Great Britain into Ireland

The colonization of Ireland by mammals has been the subject of extensive study using genetic methods and forms a central problem in understanding the phylogeography of European mammals after the Last Glacial Maximum. Ireland exhibits a depauperate mammal fauna relative to Great Britain and continental Europe, and a range of natural and anthropogenic processes have given rise to its modern fauna. Previous Europe-wide surveys of the European badger (Meles meles) have found conflicting microsatellite and mitochondrial DNA evidence in Irish populations, suggesting Irish badgers have arisen from admixture between human imported British and Scandinavian animals. The extent and history of contact between British and Irish badger populations remains unclear. We use comprehensive genetic data from Great Britain and Ireland to demonstrate that badgers in Ireland's northeastern and southeastern counties are genetically similar to contemporary British populations. Simulation analyses suggest this admixed population arose in Ireland 600–700 (CI 100–2600) years before present most likely through introduction of British badgers by people. These findings add to our knowledge of the complex colonization history of Ireland by mammals and the central role of humans in facilitating it

A Highly Magnified Gravitationally Lensed Red QSO at z = 2.5 with a Significant Flux Ratio Anomaly

We present the discovery of a gravitationally lensed dust-reddened QSO at z = 2.517, identified in a survey for QSOs by infrared selection. Hubble Space Telescope imaging reveals a quadruply lensed system in a cusp configuration, with a maximum image separation of ~1.8\arcsec. We find that compared to the central image of the cusp, the neighboring brightest image is anomalous by a factor of ~ 7 - 10, which is the largest flux anomaly measured to date in a lensed QSO. Incorporating high-resolution Jansky Very Large Array radio imaging and sub-mm imaging with the Atacama Large (sub-)Millimetre Array, we conclude that a low-mass perturber is the most likely explanation for the anomaly. The optical through near-infrared spectrum reveals that the QSO is moderately reddened with E(B - V) = 0.7 - 0.9. We see an upturn in the ultraviolet spectrum due to ~ 1% of the intrinsic emission being leaked back into the line of sight, which suggests that the reddening is intrinsic and not due to the lens. The QSO may have an Eddington ratio as high as L/L_Edd ~ 0.2. Consistent with previous red QSO samples, this source exhibits outflows in its spectrum as well as morphological properties suggestive of it being in a merger-driven transitional phase. We find a host-galaxy stellar mass of log M_*/M_Sun = 11.4, which is higher than the local M_BH vs. M_* relation, but consistent with other high redshift QSOs. When de-magnified, this QSO is at the knee of the luminosity function, allowing for the detailed study of a more typical moderate-luminosity infrared-selected QSO at high redshift.Comment: Accepted for publication in ApJ; 29 pages, 18 figures, 8 tables. arXiv admin note: text overlap with arXiv:1807.0543

Understanding the circumgalactic medium is critical for understanding galaxy evolution

Galaxies evolve under the influence of gas flows between their interstellar medium and their surrounding gaseous halos known as the circumgalactic medium (CGM). The CGM is a major reservoir of galactic baryons and metals, and plays a key role in the long cycles of accretion, feedback, and recycling of gas that drive star formation. In order to fully understand the physical processes at work within galaxies, it is therefore essential to have a firm understanding of the composition, structure, kinematics, thermodynamics, and evolution of the CGM. In this white paper we outline connections between the CGM and galactic star formation histories, internal kinematics, chemical evolution, quenching, satellite evolution, dark matter halo occupation, and the reionization of the larger-scale intergalactic medium in light of the advances that will be made on these topics in the 2020s. We argue that, in the next decade, fundamental progress on all of these major issues depends critically on improved empirical characterization and theoretical understanding of the CGM. In particular, we discuss how future advances in spatially-resolved CGM observations at high spectral resolution, broader characterization of the CGM across galaxy mass and redshift, and expected breakthroughs in cosmological hydrodynamic simulations will help resolve these major problems in galaxy evolution.Comment: Astro2020 Decadal Science White Pape

Development of an international standard set of patient-centred outcome measures for overall paediatric health: a consensus process

Objective: To develop an Overall Pediatric Health Standard Set (OPH-SS) of outcome measures that captures what matters to young people and their families and recognising the biopsychosocial aspects of health for all children and adolescents regardless of health condition. Design: A modified Delphi process. Setting: The International Consortium for Health Outcomes Measurement convened an international Working Group (WG) comprised of 23 international experts from 12 countries in the field of paediatrics, family medicine, psychometrics as well as patient advisors. The WG participated in 11 video-conferences, through a modified Delphi process and 9 surveys between March 2018 and January 2020 consensus was reached on a final recommended health outcome standard set. By a literature review conducted in March 2018, 1136 articles were screened for clinician and patient-reported or proxy-reported outcomes. Further, 4315 clinical trials and 12 paediatric health surveys were scanned. Between November 2019 and January 2020, the final standard set was endorsed by a patient validation (n=270

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer