Abstract
In evolving populations where the rate of beneficial mutations is large, subpopulations of individuals with competing beneficial mutations can be maintained over long times. Evolution with ...this kind of clonal structure is commonly observed in a wide range of microbial and viral populations. However, it can be difficult to completely resolve clonal dynamics in data. This is due to limited read lengths in high-throughput sequencing methods, which are often insufficient to directly measure linkage disequilibrium or determine clonal structure. Here, we develop a method to infer clonal structure using correlated allele frequency changes in time-series sequence data. Simulations show that our method recovers true, underlying clonal structures when they are known and accurately estimate linkage disequilibrium. This information can then be combined with other inference methods to improve estimates of the fitness effects of individual mutations. Applications to data suggest novel clonal structures in an E. coli long-term evolution experiment, and yield improved predictions of the effects of mutations on bacterial fitness and antibiotic resistance. Moreover, our method is computationally efficient, requiring orders of magnitude less run time for large data sets than existing methods. Overall, our method provides a powerful tool to infer clonal structures from data sets where only allele frequencies are available, which can also improve downstream analyses.
Viral immune evasion by sequence variation is a major hindrance to HIV-1 vaccine design. To address this challenge, our group has developed a computational model, rooted in physics, that aims to ...predict the fitness landscape of HIV-1 proteins in order to design vaccine immunogens that lead to impaired viral fitness, thus blocking viable escape routes. Here, we advance the computational models to address previous limitations, and directly test model predictions against in vitro fitness measurements of HIV-1 strains containing multiple Gag mutations. We incorporated regularization into the model fitting procedure to address finite sampling. Further, we developed a model that accounts for the specific identity of mutant amino acids (Potts model), generalizing our previous approach (Ising model) that is unable to distinguish between different mutant amino acids. Gag mutation combinations (17 pairs, 1 triple and 25 single mutations within these) predicted to be either harmful to HIV-1 viability or fitness-neutral were introduced into HIV-1 NL4-3 by site-directed mutagenesis and replication capacities of these mutants were assayed in vitro. The predicted and measured fitness of the corresponding mutants for the original Ising model (r = -0.74, p = 3.6×10-6) are strongly correlated, and this was further strengthened in the regularized Ising model (r = -0.83, p = 3.7×10-12). Performance of the Potts model (r = -0.73, p = 9.7×10-9) was similar to that of the Ising model, indicating that the binary approximation is sufficient for capturing fitness effects of common mutants at sites of low amino acid diversity. However, we show that the Potts model is expected to improve predictive power for more variable proteins. Overall, our results support the ability of the computational models to robustly predict the relative fitness of mutant viral strains, and indicate the potential value of this approach for understanding viral immune evasion, and harnessing this knowledge for immunogen design.
Genetic sequences collected over time provide an exciting opportunity to study natural selection. In such studies, it is important to account for linkage disequilibrium to accurately measure ...selection and to distinguish between selection and other effects that can cause changes in allele frequencies, such as genetic hitchhiking or clonal interference. However, most high-throughput sequencing methods cannot directly measure linkage due to short-read lengths. Here we develop a simple method to estimate linkage disequilibrium from time-series allele frequencies. This reconstructed linkage information can then be combined with other inference methods to infer the fitness effects of individual mutations. Simulations show that our approach reliably outperforms inference that ignores linkage disequilibrium and, with sufficient sampling, performs similarly to inference using the true linkage information. We also introduce two regularization methods derived from random matrix theory that help to preserve its performance under limited sampling effects. Overall, our method enables the use of linkage-aware inference methods even for data sets where only allele frequency time series are available.
In the last few years, estimating ground reaction forces by means of wearable sensors has come to be a challenging research topic paving the way to kinetic analysis and sport performance testing ...outside of labs. One possible approach involves estimating the ground reaction forces from kinematic data obtained by inertial measurement units (IMUs) worn by the subject. As estimating kinetic quantities from kinematic data is not an easy task, several models and protocols have been developed over the years. Non-wearable sensors, such as optoelectronic systems along with force platforms, remain the most accurate systems to record motion. In this review, we identified, selected and categorized the methodologies for estimating the ground reaction forces from IMUs as proposed across the years. Scopus, Google Scholar, IEEE Xplore, and PubMed databases were interrogated on the topic of Ground Reaction Forces estimation based on kinematic data obtained by IMUs. The identified papers were classified according to the methodology proposed: (i) methods based on direct modelling; (ii) methods based on machine learning. The methods based on direct modelling were further classified according to the task studied (walking, running, jumping, etc.). Finally, we comparatively examined the methods in order to identify the most reliable approaches for the implementation of a ground reaction force estimator based on IMU data.
The objective assessment of physical activity levels through wearable inertial-based motion detectors for the automatic, continuous and long-term monitoring of people in free-living environments is a ...well-known research area in the literature. However, their application to older adults can present particular constraints. This paper reviews the adoption of wearable devices in senior citizens by describing various researches for monitoring physical activity indicators, such as energy expenditure, posture transitions, activity classification, fall detection and prediction, gait and balance analysis, also by adopting consumer-grade fitness trackers with the associated limitations regarding acceptability. This review also describes and compares existing commercial products encompassing activity trackers tailored for older adults, thus providing a comprehensive outlook of the status of commercially available motion tracking systems. Finally, the impact of wearable devices on life and health insurance companies, with a description of the potential benefits for the industry and the wearables market, was analyzed as an example of the potential emerging market drivers for such technology in the future.
Center of excellence for placenta accreta Silver, Robert M., MD; Fox, Karin A., MD; Barton, John R., MD ...
American journal of obstetrics and gynecology,
05/2015, Letnik:
212, Številka:
5
Journal Article
Recenzirano
Placenta accreta spectrum is one of the most morbid conditions obstetricians will encounter. The incidence has dramatically increased in the last 20 years. The major contributing factor to this is ...believed to be the increase in the rate of cesarean delivery. Despite the increased incidence of placenta accreta, most obstetricians have personally managed only a small number of women with placenta accreta. The condition poses dramatic risk for massive hemorrhage and associated complication such as consumption coagulopathy, multisystem organ failure, and death. In addition, there is an increased risk for surgical complications such as injury to bladder, ureters, and bowel and the need for reoperation. Most women require blood transfusion, often in large quantities, and many require admission to an intensive care unit. As a result of indicated, often emergent preterm delivery, many babies require admission to a neonatal care intensive care unit. Outcomes are improved when delivery is accomplished in centers with multidisciplinary expertise and experience in the care of placenta accreta. Such expertise may include maternal-fetal medicine, gynecologic surgery, gynecologic oncology, vascular, trauma and urologic surgery, transfusion medicine, intensivists, neonatologists, interventional radiologists, anesthesiologists, specialized nursing staff, and ancillary personnel. This article highlights the desired features for a center of excellence in placenta accreta, and which patients should be referred for evaluation and/or delivery in such centers.
The growth hormone secretagogue receptor 1a (GHSR1a) is intriguing because of its potential as a therapeutic target and its diverse molecular interactions. Initial studies of the receptor focused on ...the potential therapeutic ability for growth hormone (GH) release to reduce wasting in aging individuals, as well as food intake regulation for treatment of cachexia. Known roles of GHSR1a now extend to regulation of neurogenesis, learning and memory, gastrointestinal motility, glucose/lipid metabolism, the cardiovascular system, neuronal protection, motivational salience, and hedonic feeding. Ghrelin, the endogenous agonist of GHSR1a, is primarily located in the stomach and is absent from the central nervous system (CNS), including the spinal cord. However, ghrelin in the circulation does have access to a small number of CNS sites, including the arcuate nucleus, which is important in feeding control. At some sites, such as at somatotrophs, GHSR1a has high constitutive activity. Typically, ghrelin‐dependent and constitutive GHSR1a activation occurs via Gαq/11 pathways. In vitro and in vivo data suggest that GHSR1a heterodimerises with multiple G protein‐coupled receptors (GPCRs), including dopamine D1 and D2, serotonin 2C, orexin, oxytocin and melanocortin 3 receptors (MCR3), as well as the MCR3 accessory protein, MRAP2, providing possible mechanisms for its many physiological effects. In all cases, the receptor interaction changes downstream signalling and the responses to receptor agonists. This review discusses the signalling mechanisms of GHSR1a alone and in combination with other GPCRs, and explores the physiological consequences of GHSR1a coupling with other GPCRs.
In this review, we critically assess what is presently known about interactions between GHSR1a and other G protein‐coupled receptors, both physiologically and in transfected cell systems. We synthesise models for how these interactions impact on cellular signalling pathways and responses. Where the data support it, we highlight how this may play out in a physiological setting.
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present ...in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K, and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations and combinations found in new SARS-CoV-2 Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P1) variants. Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations enhance transmission primarily by enhancing binding, the K417N/T mutations facilitate immune escape, and the E484K mutation enhances binding and immune escape.
Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the ...evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.
The Evolution of the Trade Regimeoffers a comprehensive political-economic history of the development of the world's multilateral trade institutions, the General Agreement on Tariffs and Trade (GATT) ...and its successor, the World Trade Organization (WTO). While other books confine themselves to describing contemporary GATT/WTO legal rules or analyzing their economic logic, this is the first to explain the logic and development behind these rules.
The book begins by examining the institutions' rules, principles, practices, and norms from their genesis in the early postwar period to the present. It evaluates the extent to which changes in these institutional attributes have helped maintain or rebuild domestic constituencies for open markets.
The book considers these questions by looking at the political, legal, and economic foundations of the trade regime from many angles. The authors conclude that throughout most of GATT/WTO history, power politics fundamentally shaped the creation and evolution of the GATT/WTO system. Yet in recent years, many aspects of the trade regime have failed to keep pace with shifts in underlying material interests and ideas, and the challenges presented by expanding membership and preferential trade agreements.
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