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.
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.
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.
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.
Wrist-worn activity trackers have experienced a tremendous growth lately and studies on the accuracy of mainstream trackers used by older adults are needed. This study explores the performance of six ...trackers (Fitbit Charge2, Garmin VivoSmart HR+, Philips Health Watch, Withings Pulse Ox, ActiGraph GT9X-BT, Omron HJ-72OITC) for estimating: steps, travelled distance, and heart-rate measurements for a cohort of older adults. Eighteen older adults completed a structured protocol involving walking tasks, simulated household activities, and sedentary activities. Less standardized activities were also included, such as: dusting, using a walking aid, or playing cards, in order to simulate real-life scenarios. Wrist-mounted and chest/waist-mounted devices were used. Gold-standards included treadmill, ECG-based chest strap, direct observation or video recording according to the activity and parameter. Every tracker showed a decreasing accuracy with slower walking speed, which resulted in a significant step under-counting. A large mean absolute percentage error (MAPE) was found for every monitor at slower walking speeds with the lowest reported MAPE at 2 km/h being 7.78%, increasing to 20.88% at 1.5 km/h, and 44.53% at 1 km/h. During household activities, the MAPE climbing up/down-stairs ranged from 8.38-19.3% and 10.06-19.01% (dominant and non-dominant arm), respectively. Waist-worn devices showed a more uniform performance. However, unstructured activities (e.g. dusting, playing cards), and using a walking aid represent a challenge for all wrist-worn trackers as evidenced by large MAPE (> 57.66% for dusting, > 67.32% when using a walking aid). Poor performance in travelled distance estimation was also evident during walking at low speeds and climbing up/down-stairs (MAPE > 71.44% and > 48.3%, respectively). Regarding heart-rate measurement, there was no significant difference (p-values > 0.05) in accuracy between trackers placed on the dominant or non-dominant arm. Concordant with existing literature, while the mean error was limited (between -3.57 bpm and 4.21 bpm), a single heart-rate measurement could be underestimated up to 30 beats-per-minute. This study showed a number of limitations of consumer-level wrist-based activity trackers for older adults. Therefore caution is required when used, in healthcare or in research settings, to measure activity in older adults.
The innate immune system is the body's first line of defense against infection. Natural killer (NK) cells, a vital part of the innate immune system, help to control infection and eliminate cancer. ...Studies have identified a vast array of receptors that NK cells use to discriminate between healthy and unhealthy cells. However, at present, it is difficult to explain how NK cells will respond to novel stimuli in different environments. In addition, the expression of different receptors on individual NK cells is highly stochastic, but the reason for these variegated expression patterns is unclear. Here, we studied the recognition of unhealthy target cells as an inference problem, where NK cells must distinguish between healthy targets with normal variability in ligand expression and ones that are clear "outliers." Our mathematical model fits well with experimental data, including NK cells' adaptation to changing environments and responses to different target cells. Furthermore, we find that stochastic, "sparse" receptor expression profiles are best able to detect a variety of possible threats, in agreement with experimental studies of the NK cell repertoire. While our study was specifically motivated by NK cells, our model is general and could also apply more broadly to explain principles of target recognition for other immune cell types.
Nonaqueous redox flow batteries (NAqRFBs) that utilize redox active organic molecules are an emerging energy storage concept with the possibility of meeting grid storage requirements. Sporadic and ...uneven advances in molecular discovery and development, however, have stymied efforts to quantify the performance characteristics of nonaqueous redox electrolytes and flow cells. A need exists for archetypal redox couples, with well-defined electrochemical properties, high solubility in relevant electrolytes, and broad availability, to serve as probe molecules. This work investigates the 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl (AcNH-TEMPO) redox pair for such an application. We report the physicochemical and electrochemical properties of the reduced and oxidized compounds at dilute concentrations for electroanalysis, as well as moderate-to-high concentrations for RFB applications. Changes in conductivity, viscosity, and UV–vis absorbance as a function of state-of-charge are quantified. Cyclic voltammetry investigates the redox potential, reversibility, and diffusion coefficients of dilute solutions, while symmetric flow cell cycling determines the stability of the AcNH-TEMPO redox pair over long experiment times. Finally, single electrolyte flow cell studies demonstrate the utility of this redox couple as a platform chemistry for benchmarking NAqRFB performance.
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•AcNH-TEMPO serves as a redox couple for nonaqueous flow cell diagnostics.•State-of-charge dependent physicochemical properties are quantified.•Electrochemical properties and cycle stability of AcNH-TEMPO are determined.•AcNH-TEMPO-based electrolytes used to study nonaqueous flow cell resistance.
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.
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