Browsing by Subject "Models, Biological"
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Item Open Access A Bayesian Approach to Inferring Rates of Selfing and Locus-Specific Mutation.(Genetics, 2015-11) Redelings, Benjamin D; Kumagai, Seiji; Tatarenkov, Andrey; Wang, Liuyang; Sakai, Ann K; Weller, Stephen G; Culley, Theresa M; Avise, John C; Uyenoyama, Marcy KWe present a Bayesian method for characterizing the mating system of populations reproducing through a mixture of self-fertilization and random outcrossing. Our method uses patterns of genetic variation across the genome as a basis for inference about reproduction under pure hermaphroditism, gynodioecy, and a model developed to describe the self-fertilizing killifish Kryptolebias marmoratus. We extend the standard coalescence model to accommodate these mating systems, accounting explicitly for multilocus identity disequilibrium, inbreeding depression, and variation in fertility among mating types. We incorporate the Ewens sampling formula (ESF) under the infinite-alleles model of mutation to obtain a novel expression for the likelihood of mating system parameters. Our Markov chain Monte Carlo (MCMC) algorithm assigns locus-specific mutation rates, drawn from a common mutation rate distribution that is itself estimated from the data using a Dirichlet process prior model. Our sampler is designed to accommodate additional information, including observations pertaining to the sex ratio, the intensity of inbreeding depression, and other aspects of reproduction. It can provide joint posterior distributions for the population-wide proportion of uniparental individuals, locus-specific mutation rates, and the number of generations since the most recent outcrossing event for each sampled individual. Further, estimation of all basic parameters of a given model permits estimation of functions of those parameters, including the proportion of the gene pool contributed by each sex and relative effective numbers.Item Open Access A Bidomain Model for Lens Microcirculation.(Biophysical journal, 2019-03) Zhu, Yi; Xu, Shixin; Eisenberg, Robert S; Huang, HuaxiongThere exists a large body of research on the lens of the mammalian eye over the past several decades. The objective of this work is to provide a link between the most recent computational models and some of the pioneering work in the 1970s and 80s. We introduce a general nonelectroneutral model to study the microcirculation in the lens of the eye. It describes the steady-state relationships among ion fluxes, between water flow and electric field inside cells, and in the narrow extracellular spaces between cells in the lens. Using asymptotic analysis, we derive a simplified model based on physiological data and compare our results with those in the literature. We show that our simplified model can be reduced further to the first-generation models, whereas our full model is consistent with the most recent computational models. In addition, our simplified model captures in its equations the main features of the full computational models. Our results serve as a useful link intermediate between the computational models and the first-generation analytical models. Simplified models of this sort may be particularly helpful as the roles of similar osmotic pumps of microcirculation are examined in other tissues with narrow extracellular spaces, such as cardiac and skeletal muscle, liver, kidney, epithelia in general, and the narrow extracellular spaces of the central nervous system, the "brain." Simplified models may reveal the general functional plan of these systems before full computational models become feasible and specific.Item Open Access A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice.(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014-05) Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, NicolasMechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions.Item Open Access A Logical Model of Homology for Comparative Biology.(Systematic biology, 2020-03) Mabee, Paula M; Balhoff, James P; Dahdul, Wasila M; Lapp, Hilmar; Mungall, Christopher J; Vision, Todd JThere is a growing body of research on the evolution of anatomy in a wide variety of organisms. Discoveries in this field could be greatly accelerated by computational methods and resources that enable these findings to be compared across different studies and different organisms and linked with the genes responsible for anatomical modifications. Homology is a key concept in comparative anatomy; two important types are historical homology (the similarity of organisms due to common ancestry) and serial homology (the similarity of repeated structures within an organism). We explored how to most effectively represent historical and serial homology across anatomical structures to facilitate computational reasoning. We assembled a collection of homology assertions from the literature with a set of taxon phenotypes for the skeletal elements of vertebrate fins and limbs from the Phenoscape Knowledgebase. Using seven competency questions, we evaluated the reasoning ramifications of two logical models: the Reciprocal Existential Axioms (REA) homology model and the Ancestral Value Axioms (AVA) homology model. The AVA model returned all user-expected results in addition to the search term and any of its subclasses. The AVA model also returns any superclass of the query term in which a homology relationship has been asserted. The REA model returned the user-expected results for five out of seven queries. We identify some challenges of implementing complete homology queries due to limitations of OWL reasoning. This work lays the foundation for homology reasoning to be incorporated into other ontology-based tools, such as those that enable synthetic supermatrix construction and candidate gene discovery. [Homology; ontology; anatomy; morphology; evolution; knowledgebase; phenoscape.].Item Open Access A new fully automated approach for aligning and comparing shapes.(Anatomical record (Hoboken, N.J. : 2007), 2015-01) Boyer, Doug M; Puente, Jesus; Gladman, Justin T; Glynn, Chris; Mukherjee, Sayan; Yapuncich, Gabriel S; Daubechies, IngridThree-dimensional geometric morphometric (3DGM) methods for placing landmarks on digitized bones have become increasingly sophisticated in the last 20 years, including greater degrees of automation. One aspect shared by all 3DGM methods is that the researcher must designate initial landmarks. Thus, researcher interpretations of homology and correspondence are required for and influence representations of shape. We present an algorithm allowing fully automatic placement of correspondence points on samples of 3D digital models representing bones of different individuals/species, which can then be input into standard 3DGM software and analyzed with dimension reduction techniques. We test this algorithm against several samples, primarily a dataset of 106 primate calcanei represented by 1,024 correspondence points per bone. Results of our automated analysis of these samples are compared to a published study using a traditional 3DGM approach with 27 landmarks on each bone. Data were analyzed with morphologika(2.5) and PAST. Our analyses returned strong correlations between principal component scores, similar variance partitioning among components, and similarities between the shape spaces generated by the automatic and traditional methods. While cluster analyses of both automatically generated and traditional datasets produced broadly similar patterns, there were also differences. Overall these results suggest to us that automatic quantifications can lead to shape spaces that are as meaningful as those based on observer landmarks, thereby presenting potential to save time in data collection, increase completeness of morphological quantification, eliminate observer error, and allow comparisons of shape diversity between different types of bones. We provide an R package for implementing this analysis.Item Open Access A noisy linear map underlies oscillations in cell size and gene expression in bacteria.(Nature, 2015-07-16) Tanouchi, Yu; Pai, Anand; Park, Heungwon; Huang, Shuqiang; Stamatov, Rumen; Buchler, Nicolas E; You, LingchongDuring bacterial growth, a cell approximately doubles in size before division, after which it splits into two daughter cells. This process is subjected to the inherent perturbations of cellular noise and thus requires regulation for cell-size homeostasis. The mechanisms underlying the control and dynamics of cell size remain poorly understood owing to the difficulty in sizing individual bacteria over long periods of time in a high-throughput manner. Here we measure and analyse long-term, single-cell growth and division across different Escherichia coli strains and growth conditions. We show that a subset of cells in a population exhibit transient oscillations in cell size with periods that stretch across several (more than ten) generations. Our analysis reveals that a simple law governing cell-size control-a noisy linear map-explains the origins of these cell-size oscillations across all strains. This noisy linear map implements a negative feedback on cell-size control: a cell with a larger initial size tends to divide earlier, whereas one with a smaller initial size tends to divide later. Combining simulations of cell growth and division with experimental data, we demonstrate that this noisy linear map generates transient oscillations, not just in cell size, but also in constitutive gene expression. Our work provides new insights into the dynamics of bacterial cell-size regulation with implications for the physiological processes involved.Item Open Access A quantitative formulation of biology's first law.(Evolution; international journal of organic evolution, 2019-06) McShea, Daniel W; Wang, Steve C; Brandon, Robert NThe zero-force evolutionary law (ZFEL) states that in evolutionary systems, in the absence of forces or constraints, diversity and complexity tend to increase. The reason is that diversity and complexity are both variance measures, and variances tend to increase spontaneously as random events accumulate. Here, we use random-walk models to quantify the ZFEL expectation, producing equations that give the probabilities of diversity or complexity increasing as a function of time, and that give the expected magnitude of the increase. We produce two sets of equations, one for the case in which variation occurs in discrete steps, the other for the case in which variation is continuous. The equations provide a way to decompose actual trajectories of diversity or complexity into two components, the portion due to the ZFEL and a remainder due to selection and constraint. Application of the equations is demonstrated using real and hypothetical data.Item Open Access A Sweet Embrace: Control of Protein-Protein Interactions by O-Linked β-N-Acetylglucosamine.(Biochemistry, 2018-01) Tarbet, Heather J; Toleman, Clifford A; Boyce, MichaelO-Linked β-N-acetylglucosamine (O-GlcNAc) is a critical post-translational modification (PTM) of thousands of intracellular proteins. Reversible O-GlcNAcylation governs many aspects of cell physiology and is dysregulated in numerous human diseases. Despite this broad pathophysiological significance, major aspects of O-GlcNAc signaling remain poorly understood, including the biochemical mechanisms through which O-GlcNAc transduces information. Recent work from many laboratories, including our own, has revealed that O-GlcNAc, like other intracellular PTMs, can control its substrates' functions by inhibiting or inducing protein-protein interactions. This dynamic regulation of multiprotein complexes exerts diverse downstream signaling effects in a range of processes, cell types, and organisms. Here, we review the literature about O-GlcNAc-regulated protein-protein interactions and suggest important questions for future studies in the field.Item Open Access A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest.(Cell reports, 2020-08) Tsabar, Michael; Mock, Caroline S; Venkatachalam, Veena; Reyes, Jose; Karhohs, Kyle W; Oliver, Trudy G; Regev, Aviv; Jambhekar, Ashwini; Lahav, GalitCellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA.Item Open Access A unifying framework for interpreting and predicting mutualistic systems.(Nature communications, 2019-01) Wu, Feilun; Lopatkin, Allison J; Needs, Daniel A; Lee, Charlotte T; Mukherjee, Sayan; You, LingchongCoarse-grained rules are widely used in chemistry, physics and engineering. In biology, however, such rules are less common and under-appreciated. This gap can be attributed to the difficulty in establishing general rules to encompass the immense diversity and complexity of biological systems. Furthermore, even when a rule is established, it is often challenging to map it to mechanistic details and to quantify these details. Here we report a framework that addresses these challenges for mutualistic systems. We first deduce a general rule that predicts the various outcomes of mutualistic systems, including coexistence and productivity. We further develop a standardized machine-learning-based calibration procedure to use the rule without the need to fully elucidate or characterize their mechanistic underpinnings. Our approach consistently provides explanatory and predictive power with various simulated and experimental mutualistic systems. Our strategy can pave the way for establishing and implementing other simple rules for biological systems.Item Open Access Above-ground biomass and structure of 260 African tropical forests.(Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2013-01) Lewis, Simon L; Sonké, Bonaventure; Sunderland, Terry; Begne, Serge K; Lopez-Gonzalez, Gabriela; van der Heijden, Geertje MF; Phillips, Oliver L; Affum-Baffoe, Kofi; Baker, Timothy R; Banin, Lindsay; Bastin, Jean-François; Beeckman, Hans; Boeckx, Pascal; Bogaert, Jan; De Cannière, Charles; Chezeaux, Eric; Clark, Connie J; Collins, Murray; Djagbletey, Gloria; Djuikouo, Marie Noël K; Droissart, Vincent; Doucet, Jean-Louis; Ewango, Cornielle EN; Fauset, Sophie; Feldpausch, Ted R; Foli, Ernest G; Gillet, Jean-François; Hamilton, Alan C; Harris, David J; Hart, Terese B; de Haulleville, Thales; Hladik, Annette; Hufkens, Koen; Huygens, Dries; Jeanmart, Philippe; Jeffery, Kathryn J; Kearsley, Elizabeth; Leal, Miguel E; Lloyd, Jon; Lovett, Jon C; Makana, Jean-Remy; Malhi, Yadvinder; Marshall, Andrew R; Ojo, Lucas; Peh, Kelvin S-H; Pickavance, Georgia; Poulsen, John R; Reitsma, Jan M; Sheil, Douglas; Simo, Murielle; Steppe, Kathy; Taedoumg, Hermann E; Talbot, Joey; Taplin, James RD; Taylor, David; Thomas, Sean C; Toirambe, Benjamin; Verbeeck, Hans; Vleminckx, Jason; White, Lee JT; Willcock, Simon; Woell, Hannsjorg; Zemagho, LiseWe report above-ground biomass (AGB), basal area, stem density and wood mass density estimates from 260 sample plots (mean size: 1.2 ha) in intact closed-canopy tropical forests across 12 African countries. Mean AGB is 395.7 Mg dry mass ha⁻¹ (95% CI: 14.3), substantially higher than Amazonian values, with the Congo Basin and contiguous forest region attaining AGB values (429 Mg ha⁻¹) similar to those of Bornean forests, and significantly greater than East or West African forests. AGB therefore appears generally higher in palaeo- compared with neotropical forests. However, mean stem density is low (426 ± 11 stems ha⁻¹ greater than or equal to 100 mm diameter) compared with both Amazonian and Bornean forests (cf. approx. 600) and is the signature structural feature of African tropical forests. While spatial autocorrelation complicates analyses, AGB shows a positive relationship with rainfall in the driest nine months of the year, and an opposite association with the wettest three months of the year; a negative relationship with temperature; positive relationship with clay-rich soils; and negative relationships with C : N ratio (suggesting a positive soil phosphorus-AGB relationship), and soil fertility computed as the sum of base cations. The results indicate that AGB is mediated by both climate and soils, and suggest that the AGB of African closed-canopy tropical forests may be particularly sensitive to future precipitation and temperature changes.Item Open Access Across the meiotic divide - CSF activity in the post-Emi2/XErp1 era.(J Cell Sci, 2008-11-01) Wu, Judy Qiju; Kornbluth, SallyVertebrate eggs are arrested at the metaphase stage of meiosis II. Only upon fertilization will the metaphase-II-arrested eggs exit meiosis II and enter interphase. In 1971, Masui and Markert injected egg extracts into a two-cell-stage embryo and found that the injected blastomere arrested at the next mitosis. On the basis of these observations, they proposed the existence of an activity present in the eggs that is responsible for meiosis-II arrest and can induce mitotic arrest, and named this activity cytostatic factor (CSF). Although the existence of CSF was hypothesized more than 35 years ago, its precise identity remained unclear until recently. The discovery of the Mos-MAPK pathway and characterization of the anaphase-promoting complex/cyclosome (APC/C) as a central regulator of M-phase exit provided the framework for a molecular understanding of CSF. These pathways have now been linked by the discovery and characterization of the protein Emi2, a meiotic APC/C inhibitor, the activity and stability of which are controlled by the Mos-MAPK pathway. Continued investigation into the mechanism of action and mode of regulation of Emi2 promises to shed light not only on CSF function, but also on the general principles of APC/C regulation and the control of protein function by MAPK pathways.Item Open Access Age trajectories of physiological indices in relation to healthy life course.(Mech Ageing Dev, 2011-03) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Akushevich, Igor; Kulminski, Alexander M; Arbeeva, Liubov S; Akushevich, Lucy; Culminskaya, Irina V; Yashin, Anatoliy IWe analysed relationship between the risk of onset of "unhealthy life" (defined as the onset of cancer, cardiovascular diseases, or diabetes) and longitudinal changes in body mass index, diastolic blood pressure, hematocrit, pulse pressure, pulse rate, and serum cholesterol in the Framingham Heart Study (Original Cohort) using the stochastic process model of human mortality and aging. The analyses demonstrate how decline in resistance to stresses and adaptive capacity accompanying human aging can be evaluated from longitudinal data. We showed how these components of the aging process, as well as deviation of the trajectories of physiological indices from those minimising the risk at respective ages, can lead to an increase in the risk of onset of unhealthy life with age. The results indicate the presence of substantial gender difference in aging related decline in stress resistance and adaptive capacity, which can contribute to differences in the shape of the sex-specific patterns of incidence rates of aging related diseases.Item Open Access Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes.(Molecules (Basel, Switzerland), 2021-10) Ali, Tomader; Lei, Xiaoyong; Barbour, Suzanne E; Koizumi, Akio; Chalfant, Charles E; Ramanadham, SasankaType 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student's t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages-the initiators of autoimmune responses leading to T1D-is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.Item Open Access An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.(Anesth Analg, 2010-08) Johnson, Ken B; Syroid, Noah D; Gupta, Dhanesh K; Manyam, Sandeep C; Pace, Nathan L; LaPierre, Cris D; Egan, Talmage D; White, Julia L; Tyler, Diane; Westenskow, Dwayne RINTRODUCTION: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions. METHODS: Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models. DISCUSSION: Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.Item Open Access Apoptosis in Drosophila: neither fish nor fowl (nor man, nor worm).(J Cell Sci, 2005-05-01) Kornbluth, Sally; White, KristinStudies in a wide variety of organisms have produced a general model for the induction of apoptosis in which multiple signaling pathways lead ultimately to activation of the caspase family of proteases. Once activated, these enzymes cleave key cellular substrates to promote the orderly dismantling of dying cells. A broad similarity exists in the cell death pathways operating in different organisms and there is a clear evolutionary conservation of apoptotic regulators such as caspases, Bcl-2 family members, inhibitor of apoptosis (IAP) proteins, IAP antagonists and caspase activators. Despite this, studies in Caenorhabditis elegans, Drosophila and vertebrates have revealed some apparent differences both in the way apoptosis is regulated and in the way individual molecules contribute to the propagation of the death signal. For example, whereas cytochrome c released from mitochondria clearly promotes caspase activation in vertebrates, there is no documented role for cytochrome c in C. elegans apoptosis and its role in Drosophila is highly controversial. In addition, the apoptotic potency of IAP antagonists appears to be greater in Drosophila than in vertebrates, indicating that IAPs may be of different relative importance in different organisms. Thus, although Drosophila, worms and humans share a host of apoptotic regulators, the way in which they function may not be identical.Item Open Access Assessment of the Feasibility of Using Noninvasive Wearable Biometric Monitoring Sensors to Detect Influenza and the Common Cold Before Symptom Onset.(JAMA network open, 2021-09) Grzesiak, Emilia; Bent, Brinnae; McClain, Micah T; Woods, Christopher W; Tsalik, Ephraim L; Nicholson, Bradly P; Veldman, Timothy; Burke, Thomas W; Gardener, Zoe; Bergstrom, Emma; Turner, Ronald B; Chiu, Christopher; Doraiswamy, P Murali; Hero, Alfred; Henao, Ricardo; Ginsburg, Geoffrey S; Dunn, JessilynImportance
Currently, there are no presymptomatic screening methods to identify individuals infected with a respiratory virus to prevent disease spread and to predict their trajectory for resource allocation.Objective
To evaluate the feasibility of using noninvasive, wrist-worn wearable biometric monitoring sensors to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus.Design, setting, and participants
The cohort H1N1 viral challenge study was conducted during 2018; data were collected from September 11, 2017, to May 4, 2018. The cohort rhinovirus challenge study was conducted during 2015; data were collected from September 14 to 21, 2015. A total of 39 adult participants were recruited for the H1N1 challenge study, and 24 adult participants were recruited for the rhinovirus challenge study. Exclusion criteria for both challenges included chronic respiratory illness and high levels of serum antibodies. Participants in the H1N1 challenge study were isolated in a clinic for a minimum of 8 days after inoculation. The rhinovirus challenge took place on a college campus, and participants were not isolated.Exposures
Participants in the H1N1 challenge study were inoculated via intranasal drops of diluted influenza A/California/03/09 (H1N1) virus with a mean count of 106 using the median tissue culture infectious dose (TCID50) assay. Participants in the rhinovirus challenge study were inoculated via intranasal drops of diluted human rhinovirus strain type 16 with a count of 100 using the TCID50 assay.Main outcomes and measures
The primary outcome measures included cross-validated performance metrics of random forest models to screen for presymptomatic infection and predict infection severity, including accuracy, precision, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC).Results
A total of 31 participants with H1N1 (24 men [77.4%]; mean [SD] age, 34.7 [12.3] years) and 18 participants with rhinovirus (11 men [61.1%]; mean [SD] age, 21.7 [3.1] years) were included in the analysis after data preprocessing. Separate H1N1 and rhinovirus detection models, using only data on wearble devices as input, were able to distinguish between infection and noninfection with accuracies of up to 92% for H1N1 (90% precision, 90% sensitivity, 93% specificity, and 90% F1 score, 0.85 [95% CI, 0.70-1.00] AUC) and 88% for rhinovirus (100% precision, 78% sensitivity, 100% specificity, 88% F1 score, and 0.96 [95% CI, 0.85-1.00] AUC). The infection severity prediction model was able to distinguish between mild and moderate infection 24 hours prior to symptom onset with an accuracy of 90% for H1N1 (88% precision, 88% sensitivity, 92% specificity, 88% F1 score, and 0.88 [95% CI, 0.72-1.00] AUC) and 89% for rhinovirus (100% precision, 75% sensitivity, 100% specificity, 86% F1 score, and 0.95 [95% CI, 0.79-1.00] AUC).Conclusions and relevance
This cohort study suggests that the use of a noninvasive, wrist-worn wearable device to predict an individual's response to viral exposure prior to symptoms is feasible. Harnessing this technology would support early interventions to limit presymptomatic spread of viral respiratory infections, which is timely in the era of COVID-19.Item Open Access Automatic annotation of spatial expression patterns via sparse Bayesian factor models.(PLoS Comput Biol, 2011-07) Pruteanu-Malinici, Iulian; Mace, Daniel L; Ohler, UweAdvances in reporters for gene expression have made it possible to document and quantify expression patterns in 2D-4D. In contrast to microarrays, which provide data for many genes but averaged and/or at low resolution, images reveal the high spatial dynamics of gene expression. Developing computational methods to compare, annotate, and model gene expression based on images is imperative, considering that available data are rapidly increasing. We have developed a sparse Bayesian factor analysis model in which the observed expression diversity of among a large set of high-dimensional images is modeled by a small number of hidden common factors. We apply this approach on embryonic expression patterns from a Drosophila RNA in situ image database, and show that the automatically inferred factors provide for a meaningful decomposition and represent common co-regulation or biological functions. The low-dimensional set of factor mixing weights is further used as features by a classifier to annotate expression patterns with functional categories. On human-curated annotations, our sparse approach reaches similar or better classification of expression patterns at different developmental stages, when compared to other automatic image annotation methods using thousands of hard-to-interpret features. Our study therefore outlines a general framework for large microscopy data sets, in which both the generative model itself, as well as its application for analysis tasks such as automated annotation, can provide insight into biological questions.Item Open Access Barnacle cement: a polymerization model based on evolutionary concepts.(2009-11) Dickinson, Gary H.The tenacity by which barnacles adhere has sparked a long history of scientific investigation into their adhesive mechanisms. To adhere, barnacles utilize proteinaceous cement that rapidly polymerizes and forms adhesive bonds underwater, and is insoluble once polymerized. Although progress has been made towards understanding the chemical properties of cement proteins, the biochemical mechanisms of cement polymerization remain largely unknown. In this dissertation, I used evolutionary concepts to elucidate barnacle cement polymerization. Well-studied biological phenomena (blood coagulation in vertebrates and invertebrates) were used as models to generate hypotheses on proteins/biochemical mechanisms involved in cement polymerization. These model systems are under similar selective pressures to cement polymerization (life or death situations) and show similar chemical characteristics (soluble protein that quickly/efficiently coagulates). I describe a novel method for collection of unpolymerized cement. Multiple, independent techniques (AFM, FTIR, chemical staining for peroxidase and tandem mass spectroscopy) support the validity of the collection technique. Identification of a large number of proteins besides ‘barnacle cement proteins’ with mass spectrometry, andobservations of hemocytes in unpolymerized cement inspired the hypothesis that barnacle cement is hemolymph. A striking biochemical resemblance was shown between barnacle cement polymerization and vertebrate blood coagulation. Clotted fibrin and polymerized cement were shown to be structurally similar (mesh of fibrous protein) but biochemically distinct. Heparin, trypsin inhibitor and Ca2+ chelators impeded cement polymerization, suggesting trypsin and Ca2+ involvement in polymerization. The presence/activity of a cement trypsin-like serine protease was verified and shown homologous to bovine pancreatic trypsin. Protease activity may activate cement structural precursors, allowing loose assembly with other structural proteins and surface rearrangement. Tandem mass spectrometry and Western blotting revealed a homologous protein to human coagulation factor XIII (fibrin stabilizing factor: transglutaminase that covalently cross-links fibrin monomers). Transglutaminase activity was verified and may covalently cross-link assembled cement monomers. Similar to other protein coagulation systems, heritable defects occur during cement polymerization. High plasma protein concentration combined with sub-optimal enzyme, and/or cofactor concentrations and sub-optimal physical/muscular parameters (associated with hemolymph release) results in improperly cured cement in certain individuals when polymerization occurs in contact with low surface energy silicone and its associated leached molecules.Item Open Access beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi.(Proc Natl Acad Sci U S A, 2003-02-04) Baillie, George S; Sood, Arvind; McPhee, Ian; Gall, Irene; Perry, Stephen J; Lefkowitz, Robert J; Houslay, Miles DPhosphorylation of the beta(2) adrenoreceptor (beta(2)AR) by cAMP-activated protein kinase A (PKA) switches its predominant coupling from stimulatory guanine nucleotide regulatory protein (G(s)) to inhibitory guanine nucleotide regulatory protein (G(i)). beta-Arrestins recruit the cAMP-degrading PDE4 phosphodiesterases to the beta(2)AR, thus controlling PKA activity at the membrane. Here we investigate a role for PDE4 recruitment in regulating G protein switching by the beta(2)AR. In human embryonic kidney 293 cells overexpressing a recombinant beta(2)AR, stimulation with isoprenaline recruits beta-arrestins 1 and 2 as well as both PDE4D3 and PDE4D5 to the receptor and stimulates receptor phosphorylation by PKA. The PKA phosphorylation status of the beta(2)AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)AR. Rolipram and PDE4D5-D556A also enhance beta(2)AR-mediated activation of extracellular signal-regulated kinases ERK12. This is consistent with a switch in coupling of the receptor from G(s) to G(i), because the ERK12 activation is sensitive to both inhibitors of PKA (H89) and G(i) (pertussis toxin). In cardiac myocytes, the beta(2)AR also switches from G(s) to G(i) coupling. Treating primary cardiac myocytes with isoprenaline induces recruitment of PDE4D3 and PDE4D5 to membranes and activates ERK12. Rolipram robustly enhances this activation in a manner sensitive to both pertussis toxin and H89. Adenovirus-mediated expression of PDE4D5-D556A also potentiates ERK12 activation. Thus, receptor-stimulated beta-arrestin-mediated recruitment of PDE4 plays a central role in the regulation of G protein switching by the beta(2)AR in a physiological system, the cardiac myocyte.