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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Algorithms for incorporating prior topological information in HMMs: application to transmembrane proteins.

BACKGROUND: Hidden Markov Models (HMMs) have been extensively used in computational molecular biology, for modelling protein and nucleic acid sequences. In many applications, such as transmembrane protein topology prediction, the incorporation of limited amount of information regarding the topology, arising from biochemical experiments, has been proved a very useful strategy that increased remarkably the performance of even the top-scoring methods. However, no clear and formal explanation of the algorithms that retains the probabilistic interpretation of the models has been presented so far in the literature. RESULTS: We present here, a simple method that allows incorporation of prior topological information concerning the sequences at hand, while at the same time the HMMs retain their full probabilistic interpretation in terms of conditional probabilities. We present modifications to the standard Forward and Backward algorithms of HMMs and we also show explicitly, how reliable predictions may arise by these modifications, using all the algorithms currently available for decoding HMMs. A similar procedure may be used in the training procedure, aiming at optimizing the labels of the HMM's classes, especially in cases such as transmembrane proteins where the labels of the membrane-spanning segments are inherently misplaced. We present an application of this approach developing a method to predict the transmembrane regions of alpha-helical membrane proteins, trained on crystallographically solved data. We show that this method compares well against already established algorithms presented in the literature, and it is extremely useful in practical applications. CONCLUSION: The algorithms presented here, are easily implemented in any kind of a Hidden Markov Model, whereas the prediction method (HMM-TM) is freely available for academic users at http://bioinformatics.biol.uoa.gr/HMM-TM, offering the most advanced decoding options currently available.

Algorithms↗
PubMed2002

Phase singularities and termination of spiral wave reentry.

INTRODUCTION: Recent defibrillation studies show that electric fields interact with reentrant activity in myocardial tissue through virtual electrode polarization (VEP). This study focuses on determining how VEP relates to the creation and survival of postshock phase singularities in cardiac tissue and demonstrating that interactions between VEP and preshock tissue state engender the probabilistic nature of defibrillation. METHODS AND RESULTS: We constructed a two-dimensional tissue model representing a ventricular cross-section with fiber architecture and surrounding bath. We initiated spiral wave reentry and subjected the tissue to a monophasic shock. We estimated the shock success probability for a given strength by testing 16 coupling intervals throughout a single rotation of the wavefront. Over a range of shock strengths, our model exhibits dose-response behavior similar to experimental defibrillation efficacy curves. At the 50% effective strength (ED50), successful termination of reentry depends upon the interaction between preshock excitable gap and postshock phase singularities. We also found that increasing the stimulus strength toward ED50 increases the number of postshock singularities, whereas further strength increases above ED50 decrease the number of singularities. CONCLUSION: Our results show for the first time that a computational model can account for the probabilistic nature of defibrillation as VEP interacts with the dynamics of an ongoing reentrant wavefront. Further, we demonstrate that success of a shock depends on the annihilation of the phase singularities that arise after any strong stimulus. Our findings imply that VEP completely overrides the preshock tissue state in shocks that are highly likely to defibrillate (ED95).

Biophysical Phenomena↗
PubMed2007

Probabilistic epigenesis.

The notion that phenotypic traits, including behavior, can be predetermined has slowly given way in biology and psychology over the last two decades. This shift in thinking is due in large part to the growing evidence for the fundamental role of developmental processes in the generation of the stability and variations in phenotype that researchers in developmental and evolutionary sciences seek to understand. Here I review the tenets of a metatheoretical model of development called probabilistic epigenesis (PE) and explore its implications for furthering our understanding of developmental and evolutionary processes. The PE framework emphasizes the reciprocity of influences within and between levels of an organism's developmental manifold (genetic activity, neural activity, behavior, and the physical, social, and cultural influences of the external environment) and the ubiquity of gene-environment interaction in the realization of all phenotypes.

Biological Evolution↗
PubMed2004

A complex systems model approach to quantified mineral resource appraisal.

For federal and state land management agencies, mineral resource appraisal has evolved from value-based to outcome-based procedures wherein the consequences of resource development are compared with those of other management options. Complex systems modeling is proposed as a general framework in which to build models that can evaluate outcomes. Three frequently used methods of mineral resource appraisal (subjective probabilistic estimates, weights of evidence modeling, and fuzzy logic modeling) are discussed to obtain insight into methods of incorporating complexity into mineral resource appraisal models. Fuzzy logic and weights of evidence are most easily utilized in complex systems models. A fundamental product of new appraisals is the production of reusable, accessible databases and methodologies so that appraisals can easily be repeated with new or refined data. The data are representations of complex systems and must be so regarded if all of their information content is to be utilized. The proposed generalized model framework is applicable to mineral assessment and other geoscience problems. We begin with a (fuzzy) cognitive map using (+1,0,-1) values for the links and evaluate the map for various scenarios to obtain a ranking of the importance of various links. Fieldwork and modeling studies identify important links and help identify unanticipated links. Next, the links are given membership functions in accordance with the data. Finally, processes are associated with the links; ideally, the controlling physical and chemical events and equations are found for each link. After calibration and testing, this complex systems model is used for predictions under various scenarios.

Conservation of Natural Resources↗
PubMed2002

A quantitative model of optimal data selection in Wason's selection task.

The optimal data selection model proposed by Oaksford and Chater (1994) successfully formalized Wason's selection task (Wason, 1966). The model, however, involved some questionable assumptions and was also not sufficient as a model of the task because it could not provide quantitative predictions of the card selection frequencies. In this paper, the model was revised to provide quantitative fits to the data. The model can predict the selection frequencies of cards based on a selection tendency function (STF), or conversely, it enables the estimation of subjective probabilities from data. Past experimental data were first re-analysed based on the model. In Experiment 1, the superiority of the revised model was shown. However, when the relationship between antecedent and consequent was forced to deviate from the biconditional form, the model was not supported. In Experiment 2, it was shown that sufficient emphasis on probabilistic information can affect participants' performance. A detailed experimental method to sort participants by probabilistic strategies was introduced. Here, the model was supported by a subgroup of participants who used the probabilistic strategy. Finally, the results were discussed from the viewpoint of adaptive rationality.

Adult↗
PubMed2002

Applications of generalized pair hidden Markov models to alignment and gene finding problems.

Hidden Markov models (HMMs) have been successfully applied to a variety of problems in molecular biology, ranging from alignment problems to gene finding and annotation. Alignment problems can be solved with pair HMMs, while gene finding programs rely on generalized HMMs in order to model exon lengths. In this paper, we introduce the generalized pair HMM (GPHMM), which is an extension of both pair and generalized HMMs. We show how GPHMMs, in conjunction with approximate alignments, can be used for cross-species gene finding and describe applications to DNA-cDNA and DNA-protein alignment. GPHMMs provide a unifying and probabilistically sound theory for modeling these problems.

Algorithms↗
PubMed2004

Methods for applying the quantitative structure-activity relationship paradigm.

There are several Quantitative Structure-Activity Relationship (QSAR) methods to assist in the design of compounds for medicinal use. Owing to the different QSAR methodologies, deciding which QSAR method to use depends on the composition of system of interest and the desired results. The relationship between a compound's binding affinity/activity to its structural properties was first noted in the 1930s by Hammett and later refined by Hansch and Fujita in the mid-1960s. In 1988 Cramer and coworkers created Comparative Molecular Field Analysis (CoMFA) incorporating the three-dimensional (3D) aspects of the compounds, specifically the electrostatic fields of the compound, into the QSAR model. Hopfinger and coworkers included an additional dimension to 3D-QSAR methodology in 1997 that eliminated the question of "Which conformation to use in a QSAR study?", creating 4D-QSAR. In 1999 Chemical Computing Group Inc. (CCG) developed the Binary-QSAR methodology and added novel 3D-QSAR descriptors to the traditional QSAR model allowing the 3D properties of compounds to be incorporated into the traditional QSAR model. Recently CCG released Probabilistic Receptor Potentials to calculate the substrate's atomic preferences in the active site. These potentials are constructed by fitting analytical functions to experimental properties of the substrates using knowledge-based methods. An overview of these and other QSAR methods will be discussed along with an in-depth examination of the methodologies used to construct QSAR models. Also, included in this chapter is a case study of molecules used to create QSAR models utilizing different methodologies and QSAR programs.

Algorithms↗
PubMed1998

Observer biases in the 3D interpretation of line drawings.

Line drawings produced by contours traced on a surface can produce a vivid impression of the surface shape. The stability of this perception is notable considering that the information provided by the surface contours is quite ambiguous. We have studied the stability of line drawing perception from psychophysical and computational standpoints. For a given family of simple line drawings, human observers could perceive the drawings as depicting either an elliptic (egg-shaped) or hyperbolic (saddle-shaped) smooth surface patch. Rotation of the image along the line of sight and change in aspect ratio of the line drawing could bias the observer toward either interpretation. The results were modeled by a simple Bayesian observer that computes the probability to choose either interpretation given the information in the image and prior preferences. The model's decision rule is noncommitting: for a given input image its responses are still probabilistic, reflecting variability in the modeled observers' judgements. A good fit to the data was obtained when three observer assumptions were introduced: a preference for convex surfaces, a preference for surface contours aligned with the principal lines of curvature, and a preference for a surface orientation consistent with an object viewed from above. We discuss how these assumptions might reflect regularities of the visual world.

Adult↗
PubMed2005

Spatial-temporal modeling of malware propagation in networks.

Network security is an important task of network management. One threat to network security is malware (malicious software) propagation. One type of malware is called topological scanning that spreads based on topology information. The focus of this work is on modeling the spread of topological malwares, which is important for understanding their potential damages, and for developing countermeasures to protect the network infrastructure. Our model is motivated by probabilistic graphs, which have been widely investigated in machine learning. We first use a graphical representation to abstract the propagation of malwares that employ different scanning methods. We then use a spatial-temporal random process to describe the statistical dependence of malware propagation in arbitrary topologies. As the spatial dependence is particularly difficult to characterize, the problem becomes how to use simple (i.e., biased) models to approximate the spatially dependent process. In particular, we propose the independent model and the Markov model as simple approximations. We conduct both theoretical analysis and extensive simulations on large networks using both real measurements and synthesized topologies to test the performance of the proposed models. Our results show that the independent model can capture temporal dependence and detailed topology information and, thus, outperforms the previous models, whereas the Markov model incorporates a certain spatial dependence and, thus, achieves a greater accuracy in characterizing both transient and equilibrium behaviors of malware propagation.

Algorithms↗
PubMed2007

The cost-effectiveness of oral triptan therapy in Sweden.

The literature suggests that triptans are cost effective compared with older types of migraine treatment. However, which of the triptans that is most cost effective has not been established. We compared the costs and effects of triptan treatment from a Swedish societal perspective, using evidence from the literature. A probabilistic cost-effectiveness model was constructed to investigate the costs and effects of treating a single attack in a typical migraine patient. The end-point used in the base-case analysis was sustained pain free without any adverse events (SNAE). We searched the scientific literature for meta-analyses reporting the efficacy of oral triptans. All treatments except rizatriptan 10 mg and eletriptan 40 mg were dominated. The incremental cost per SNAE of rizatriptan 10 mg compared with eletriptan 40 mg was approximately 100 euro. There was substantial uncertainty concerning the results, but probabilistic analysis showed that rizatriptan 10 mg and eletriptan 40 mg had the highest probability of being cost-effective.

Administration, Oral↗
PubMed1998

Category-specific semantic deficits in focal and widespread brain damage: a computational account.

Category-specific semantic impairments have been explained in terms of preferential damage to different types of features (e.g., perceptual vs. functional). This account is compatible with cases in which the impairments were the result of relatively focal lesions, as in herpes encephalitis. Recently, however, there have been reports of category-specific impairments associated with Alzheimer's disease, in which there is more widespread, patchy damage. We present experiments with a connectionist model that show how "category-specific" impairments can arise in cases of both localized and widespread damage; in this model, types of features are topographically organized, but specific categories are not. These effects mainly depend on differences between categories in the distribution of correlated features. The model's predictions about degree of impairment on natural kinds and artifacts over the course of semantic deterioration are shown to be consistent with existing patient data. The model shows how the probabilistic nature of damage in Alzheimer's disease interacts with the structure of semantic memory to yield different patterns of impairment between patients and categories over time.

Alzheimer Disease↗
PubMed1989

Retinoblastoma. Analysis of 75 cases and proposal for a new model of oncogenesis and tumor growth kinetics.

A series of 75 retinoblastoma patients were analyzed at the Institute of Ophthalmology, Siena, and a mathematical model for the 'nodule to cancer' transformation applied to it. The authors obtained data in disagreement with Knudson's 'two hit' hypothesis but fitting an alternative model of oncogenesis. This model is based on probabilistic arguments and a possible pattern of tumor growth and evolution is given in detail.

Adolescent↗
PubMed2006

A comparison of the cost-effectiveness of five strategies for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

OBJECTIVES: To assess the relative effectiveness, patient acceptability, costs and cost-effectiveness of four strategies for the prevention of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal (GI) toxicity: (1) Cox-1 NSAIDs plus histamine-2 receptor antagonist (H2RA), (2) Cox-1 NSAIDs plus proton pump inhibitors (PPIs), (3) Cox-1 NSAIDs plus misoprostol, and (4) Cox-2 NSAIDs (later expanded to 4a Cox-2 coxibNSAIDs and 4b Cox-2 preferential NSAIDs). DATA SOURCES: Electronic databases up to May 2002. REVIEW METHODS: Relevant studies were selected, assessed and analysed. Pooled relative risk ratios (RR) from the systematic review were combined with up-to-date UK resource use and unit costs data in an incremental economic analysis. A probabilistic decision-analytic model was designed and populated with data to carry out incremental economic analysis. Incremental cost-effectiveness ratios (ICERs) were generated for the outcome measure, endoscopic ulcer or serious GI event averted, against total cost, and non-parametric bootstrapping was used to simulate variance of these ICERs. RESULTS: Of 118 selected trials, including 125 relevant comparisons (which included 76,322 participants) only 138 deaths and 248 serious GI events were reported. Seven comparisons were judged to be at low risk of bias. Comparing the gastroprotective strategies against placebo, there was no evidence of effectiveness of H2RAs against any primary outcomes (few events reported), PPIs may reduce the risk of symptomatic ulcers [RR 0.09, 95% confidence interval (CI) 0.02 to 0.47], misoprostol reduces the risk of serious GI complications (RR 0.57, 95% CI 0.36 to 0.91) and symptomatic ulcers (RR 0.36, 95% CI 0.20 to 0.67), Cox-2 'preferentials' reduce the risk of symptomatic ulcers (RR 0.41, 95% CI 0.26 to 0.65) and Cox-2 'coxibs' reduce the risk of symptomatic ulcers (RR 0.49, 95% CI 0.38 to 0.62) and possibly serious GI events (RR 0.55, 95% CI 0.38 to 0.80). All strategies except Cox-2 'preferentials' reduce the risk of endoscopic ulcers. There were only 12 direct comparisons between gastroprotective strategies. All they suggest is that Cox-2 preferentials are better than misoprostol for preventing GI complications. Indirect comparisons suggested that PPIs may prevent symptomatic ulcers better than Cox-2 coxibs, but this is very weak evidence. For prevention of endoscopic ulcers PPIs and misoprostol appear more successful than H2RAs and misoprostol is better than Cox-2 preferentials. There were no UK head-to-head published economic analyses with regard to the main gastroprotective strategies. There were generally insufficient data with regards to cardiac or renal outcomes, serious GI outcomes or life-years gained to populate the mode. Mean (2.5th and 97.5th percentile) costs per endoscopic ulcer averted compared with Cox-1 NSAIDs alone were as follows: Cox-1 plus H2RAs, -186 pounds (-555 to 804); Cox-1 plus PPIs, 454 pounds (251 to 877); Cox-1 plus misoprostol, 54 pounds (-112 to 238); Cox-2 selective NSAIDs, 263 pounds (-570 to 1280), or Cox-2 specific NSAIDs, 301 pounds (189 to 418). With regard to the prevention of endoscopic ulcers, Cox-1 NSAID plus H2RA is a dominant option. Cost-effectiveness acceptability analysis showed a 95% probability that this combination was less costly and more effective. Cost-effectiveness acceptability frontiers showed that if the decision-maker is willing to pay up to 750 pounds to avoid an endoscopic ulcer, then Cox-1 plus H2RA is the optimal strategy. If the decision-maker is willing to pay over 750 pounds, the optimal strategy is NSAID plus misoprostol. Between 1900 pounds and 3750 pounds, Cox-2 selective inhibitors are optimal, and over 3750 pounds, Cox-2 specific inhibitors become optimal. NSAID plus PPI is never the optimal strategy. Sensitivity and subgroup analyses suggest that Cox-1 NSAID plus H2RA and Cox-1 NSAID plus misoprostol become more cost-effective in the older age group. Some conclusions were associated with high levels of uncertainty. CONCLUSIONS: Although there is a very large body of evidence comparing Cox-2 NSAIDs with Cox-1 NSAIDs, this is not matched by studies of the other types of gastroprotectors or by studies directly comparing active gastroprotective strategies. This lack of direct comparisons led to the use of indirect comparisons to help understand the relative efficacy of these strategies. Indirect evidence in itself is weak and was also hampered by lack of evidence in the underlying studies (where the gastroprotectors were compared with placebo). Economic modelling suggests that Cox-1 NSAID plus H2RA or Cox-1 NSAID plus PPI are the most cost-effective strategies for avoiding endoscopic ulcers in patients requiring long-term NSAID therapy. All strategies other than Cox-2 selective inhibitors reduce the rate of endoscopic ulcer compared with Cox-1 alone. The economic analysis suggests that there may be a case for prescribing H2RAs in all patients requiring NSAIDs. Misoprostol is more effective, but is associated with a greater cost and GI side-effects which may be unacceptable for patients. However, when assessing serious GI events, the economic analysis is sufficiently weakened by the data available as to render clear practice recommendations impossible. Further large, independent RCTs directly comparing various gastroprotective strategies are needed. These should report items such as major outcomes, primary data, adverse events, assessment of practice and patient preference.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

A systematic approach to simulating metabolism in computational toxicology. I. The TIMES heuristic modelling framework.

Designing biologically active chemicals and managing their risks requires a holistic perspective on the chemical-biological interactions that form the basis of selective toxicity. The balance of therapeutic and adverse outcomes for new drugs and pesticides is managed by shaping the probabilities for transport, metabolism, and molecular initiating events. For chemicals activated as well as detoxified by metabolism, selective toxicity may be considered in terms of relative probabilities, which shift dramatically across species as well as within a population, depending on many factors. The complexity in toxicology that results from metabolism has been troublesome in QSAR research because the parent structure is less relevant to predicting ultimate effects and finding reference species/conditions for metabolic rates seems hopeless. Even the complexity of comparative xenobiotic metabolism itself seems paradoxical in light of the evidence of highly conserved catabolic processes across species. Clearly, predicting the role of metabolism in selective toxicity and adverse health outcomes requires a probabilistic framework for deterministic models as well as the many factors shaping the metabolic probability distributions under specific conditions. This paper presents a tissue metabolism simulator (TIMES), which uses a heuristic algorithm to generate plausible metabolic maps from a comprehensive library of biotransformations and abiotic reactions and estimates for system-specific transformation probabilities. The transformation probabilities can be calibrated to specific reference conditions using transformation rate information from systematic testing. In the absence of rate data, a combinatorial algorithm is used to translate known metabolic maps taken from reference systems into best-fit transformation probabilities. Finally, toxicity test data itself can be used to shape the transformation probabilities for toxicity pathways in which the metabolic activation is the rate-limiting process leading to a toxic effect. The conceptual approach for metabolic simulation will be presented along with practical uses in forecasting plausible activated metabolites.

Animals↗
PubMed2000

Guidance for the performance evaluation of three-dimensional air quality modeling systems for particulate matter and visibility.

Guidance for the performance evaluation of three-dimensional air quality modeling systems for particulate matter and visibility is presented. Four levels are considered: operational, diagnostic, mechanistic, and probabilistic evaluations. First, a comprehensive model evaluation should be conducted in at least two distinct geographical locations and for several meteorological episodes. Next, streamlined evaluations can be conducted for other similar applications if the comprehensive evaluation is deemed satisfactory. In all cases, the operational evaluation alone is insufficient, and some diagnostic evaluation must always be carried out. Recommendations are provided for designing field measurement programs that can provide the data needed for such model performance evaluations.

Air Pollution↗
PubMed2005

Estimating cancer survival and clinical outcome based on genetic tumor progression scores.

MOTIVATION: In cancer research, prediction of time to death or relapse is important for a meaningful tumor classification and selecting appropriate therapies. Survival prognosis is typically based on clinical and histological parameters. There is increasing interest in identifying genetic markers that better capture the status of a tumor in order to improve on existing predictions. The accumulation of genetic alterations during tumor progression can be used for the assessment of the genetic status of the tumor. For modeling dependences between the genetic events, evolutionary tree models have been applied. RESULTS: Mixture models of oncogenetic trees provide a probabilistic framework for the estimation of typical pathogenetic routes. From these models we derive a genetic progression score (GPS) that estimates the genetic status of a tumor. GPS is calculated for glioblastoma patients from loss of heterozygosity measurements and for prostate cancer patients from comparative genomic hybridization measurements. Cox proportional hazard models are then fitted to observed survival times of glioblastoma patients and to times until PSA relapse following radical prostatectomy of prostate cancer patients. It turns out that the genetically defined GPS is predictive even after adjustment for classical clinical markers and thus can be considered a medically relevant prognostic factor. AVAILABILITY: Mtreemix, a software package for estimating tree mixture models, is freely available for non-commercial users at http://mtreemix.bioinf.mpi-sb.mpg.de. The raw cancer datasets and R code for the analysis with Cox models are available upon request from the corresponding author.

Biomarkers, Tumor↗
PubMed2005

Fast and cheap genome wide haplotype construction via optical mapping.

We describe an efficient algorithm to construct genome wide haplotype restriction maps of an individual by aligning single molecule DNA fragments collected with Optical Mapping technology. Using this algorithm and small amount of genomic material, we can construct the parental haplotypes for each diploid chromosome for any individual. Since such haplotype maps reveal the polymorphisms due to single nucleotide differences (SNPs) and small insertions and deletions (RFLPs), they are useful in association studies, studies involving genomic instabilities in cancer, and genetics, and yet incur relatively low cost and provide high throughput. If the underlying problem is formulated as a combinatorial optimization problem, it can be shown to be NP-complete (a special case of K-population problem). But by effectively exploiting the structure of the underlying error processes and using a novel analog of the Baum-Welch algorithm for HMM models, we devise a probabilistic algorithm with a time complexity that is linear in the number of markers for an epsilon-approximate solution. The algorithms were tested by constructing the first genome wide haplotype restriction map of the microbe T. pseudoana, as well as constructing a haplotype restriction map of a 120 Mb region of Human chromosome 4. The frequency of false positives and false negatives was estimated using simulated data. The empirical results were found very promising.

Algorithms↗
PubMed2005

A PBTK/TD modeling-based approach can assess arsenic bioaccumulation in farmed tilapia (Oreochromis mossambicus) and human health risks.

A biologically based risk-assessment model of arsenic (As) exposure evaluated farmed tilapia (Orechromis mossambicus) and human health during tilapia consumption in an area of southwestern Taiwan where blackfoot disease (BFD) occurs. The risk assessment addressed exposures to city residents who lived in Taipei, Taichung, and Kaohsiung, as well as subsistence fishers living in the BFD area who consumed tilapia. The models implemented included a physiologically based toxicokinetic and toxicodynamic (PBTK/TD) model to account for As exposure and dose-response profiles in tilapia and a human health exposure/risk model that accounts for target lifetime risk (TR) and hazard quotient (HQ) for humans consuming farmed tilapia. Results demonstrated that 90th percentiles of TR ranged from 1.53 x 10(-8) to 1.62 x 10(-6) for city residents with farmed tilapia consumption rates of 0.41 to 1.37 g/d. The 90th percentiles ranged from 2.07 x 10(-6) to 7.89 x 10(-5) for subsistence fishers in the BFD area with farmed tilapia consumption rates of 16.80 to 59.15 g/d. All predicted 90th percentiles of HQ were less than 1 for city residents and subsistence fishers in the BFD area, indicating small contributions from farmed tilapia consumption. Critical variables included whole-fish body weight, water As content, and As level in tilapia muscle. Although bioaccumulation of As seems unlikely to result in toxicity to farmed tilapia and humans consuming tilapia, the theoretical human health risks in the BFD area are alarming, using a probabilistic risk-assessment model based on conservative assumptions.

Animals↗