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Friday, August 25, 2023

Affective computing

From Wikipedia, the free encyclopedia

Affective computing is the study and development of systems and devices that can recognize, interpret, process, and simulate human affects. It is an interdisciplinary field spanning computer science, psychology, and cognitive science. While some core ideas in the field may be traced as far back as to early philosophical inquiries into emotion, the more modern branch of computer science originated with Rosalind Picard's 1995 paper on affective computing and her book Affective Computing published by MIT Press. One of the motivations for the research is the ability to give machines emotional intelligence, including to simulate empathy. The machine should interpret the emotional state of humans and adapt its behavior to them, giving an appropriate response to those emotions.

Areas

Detecting and recognizing emotional information

Detecting emotional information usually begins with passive sensors that capture data about the user's physical state or behavior without interpreting the input. The data gathered is analogous to the cues humans use to perceive emotions in others. For example, a video camera might capture facial expressions, body posture, and gestures, while a microphone might capture speech. Other sensors detect emotional cues by directly measuring physiological data, such as skin temperature and galvanic resistance.

Recognizing emotional information requires the extraction of meaningful patterns from the gathered data. This is done using machine learning techniques that process different modalities, such as speech recognition, natural language processing, or facial expression detection. The goal of most of these techniques is to produce labels that would match the labels a human perceiver would give in the same situation: For example, if a person makes a facial expression furrowing their brow, then the computer vision system might be taught to label their face as appearing "confused" or as "concentrating" or "slightly negative" (as opposed to positive, which it might say if they were smiling in a happy-appearing way). These labels may or may not correspond to what the person is actually feeling.

Emotion in machines

Another area within affective computing is the design of computational devices proposed to exhibit either innate emotional capabilities or that are capable of convincingly simulating emotions. A more practical approach, based on current technological capabilities, is the simulation of emotions in conversational agents in order to enrich and facilitate interactivity between human and machine.

Marvin Minsky, one of the pioneering computer scientists in artificial intelligence, relates emotions to the broader issues of machine intelligence stating in The Emotion Machine that emotion is "not especially different from the processes that we call 'thinking.'"

Technologies

In psychology, cognitive science, and in neuroscience, there have been two main approaches for describing how humans perceive and classify emotion: continuous or categorical. The continuous approach tends to use dimensions such as negative vs. positive, calm vs. aroused.

The categorical approach tends to use discrete classes such as happy, sad, angry, fearful, surprise, disgust. Different kinds of machine learning regression and classification models can be used for having machines produce continuous or discrete labels. Sometimes models are also built that allow combinations across the categories, e.g. a happy-surprised face or a fearful-surprised face.

The following sections consider many of the kinds of input data used for the task of emotion recognition.

Emotional speech

Various changes in the autonomic nervous system can indirectly alter a person's speech, and affective technologies can leverage this information to recognize emotion. For example, speech produced in a state of fear, anger, or joy becomes fast, loud, and precisely enunciated, with a higher and wider range in pitch, whereas emotions such as tiredness, boredom, or sadness tend to generate slow, low-pitched, and slurred speech. Some emotions have been found to be more easily computationally identified, such as anger or approval.

Emotional speech processing technologies recognize the user's emotional state using computational analysis of speech features. Vocal parameters and prosodic features such as pitch variables and speech rate can be analyzed through pattern recognition techniques.

Speech analysis is an effective method of identifying affective state, having an average reported accuracy of 70 to 80% in research from 2003 and 2006. These systems tend to outperform average human accuracy (approximately 60%) but are less accurate than systems which employ other modalities for emotion detection, such as physiological states or facial expressions. However, since many speech characteristics are independent of semantics or culture, this technique is considered to be a promising route for further research.

Algorithms

The process of speech/text affect detection requires the creation of a reliable database, knowledge base, or vector space model, broad enough to fit every need for its application, as well as the selection of a successful classifier which will allow for quick and accurate emotion identification.

As of 2010, the most frequently used classifiers were linear discriminant classifiers (LDC), k-nearest neighbor (k-NN), Gaussian mixture model (GMM), support vector machines (SVM), artificial neural networks (ANN), decision tree algorithms and hidden Markov models (HMMs). Various studies showed that choosing the appropriate classifier can significantly enhance the overall performance of the system. The list below gives a brief description of each algorithm:

  • LDC – Classification happens based on the value obtained from the linear combination of the feature values, which are usually provided in the form of vector features.
  • k-NN – Classification happens by locating the object in the feature space, and comparing it with the k nearest neighbors (training examples). The majority vote decides on the classification.
  • GMM – is a probabilistic model used for representing the existence of subpopulations within the overall population. Each sub-population is described using the mixture distribution, which allows for classification of observations into the sub-populations.
  • SVM – is a type of (usually binary) linear classifier which decides in which of the two (or more) possible classes, each input may fall into.
  • ANN – is a mathematical model, inspired by biological neural networks, that can better grasp possible non-linearities of the feature space.
  • Decision tree algorithms – work based on following a decision tree in which leaves represent the classification outcome, and branches represent the conjunction of subsequent features that lead to the classification.
  • HMMs – a statistical Markov model in which the states and state transitions are not directly available to observation. Instead, the series of outputs dependent on the states are visible. In the case of affect recognition, the outputs represent the sequence of speech feature vectors, which allow the deduction of states' sequences through which the model progressed. The states can consist of various intermediate steps in the expression of an emotion, and each of them has a probability distribution over the possible output vectors. The states' sequences allow us to predict the affective state which we are trying to classify, and this is one of the most commonly used techniques within the area of speech affect detection.

It is proved that having enough acoustic evidence available the emotional state of a person can be classified by a set of majority voting classifiers. The proposed set of classifiers is based on three main classifiers: kNN, C4.5 and SVM-RBF Kernel. This set achieves better performance than each basic classifier taken separately. It is compared with two other sets of classifiers: one-against-all (OAA) multiclass SVM with Hybrid kernels and the set of classifiers which consists of the following two basic classifiers: C5.0 and Neural Network. The proposed variant achieves better performance than the other two sets of classifiers.

Databases

The vast majority of present systems are data-dependent. This creates one of the biggest challenges in detecting emotions based on speech, as it implicates choosing an appropriate database used to train the classifier. Most of the currently possessed data was obtained from actors and is thus a representation of archetypal emotions. Those so-called acted databases are usually based on the Basic Emotions theory (by Paul Ekman), which assumes the existence of six basic emotions (anger, fear, disgust, surprise, joy, sadness), the others simply being a mix of the former ones. Nevertheless, these still offer high audio quality and balanced classes (although often too few), which contribute to high success rates in recognizing emotions.

However, for real life application, naturalistic data is preferred. A naturalistic database can be produced by observation and analysis of subjects in their natural context. Ultimately, such database should allow the system to recognize emotions based on their context as well as work out the goals and outcomes of the interaction. The nature of this type of data allows for authentic real life implementation, due to the fact it describes states naturally occurring during the human–computer interaction (HCI).

Despite the numerous advantages which naturalistic data has over acted data, it is difficult to obtain and usually has low emotional intensity. Moreover, data obtained in a natural context has lower signal quality, due to surroundings noise and distance of the subjects from the microphone. The first attempt to produce such database was the FAU Aibo Emotion Corpus for CEICES (Combining Efforts for Improving Automatic Classification of Emotional User States), which was developed based on a realistic context of children (age 10–13) playing with Sony's Aibo robot pet. Likewise, producing one standard database for all emotional research would provide a method of evaluating and comparing different affect recognition systems.

Speech descriptors

The complexity of the affect recognition process increases with the number of classes (affects) and speech descriptors used within the classifier. It is, therefore, crucial to select only the most relevant features in order to assure the ability of the model to successfully identify emotions, as well as increasing the performance, which is particularly significant to real-time detection. The range of possible choices is vast, with some studies mentioning the use of over 200 distinct features. It is crucial to identify those that are redundant and undesirable in order to optimize the system and increase the success rate of correct emotion detection. The most common speech characteristics are categorized into the following groups.

  1. Frequency characteristics
    • Accent shape – affected by the rate of change of the fundamental frequency.
    • Average pitch – description of how high/low the speaker speaks relative to the normal speech.
    • Contour slope – describes the tendency of the frequency change over time, it can be rising, falling or level.
    • Final lowering – the amount by which the frequency falls at the end of an utterance.
    • Pitch range – measures the spread between the maximum and minimum frequency of an utterance.
  2. Time-related features:
    • Speech rate – describes the rate of words or syllables uttered over a unit of time
    • Stress frequency – measures the rate of occurrences of pitch accented utterances
  3. Voice quality parameters and energy descriptors:
    • Breathiness – measures the aspiration noise in speech
    • Brilliance – describes the dominance of high Or low frequencies In the speech
    • Loudness – measures the amplitude of the speech waveform, translates to the energy of an utterance
    • Pause Discontinuity – describes the transitions between sound and silence
    • Pitch Discontinuity – describes the transitions of the fundamental frequency.

Facial affect detection

The detection and processing of facial expression are achieved through various methods such as optical flow, hidden Markov models, neural network processing or active appearance models. More than one modalities can be combined or fused (multimodal recognition, e.g. facial expressions and speech prosody, facial expressions and hand gestures, or facial expressions with speech and text for multimodal data and metadata analysis) to provide a more robust estimation of the subject's emotional state.

Facial expression databases

Creation of an emotion database is a difficult and time-consuming task. However, database creation is an essential step in the creation of a system that will recognize human emotions. Most of the publicly available emotion databases include posed facial expressions only. In posed expression databases, the participants are asked to display different basic emotional expressions, while in spontaneous expression database, the expressions are natural. Spontaneous emotion elicitation requires significant effort in the selection of proper stimuli which can lead to a rich display of intended emotions. Secondly, the process involves tagging of emotions by trained individuals manually which makes the databases highly reliable. Since perception of expressions and their intensity is subjective in nature, the annotation by experts is essential for the purpose of validation.

Researchers work with three types of databases, such as a database of peak expression images only, a database of image sequences portraying an emotion from neutral to its peak, and video clips with emotional annotations. Many facial expression databases have been created and made public for expression recognition purpose. Two of the widely used databases are CK+ and JAFFE.

Emotion classification

By doing cross-cultural research in Papua New Guinea, on the Fore Tribesmen, at the end of the 1960s, Paul Ekman proposed the idea that facial expressions of emotion are not culturally determined, but universal. Thus, he suggested that they are biological in origin and can, therefore, be safely and correctly categorized. He therefore officially put forth six basic emotions, in 1972:

However, in the 1990s Ekman expanded his list of basic emotions, including a range of positive and negative emotions not all of which are encoded in facial muscles. The newly included emotions are:

  1. Amusement
  2. Contempt
  3. Contentment
  4. Embarrassment
  5. Excitement
  6. Guilt
  7. Pride in achievement
  8. Relief
  9. Satisfaction
  10. Sensory pleasure
  11. Shame

Facial Action Coding System

A system has been conceived by psychologists in order to formally categorize the physical expression of emotions on faces. The central concept of the Facial Action Coding System, or FACS, as created by Paul Ekman and Wallace V. Friesen in 1978 based on earlier work by Carl-Herman Hjortsjö are action units (AU). They are, basically, a contraction or a relaxation of one or more muscles. Psychologists have proposed the following classification of six basic emotions, according to their action units ("+" here mean "and"):

Emotion Action units
Happiness 6+12
Sadness 1+4+15
Surprise 1+2+5B+26
Fear 1+2+4+5+20+26
Anger 4+5+7+23
Disgust 9+15+16
Contempt R12A+R14A

Challenges in facial detection

As with every computational practice, in affect detection by facial processing, some obstacles need to be surpassed, in order to fully unlock the hidden potential of the overall algorithm or method employed. In the early days of almost every kind of AI-based detection (speech recognition, face recognition, affect recognition), the accuracy of modeling and tracking has been an issue. As hardware evolves, as more data are collected and as new discoveries are made and new practices introduced, this lack of accuracy fades, leaving behind noise issues. However, methods for noise removal exist including neighborhood averaging, linear Gaussian smoothing, median filtering, or newer methods such as the Bacterial Foraging Optimization Algorithm.

Other challenges include

  • The fact that posed expressions, as used by most subjects of the various studies, are not natural, and therefore algorithms trained on these may not apply to natural expressions.
  • The lack of rotational movement freedom. Affect detection works very well with frontal use, but upon rotating the head more than 20 degrees, "there've been problems".
  • Facial expressions do not always correspond to an underlying emotion that matches them (e.g. they can be posed or faked, or a person can feel emotions but maintain a "poker face").
  • FACS did not include dynamics, while dynamics can help disambiguate (e.g. smiles of genuine happiness tend to have different dynamics than "try to look happy" smiles.)
  • The FACS combinations do not correspond in a 1:1 way with the emotions that the psychologists originally proposed (note that this lack of a 1:1 mapping also occurs in speech recognition with homophones and homonyms and many other sources of ambiguity, and may be mitigated by bringing in other channels of information).
  • Accuracy of recognition is improved by adding context; however, adding context and other modalities increases computational cost and complexity

Body gesture

Gestures could be efficiently used as a means of detecting a particular emotional state of the user, especially when used in conjunction with speech and face recognition. Depending on the specific action, gestures could be simple reflexive responses, like lifting your shoulders when you don't know the answer to a question, or they could be complex and meaningful as when communicating with sign language. Without making use of any object or surrounding environment, we can wave our hands, clap or beckon. On the other hand, when using objects, we can point at them, move, touch or handle these. A computer should be able to recognize these, analyze the context and respond in a meaningful way, in order to be efficiently used for Human–Computer Interaction.

There are many proposed methods to detect the body gesture. Some literature differentiates 2 different approaches in gesture recognition: a 3D model based and an appearance-based. The foremost method makes use of 3D information of key elements of the body parts in order to obtain several important parameters, like palm position or joint angles. On the other hand, appearance-based systems use images or videos to for direct interpretation. Hand gestures have been a common focus of body gesture detection methods.

Physiological monitoring

This could be used to detect a user's affective state by monitoring and analyzing their physiological signs. These signs range from changes in heart rate and skin conductance to minute contractions of the facial muscles and changes in facial blood flow. This area is gaining momentum and we are now seeing real products that implement the techniques. The four main physiological signs that are usually analyzed are blood volume pulse, galvanic skin response, facial electromyography, and facial color patterns.

Blood volume pulse

Overview

A subject's blood volume pulse (BVP) can be measured by a process called photoplethysmography, which produces a graph indicating blood flow through the extremities. The peaks of the waves indicate a cardiac cycle where the heart has pumped blood to the extremities. If the subject experiences fear or is startled, their heart usually 'jumps' and beats quickly for some time, causing the amplitude of the cardiac cycle to increase. This can clearly be seen on a photoplethysmograph when the distance between the trough and the peak of the wave has decreased. As the subject calms down, and as the body's inner core expands, allowing more blood to flow back to the extremities, the cycle will return to normal.

Methodology

Infra-red light is shone on the skin by special sensor hardware, and the amount of light reflected is measured. The amount of reflected and transmitted light correlates to the BVP as light is absorbed by hemoglobin which is found richly in the bloodstream.

Disadvantages

It can be cumbersome to ensure that the sensor shining an infra-red light and monitoring the reflected light is always pointing at the same extremity, especially seeing as subjects often stretch and readjust their position while using a computer. There are other factors that can affect one's blood volume pulse. As it is a measure of blood flow through the extremities, if the subject feels hot, or particularly cold, then their body may allow more, or less, blood to flow to the extremities, all of this regardless of the subject's emotional state.

The corrugator supercilii muscle and zygomaticus major muscle are the 2 main muscles used for measuring the electrical activity, in facial electromyography.

Facial electromyography

Facial electromyography is a technique used to measure the electrical activity of the facial muscles by amplifying the tiny electrical impulses that are generated by muscle fibers when they contract. The face expresses a great deal of emotion, however, there are two main facial muscle groups that are usually studied to detect emotion: The corrugator supercilii muscle, also known as the 'frowning' muscle, draws the brow down into a frown, and therefore is the best test for negative, unpleasant emotional response.↵The zygomaticus major muscle is responsible for pulling the corners of the mouth back when you smile, and therefore is the muscle used to test for a positive emotional response.

Here we can see a plot of skin resistance measured using GSR and time whilst the subject played a video game. There are several peaks that are clear in the graph, which suggests that GSR is a good method of differentiating between an aroused and a non-aroused state. For example, at the start of the game where there is usually not much exciting game play, there is a high level of resistance recorded, which suggests a low level of conductivity and therefore less arousal. This is in clear contrast with the sudden trough where the player is killed as one is usually very stressed and tense as their character is killed in the game.

Galvanic skin response

Galvanic skin response (GSR) is an outdated term for a more general phenomenon known as [Electrodermal Activity] or EDA. EDA is a general phenomena whereby the skin's electrical properties change. The skin is innervated by the [sympathetic nervous system], so measuring its resistance or conductance provides a way to quantify small changes in the sympathetic branch of the autonomic nervous system. As the sweat glands are activated, even before the skin feels sweaty, the level of the EDA can be captured (usually using conductance) and used to discern small changes in autonomic arousal. The more aroused a subject is, the greater the skin conductance tends to be.

Skin conductance is often measured using two small silver-silver chloride electrodes placed somewhere on the skin and applying a small voltage between them. To maximize comfort and reduce irritation the electrodes can be placed on the wrist, legs, or feet, which leaves the hands fully free for daily activity.

Facial color

Overview

The surface of the human face is innervated with a large network of blood vessels. Blood flow variations in these vessels yield visible color changes on the face. Whether or not facial emotions activate facial muscles, variations in blood flow, blood pressure, glucose levels, and other changes occur. Also, the facial color signal is independent from that provided by facial muscle movements.

Methodology

Approaches are based on facial color changes. Delaunay triangulation is used to create the triangular local areas. Some of these triangles which define the interior of the mouth and eyes (sclera and iris) are removed. Use the left triangular areas’ pixels to create feature vectors. It shows that converting the pixel color of the standard RGB color space to a color space such as oRGB color space or LMS channels perform better when dealing with faces. So, map the above vector onto the better color space and decompose into red-green and yellow-blue channels. Then use deep learning methods to find equivalent emotions.

Visual aesthetics

Aesthetics, in the world of art and photography, refers to the principles of the nature and appreciation of beauty. Judging beauty and other aesthetic qualities is a highly subjective task. Computer scientists at Penn State treat the challenge of automatically inferring the aesthetic quality of pictures using their visual content as a machine learning problem, with a peer-rated on-line photo sharing website as a data source. They extract certain visual features based on the intuition that they can discriminate between aesthetically pleasing and displeasing images.

Potential applications

Education

Affection influences learners' learning state. Using affective computing technology, computers can judge the learners' affection and learning state by recognizing their facial expressions. In education, the teacher can use the analysis result to understand the student's learning and accepting ability, and then formulate reasonable teaching plans. At the same time, they can pay attention to students' inner feelings, which is helpful to students' psychological health. Especially in distance education, due to the separation of time and space, there is no emotional incentive between teachers and students for two-way communication. Without the atmosphere brought by traditional classroom learning, students are easily bored, and affect the learning effect. Applying affective computing in distance education system can effectively improve this situation. 

Healthcare

Social robots, as well as a growing number of robots used in health care benefit from emotional awareness because they can better judge users' and patient's emotional states and alter their actions/programming appropriately. This is especially important in those countries with growing aging populations and/or a lack of younger workers to address their needs.

Affective computing is also being applied to the development of communicative technologies for use by people with autism. The affective component of a text is also increasingly gaining attention, particularly its role in the so-called emotional or emotive Internet.

Video games

Affective video games can access their players' emotional states through biofeedback devices. A particularly simple form of biofeedback is available through gamepads that measure the pressure with which a button is pressed: this has been shown to correlate strongly with the players' level of arousal; at the other end of the scale are brain–computer interfaces. Affective games have been used in medical research to support the emotional development of autistic children.

Other applications

Other potential applications are centered around social monitoring. For example, a car can monitor the emotion of all occupants and engage in additional safety measures, such as alerting other vehicles if it detects the driver to be angry. Affective computing has potential applications in human–computer interaction, such as affective mirrors allowing the user to see how he or she performs; emotion monitoring agents sending a warning before one sends an angry email; or even music players selecting tracks based on mood.

One idea put forth by the Romanian researcher Dr. Nicu Sebe in an interview is the analysis of a person's face while they are using a certain product (he mentioned ice cream as an example). Companies would then be able to use such analysis to infer whether their product will or will not be well received by the respective market.

One could also use affective state recognition in order to judge the impact of a TV advertisement through a real-time video recording of that person and through the subsequent study of his or her facial expression. Averaging the results obtained on a large group of subjects, one can tell whether that commercial (or movie) has the desired effect and what the elements which interest the watcher most are.

Cognitivist vs. interactional approaches

Within the field of human–computer interaction, Rosalind Picard's cognitivist or "information model" concept of emotion has been criticized by and contrasted with the "post-cognitivist" or "interactional" pragmatist approach taken by Kirsten Boehner and others which views emotion as inherently social.

Picard's focus is human–computer interaction, and her goal for affective computing is to "give computers the ability to recognize, express, and in some cases, 'have' emotions". In contrast, the interactional approach seeks to help "people to understand and experience their own emotions" and to improve computer-mediated interpersonal communication. It does not necessarily seek to map emotion into an objective mathematical model for machine interpretation, but rather let humans make sense of each other's emotional expressions in open-ended ways that might be ambiguous, subjective, and sensitive to context.

Picard's critics describe her concept of emotion as "objective, internal, private, and mechanistic". They say it reduces emotion to a discrete psychological signal occurring inside the body that can be measured and which is an input to cognition, undercutting the complexity of emotional experience.

The interactional approach asserts that though emotion has biophysical aspects, it is "culturally grounded, dynamically experienced, and to some degree constructed in action and interaction". Put another way, it considers "emotion as a social and cultural product experienced through our interactions".

Metabolomics

From Wikipedia, the free encyclopedia
The central dogma of biology showing the flow of information from DNA to the phenotype. Associated with each stage is the corresponding systems biology tool, from genomics to metabolomics.

Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles. The metabolome represents the complete set of metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular processes.[2] Messenger RNA (mRNA), gene expression data, and proteomic analyses reveal the set of gene products being produced in the cell, data that represents one aspect of cellular function. Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell, and thus, metabolomics provides a direct "functional readout of the physiological state" of an organism. There are indeed quantifiable correlations between the metabolome and the other cellular ensembles (genome, transcriptome, proteome, and lipidome), which can be used to predict metabolite abundances in biological samples from, for example mRNA abundances. One of the ultimate challenges of systems biology is to integrate metabolomics with all other -omics information to provide a better understanding of cellular biology.

History

The concept that individuals might have a "metabolic profile" that could be reflected in the makeup of their biological fluids was introduced by Roger Williams in the late 1940s, who used paper chromatography to suggest characteristic metabolic patterns in urine and saliva were associated with diseases such as schizophrenia. However, it was only through technological advancements in the 1960s and 1970s that it became feasible to quantitatively (as opposed to qualitatively) measure metabolic profiles. The term "metabolic profile" was introduced by Horning, et al. in 1971 after they demonstrated that gas chromatography-mass spectrometry (GC-MS) could be used to measure compounds present in human urine and tissue extracts. The Horning group, along with that of Linus Pauling and Arthur B. Robinson led the development of GC-MS methods to monitor the metabolites present in urine through the 1970s.

Concurrently, NMR spectroscopy, which was discovered in the 1940s, was also undergoing rapid advances. In 1974, Seeley et al. demonstrated the utility of using NMR to detect metabolites in unmodified biological samples. This first study on muscle highlighted the value of NMR in that it was determined that 90% of cellular ATP is complexed with magnesium. As sensitivity has improved with the evolution of higher magnetic field strengths and magic angle spinning, NMR continues to be a leading analytical tool to investigate metabolism. Recent efforts to utilize NMR for metabolomics have been largely driven by the laboratory of Jeremy K. Nicholson at Birkbeck College, University of London and later at Imperial College London. In 1984, Nicholson showed 1H NMR spectroscopy could potentially be used to diagnose diabetes mellitus, and later pioneered the application of pattern recognition methods to NMR spectroscopic data.

In 1994 and 1996 liquid chromatography mass spectrometry metabolomics experiments were performed by Gary Siuzdak while working with Richard Lerner (then president of The Scripps Research Institute) and Benjamin Cravatt, to analyze the cerebral spinal fluid from sleep deprived animals. One molecule of particular interest, oleamide, was observed and later shown to have sleep inducing properties. This work is one of the earliest such experiments combining liquid chromatography and mass spectrometry in metabolomics.

In 2005, the first metabolomics tandem mass spectrometry database, METLIN, for characterizing human metabolites was developed in the Siuzdak laboratory at The Scripps Research Institute. METLIN has since grown and as of July 1, 2019, METLIN contains over 450,000 metabolites and other chemical entities, each compound having experimental tandem mass spectrometry data generated from molecular standards at multiple collision energies and in positive and negative ionization modes. METLIN is the largest repository of tandem mass spectrometry data of its kind. The dedicated academic journal Metabolomics first appeared in 2005, founded by its current editor-in-chief Roy Goodacre.

In 2005, the Siuzdak lab was engaged in identifying metabolites associated with sepsis and in an effort to address the issue of statistically identifying the most relevant dysregulated metabolites across hundreds of LC/MS datasets, the first algorithm was developed to allow for the nonlinear alignment of mass spectrometry metabolomics data. Called XCMS, it has since (2012) been developed as an online tool and as of 2019 (with METLIN) has over 30,000 registered users.

On 23 January 2007, the Human Metabolome Project, led by David S. Wishart, completed the first draft of the human metabolome, consisting of a database of approximately 2,500 metabolites, 1,200 drugs and 3,500 food components. Similar projects have been underway in several plant species, most notably Medicago truncatula and Arabidopsis thaliana for several years.

As late as mid-2010, metabolomics was still considered an "emerging field". Further, it was noted that further progress in the field depended in large part, through addressing otherwise "irresolvable technical challenges", by technical evolution of mass spectrometry instrumentation.

In 2015, real-time metabolome profiling was demonstrated for the first time.

Metabolome

Human metabolome project

The metabolome refers to the complete set of small-molecule (<1.5 kDa) metabolites (such as metabolic intermediates, hormones and other signaling molecules, and secondary metabolites) to be found within a biological sample, such as a single organism. The word was coined in analogy with transcriptomics and proteomics; like the transcriptome and the proteome, the metabolome is dynamic, changing from second to second. Although the metabolome can be defined readily enough, it is not currently possible to analyse the entire range of metabolites by a single analytical method.

The first metabolite database (called METLIN) for searching fragmentation data from tandem mass spectrometry experiments was developed by the Siuzdak lab at The Scripps Research Institute in 2005. METLIN contains over 450,000 metabolites and other chemical entities, each compound having experimental tandem mass spectrometry data. In 2006, the Siuzdak lab also developed the first algorithm to allow for the nonlinear alignment of mass spectrometry metabolomics data. Called XCMS, where the "X" constitutes any chromatographic technology, it has been developed as an online tool.

In January 2007, scientists at the University of Alberta and the University of Calgary completed the first draft of the human metabolome. The Human Metabolome Database (HMDB) is perhaps the most extensive public metabolomic spectral database to date and is a freely available electronic database (www.hmdb.ca) containing detailed information about small molecule metabolites found in the human body. It is intended to be used for applications in metabolomics, clinical chemistry, biomarker discovery and general education. The database is designed to contain or link three kinds of data:

  1. Chemical data,
  2. Clinical data and
  3. Molecular biology/biochemistry data.

The database contains 220,945 metabolite entries including both water-soluble and lipid soluble metabolites. Additionally, 8,610 protein sequences (enzymes and transporters) are linked to these metabolite entries. Each MetaboCard entry contains 130 data fields with 2/3 of the information being devoted to chemical/clinical data and the other 1/3 devoted to enzymatic or biochemical data. The version 3.5 of the HMDB contains >16,000 endogenous metabolites, >1,500 drugs and >22,000 food constituents or food metabolites. This information, available at the Human Metabolome Database and based on analysis of information available in the current scientific literature, is far from complete. In contrast, much more is known about the metabolomes of other organisms. For example, over 50,000 metabolites have been characterized from the plant kingdom, and many thousands of metabolites have been identified and/or characterized from single plants.

Each type of cell and tissue has a unique metabolic ‘fingerprint’ that can elucidate organ or tissue-specific information. Bio-specimens used for metabolomics analysis include but not limit to plasma, serum, urine, saliva, feces, muscle, sweat, exhaled breath and gastrointestinal fluid. The ease of collection facilitates high temporal resolution, and because they are always at dynamic equilibrium with the body, they can describe the host as a whole. Genome can tell what could happen, transcriptome can tell what appears to be happening, proteome can tell what makes it happen and metabolome can tell what has happened and what is happening.

Metabolites

Metabolites are the substrates, intermediates and products of metabolism. Within the context of metabolomics, a metabolite is usually defined as any molecule less than 1.5 kDa in size. However, there are exceptions to this depending on the sample and detection method. For example, macromolecules such as lipoproteins and albumin are reliably detected in NMR-based metabolomics studies of blood plasma. In plant-based metabolomics, it is common to refer to "primary" and "secondary" metabolites. A primary metabolite is directly involved in the normal growth, development, and reproduction. A secondary metabolite is not directly involved in those processes, but usually has important ecological function. Examples include antibiotics and pigments. By contrast, in human-based metabolomics, it is more common to describe metabolites as being either endogenous (produced by the host organism) or exogenous. Metabolites of foreign substances such as drugs are termed xenometabolites.

The metabolome forms a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other chemical reactions. Such systems have been described as hypercycles.

Metabonomics

Metabonomics is defined as "the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification". The word origin is from the Greek μεταβολή meaning change and nomos meaning a rule set or set of laws. This approach was pioneered by Jeremy Nicholson at Murdoch University and has been used in toxicology, disease diagnosis and a number of other fields. Historically, the metabonomics approach was one of the first methods to apply the scope of systems biology to studies of metabolism.

There has been some disagreement over the exact differences between 'metabolomics' and 'metabonomics'. The difference between the two terms is not related to choice of analytical platform: although metabonomics is more associated with NMR spectroscopy and metabolomics with mass spectrometry-based techniques, this is simply because of usages amongst different groups that have popularized the different terms. While there is still no absolute agreement, there is a growing consensus that 'metabolomics' places a greater emphasis on metabolic profiling at a cellular or organ level and is primarily concerned with normal endogenous metabolism. 'Metabonomics' extends metabolic profiling to include information about perturbations of metabolism caused by environmental factors (including diet and toxins), disease processes, and the involvement of extragenomic influences, such as gut microflora. This is not a trivial difference; metabolomic studies should, by definition, exclude metabolic contributions from extragenomic sources, because these are external to the system being studied. However, in practice, within the field of human disease research there is still a large degree of overlap in the way both terms are used, and they are often in effect synonymous.

Exometabolomics

Exometabolomics, or "metabolic footprinting", is the study of extracellular metabolites. It uses many techniques from other subfields of metabolomics, and has applications in biofuel development, bioprocessing, determining drugs' mechanism of action, and studying intercellular interactions.

Analytical technologies

Key stages of a metabolomics study

The typical workflow of metabolomics studies is shown in the figure. First, samples are collected from tissue, plasma, urine, saliva, cells, etc. Next, metabolites extracted often with the addition of internal standards and derivatization. During sample analysis, metabolites are quantified (liquid chromatography or gas chromatography coupled with MS and/or NMR spectroscopy). The raw output data can be used for metabolite feature extraction and further processed before statistical analysis (such as PCA). Many bioinformatic tools and software are available to identify associations with disease states and outcomes, determine significant correlations, and characterize metabolic signatures with existing biological knowledge.

Separation methods

Initially, analytes in a metabolomic sample comprise a highly complex mixture. This complex mixture can be simplified prior to detection by separating some analytes from others. Separation achieves various goals: analytes which cannot be resolved by the detector may be separated in this step; in MS analysis, ion suppression is reduced; the retention time of the analyte serves as information regarding its identity. This separation step is not mandatory and is often omitted in NMR and "shotgun" based approaches such as shotgun lipidomics.

Gas chromatography (GC), especially when interfaced with mass spectrometry (GC-MS), is a widely used separation technique for metabolomic analysis. GC offers very high chromatographic resolution, and can be used in conjunction with a flame ionization detector (GC/FID) or a mass spectrometer (GC-MS). The method is especially useful for identification and quantification of small and volatile molecules. However, a practical limitation of GC is the requirement of chemical derivatization for many biomolecules as only volatile chemicals can be analysed without derivatization. In cases where greater resolving power is required, two-dimensional chromatography (GCxGC) can be applied.

High performance liquid chromatography (HPLC) has emerged as the most common separation technique for metabolomic analysis. With the advent of electrospray ionization, HPLC was coupled to MS. In contrast with GC, HPLC has lower chromatographic resolution, but requires no derivatization for polar molecules, and separates molecules in the liquid phase. Additionally HPLC has the advantage that a much wider range of analytes can be measured with a higher sensitivity than GC methods.

Capillary electrophoresis (CE) has a higher theoretical separation efficiency than HPLC (although requiring much more time per separation), and is suitable for use with a wider range of metabolite classes than is GC. As for all electrophoretic techniques, it is most appropriate for charged analytes.

Detection methods

Mass spectrometry (MS) is used to identify and quantify metabolites after optional separation by GC, HPLC, or CE. GC-MS was the first hyphenated technique to be developed. Identification leverages the distinct patterns in which analytes fragment. These patterns can be thought of as a mass spectral fingerprint. Libraries exist that allow identification of a metabolite according to this fragmentation pattern. MS is both sensitive and can be very specific. There are also a number of techniques which use MS as a stand-alone technology: the sample is infused directly into the mass spectrometer with no prior separation, and the MS provides sufficient selectivity to both separate and to detect metabolites.

For analysis by mass spectrometry, the analytes must be imparted with a charge and transferred to the gas phase. Electron ionization (EI) is the most common ionization technique applied to GC separations as it is amenable to low pressures. EI also produces fragmentation of the analyte, both providing structural information while increasing the complexity of the data and possibly obscuring the molecular ion. Atmospheric-pressure chemical ionization (APCI) is an atmospheric pressure technique that can be applied to all the above separation techniques. APCI is a gas phase ionization method, which provides slightly more aggressive ionization than ESI which is suitable for less polar compounds. Electrospray ionization (ESI) is the most common ionization technique applied in LC/MS. This soft ionization is most successful for polar molecules with ionizable functional groups. Another commonly used soft ionization technique is secondary electrospray ionization (SESI).

In the 2000s, surface-based mass analysis has seen a resurgence, with new MS technologies focused on increasing sensitivity, minimizing background, and reducing sample preparation. The ability to analyze metabolites directly from biofluids and tissues continues to challenge current MS technology, largely because of the limits imposed by the complexity of these samples, which contain thousands to tens of thousands of metabolites. Among the technologies being developed to address this challenge is Nanostructure-Initiator MS (NIMS), a desorption/ ionization approach that does not require the application of matrix and thereby facilitates small-molecule (i.e., metabolite) identification. MALDI is also used; however, the application of a MALDI matrix can add significant background at <1000 Da that complicates analysis of the low-mass range (i.e., metabolites). In addition, the size of the resulting matrix crystals limits the spatial resolution that can be achieved in tissue imaging. Because of these limitations, several other matrix-free desorption/ionization approaches have been applied to the analysis of biofluids and tissues.

Secondary ion mass spectrometry (SIMS) was one of the first matrix-free desorption/ionization approaches used to analyze metabolites from biological samples. SIMS uses a high-energy primary ion beam to desorb and generate secondary ions from a surface. The primary advantage of SIMS is its high spatial resolution (as small as 50 nm), a powerful characteristic for tissue imaging with MS. However, SIMS has yet to be readily applied to the analysis of biofluids and tissues because of its limited sensitivity at >500 Da and analyte fragmentation generated by the high-energy primary ion beam. Desorption electrospray ionization (DESI) is a matrix-free technique for analyzing biological samples that uses a charged solvent spray to desorb ions from a surface. Advantages of DESI are that no special surface is required and the analysis is performed at ambient pressure with full access to the sample during acquisition. A limitation of DESI is spatial resolution because "focusing" the charged solvent spray is difficult. However, a recent development termed laser ablation ESI (LAESI) is a promising approach to circumvent this limitation. Most recently, ion trap techniques such as orbitrap mass spectrometry are also applied to metabolomics research.

Nuclear magnetic resonance (NMR) spectroscopy is the only detection technique which does not rely on separation of the analytes, and the sample can thus be recovered for further analyses. All kinds of small molecule metabolites can be measured simultaneously - in this sense, NMR is close to being a universal detector. The main advantages of NMR are high analytical reproducibility and simplicity of sample preparation. Practically, however, it is relatively insensitive compared to mass spectrometry-based techniques.

Although NMR and MS are the most widely used, modern day techniques other methods of detection that have been used. These include Fourier-transform ion cyclotron resonance, ion-mobility spectrometry, electrochemical detection (coupled to HPLC), Raman spectroscopy and radiolabel (when combined with thin-layer chromatography).

Table 1. Comparison of most common used metabolomics methods
Technology Sensitivity (LOD) Sample volume Compatible with gases Compatible with liquids Compatible with solids Start-up cost Can be used in metabolite imaging (MALDI or DESI) Advantages Disadvantages
GC-MS 0.5 µM 0.1-0.2 mL Yes Yes No <$300,000 No
  • Quantitative (with calibration)
  • Large body of software and databases for metabolite identification
  • Detects most organic and some inorganic molecules
  • Excellent separation reproductibility
  • Destructive (not recoverable)
  • Requires sample separation
  • Slow (20—40 min per sample)
LC-MS 0.5 nM 10—100 µL No Yes Yes >$300,000 Yes
  • Very flexible technology
  • Detects most organic and some inorganic molecules
  • Destructive (not recoverable)
  • Not very quantitative
  • Slow (15—40 min per sample)
  • Usually requires separation
NMR spectroscopy 5 µM 10—100 µL No Yes Yes >US$1 million Yes
  • Very flexible technology
  • Detects most organic and some inorganic molecules
  • Large instrument footprint
  • Cannot detect or identify salts and inorganic ions
  • Cannot detect non-protonated compounds
  • Requires large sample volumes (0.1—0.5 mL)

Statistical methods

The data generated in metabolomics usually consist of measurements performed on subjects under various conditions. These measurements may be digitized spectra, or a list of metabolite features. In its simplest form, this generates a matrix with rows corresponding to subjects and columns corresponding with metabolite features (or vice versa). Several statistical programs are currently available for analysis of both NMR and mass spectrometry data. A great number of free software are already available for the analysis of metabolomics data shown in the table. Some statistical tools listed in the table were designed for NMR data analyses were also useful for MS data. For mass spectrometry data, software is available that identifies molecules that vary in subject groups on the basis of mass-over-charge value and sometimes retention time depending on the experimental design.

Once metabolite data matrix is determined, unsupervised data reduction techniques (e.g. PCA) can be used to elucidate patterns and connections. In many studies, including those evaluating drug-toxicity and some disease models, the metabolites of interest are not known a priori. This makes unsupervised methods, those with no prior assumptions of class membership, a popular first choice. The most common of these methods includes principal component analysis (PCA) which can efficiently reduce the dimensions of a dataset to a few which explain the greatest variation. When analyzed in the lower-dimensional PCA space, clustering of samples with similar metabolic fingerprints can be detected. PCA algorithms aim to replace all correlated variables with a much smaller number of uncorrelated variables (referred to as principal components (PCs)) and retain most of the information in the original dataset. This clustering can elucidate patterns and assist in the determination of disease biomarkers - metabolites that correlate most with class membership.

Linear models are commonly used for metabolomics data, but are affected by multicollinearity. On the other hand, multivariate statistics are thriving methods for high-dimensional correlated metabolomics data, of which the most popular one is Projection to Latent Structures (PLS) regression and its classification version PLS-DA. Other data mining methods, such as random forest, support-vector machines, etc. are received increasing attention for untargeted metabolomics data analysis. In the case of univariate methods, variables are analyzed one by one using classical statistics tools (such as Student's t-test, ANOVA or mixed models) and only these with sufficient small p-values are considered relevant. However, correction strategies should be used to reduce false discoveries when multiple comparisons are conducted since there is no standard method for measuring the total amount of metabolites directly in untargeted metabolomics. For multivariate analysis, models should always be validated to ensure that the results can be generalized.

Machine learning and data mining

Machine learning is a powerful tool that can be used in metabolomics analysis. Recently, scientists have developed retention time prediction software. These tools allow researchers to apply artificial intelligence to the retention time prediction of small molecules in complex mixture, such as human plasma, plant extracts, foods, or microbial cultures. Retention time prediction increases the identification rate in liquid chromatography and can lead to an improved biological interpretation of metabolomics data.

Key applications

Toxicity assessment/toxicology by metabolic profiling (especially of urine or blood plasma samples) detects the physiological changes caused by toxic insult of a chemical (or mixture of chemicals). In many cases, the observed changes can be related to specific syndromes, e.g. a specific lesion in liver or kidney. This is of particular relevance to pharmaceutical companies wanting to test the toxicity of potential drug candidates: if a compound can be eliminated before it reaches clinical trials on the grounds of adverse toxicity, it saves the enormous expense of the trials.

For functional genomics, metabolomics can be an excellent tool for determining the phenotype caused by a genetic manipulation, such as gene deletion or insertion. Sometimes this can be a sufficient goal in itself—for instance, to detect any phenotypic changes in a genetically modified plant intended for human or animal consumption. More exciting is the prospect of predicting the function of unknown genes by comparison with the metabolic perturbations caused by deletion/insertion of known genes. Such advances are most likely to come from model organisms such as Saccharomyces cerevisiae and Arabidopsis thaliana. The Cravatt laboratory at The Scripps Research Institute has recently applied this technology to mammalian systems, identifying the N-acyltaurines as previously uncharacterized endogenous substrates for the enzyme fatty acid amide hydrolase (FAAH) and the monoalkylglycerol ethers (MAGEs) as endogenous substrates for the uncharacterized hydrolase KIAA1363.

Metabologenomics is a novel approach to integrate metabolomics and genomics data by correlating microbial-exported metabolites with predicted biosynthetic genes. This bioinformatics-based pairing method enables natural product discovery at a larger-scale by refining non-targeted metabolomic analyses to identify small molecules with related biosynthesis and to focus on those that may not have previously well known structures.

Fluxomics is a further development of metabolomics. The disadvantage of metabolomics is that it only provides the user with abundances or concentrations of metabolites, while fluxomics determines the reaction rates of metabolic reactions and can trace metabolites in a biological system over time.

Nutrigenomics is a generalised term which links genomics, transcriptomics, proteomics and metabolomics to human nutrition. In general, in a given body fluid, a metabolome is influenced by endogenous factors such as age, sex, body composition and genetics as well as underlying pathologies. The large bowel microflora are also a very significant potential confounder of metabolic profiles and could be classified as either an endogenous or exogenous factor. The main exogenous factors are diet and drugs. Diet can then be broken down to nutrients and non-nutrients. Metabolomics is one means to determine a biological endpoint, or metabolic fingerprint, which reflects the balance of all these forces on an individual's metabolism. Thanks to recent cost reductions, metabolomics has now become accessible for companion animals, such as pregnant dogs.

Plant metabolomics is designed to study the overall changes in metabolites of plant samples and then conduct deep data mining and chemometric analysis. Specialized metabolites are considered components of plant defense systems biosynthesized in response to biotic and abiotic stresses.Metabolomics approaches have recently been used to assess the natural variance in metabolite content between individual plants, an approach with great potential for the improvement of the compositional quality of crops.

Mixed reality

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Mixed_reality

Mixed reality (MR) is a term used to describe the merging of a real-world environment and a computer-generated one. Physical and virtual objects may co-exist in mixed reality environments and interact in real time.

Mixed reality that incorporates haptics has sometimes been referred to as Visuo-haptic mixed reality.

In a physics context, the term "interreality system" refers to a virtual reality system coupled with its real-world counterpart. A 2007 paper describes an interreality system comprising a real physical pendulum coupled to a pendulum that only exists in virtual reality. This system has two stable states of motion: a "Dual Reality" state in which the motion of the two pendula are uncorrelated, and a "Mixed Reality" state in which the pendula exhibit stable phase-locked motion, which is highly correlated. The use of the terms "mixed reality" and "interreality" is clearly defined in the context of physics and may be slightly different in other fields, however, it is generally seen as, "bridging the physical and virtual world".

Applications

Mixed reality has been used in applications across fields including design, education, entertainment, military training, healthcare, product content management, and human-in-the-loop operation of robots.

Education

Simulation-based learning includes VR and AR based training and interactive, experiential learning. There are many potential use cases for Mixed Reality in both educational settings and professional training settings. Notably in education, AR has been used to simulate historical battles, providing an unparalleled immersive experience for students and potentially enhanced learning experiences. In addition, AR has shown effectiveness in university education for health science and medical students within disciplines that benefit from 3D representations of models, such as physiology and anatomy.

Entertainment

From television shows to game consoles, mixed reality has many applications in the field of entertainment.

The 2004 British game show Bamzooki called upon child contestants to create virtual "Zooks" and watch them compete in a variety of challenges. The show used mixed reality to bring the Zooks to life. The television show ran for one season, ending in 2010.

The 2003 game show FightBox also called upon contestants to create competitive characters and used mixed reality to allow them to interact. Unlike Bamzoomi's generally non-violent challenges, the goal of FightBox was for new contestants to create the strongest fighter to win the competition.

In 2009, researchers presented to the International Symposium on Mixed and Augmented Reality (ISMAR) their social product called "BlogWall," which consisted of a projected screen on a wall. Users could post short text clips or images on the wall and play simple games such as Pong. The BlogWall also featured a poetry mode where it would rearrange the messages it received to form a poem and a polling mode where users could ask others to answer their polls.

Mario Kart Live: Home Circuit is a mixed reality racing game for the Nintendo Switch that was released in October 2020.[16a-New] The game allows players to use their home as a race track. Within the first week of release, 73,918 copies were sold in Japan, making it the country's best selling game of the week.

Other research has examined the potential for mixed reality to be applied to theatre, film, and theme parks.

Military training

The first fully immersive mixed reality system was the Virtual Fixtures platform, which was developed in 1992 by Louis Rosenberg at the Armstrong Laboratories of the United States Air Force. It enabled human users to control robots in real-world environments that included real physical objects and 3D virtual overlays ("fixtures") that were added enhance human performance of manipulation tasks. Published studies showed that by introducing virtual objects into the real world, significant performance increases could be achieved by human operators.

Combat reality can be simulated and represented using complex, layered data and visual aides, most of which are head-mounted displays (HMD), which encompass any display technology that can be worn on the user's head. Military training solutions are often built on commercial off-the-shelf (COTS) technologies, such as Improbable's synthetic environment platform, Virtual Battlespace 3 and VirTra, with the latter two platforms used by the United States Army. As of 2018, VirTra is being used by both civilian and military law enforcement to train personnel in a variety of scenarios, including active shooter, domestic violence, and military traffic stops. Mixed reality technologies have been used by the United States Army Research Laboratory to study how this stress affects decision-making. With mixed reality, researchers may safely study military personnel in scenarios where soldiers would not likely survive.

In 2017, the U.S. Army was developing the Synthetic Training Environment (STE), a collection of technologies for training purposes that was expected to include mixed reality. As of 2018, STE was still in development without a projected completion date. Some recorded goals of STE included enhancing realism and increasing simulation training capabilities and STE availability to other systems.

It was claimed that mixed-reality environments like STE could reduce training costs, such as reducing the amount of ammunition expended during training. In 2018, it was reported that STE would include representation of any part of the world's terrain for training purposes. STE would offer a variety of training opportunities for squad brigade and combat teams, including Stryker, armory, and infantry teams.

BlueRoomTM 

BlueRoom, is a mixed reality (MR) technology utilising the Varjo XR3 headset designed to blend both real and synthetic worlds, allowing users to practice fine motor skills combined with decision-making in a reconfigurable virtual world. The system was invented by an Australian company called Real Response.

MR allows users to hone their physical and fine motor skills with actual tools, rather than relying on controllers, as is the case in VR. Additionally, MR allows users to enter the virtual world as themselves, providing a more immersive experience that is closer to real-world interactions.

Specifically, BlueRoom allows medics to insert an IV and draw up medications in the back of a C130J Hercules as they fly across the Pacific Ocean, or insert a chest tube as they prepare to takeoff with a patient in the back of a C17 Globemaster - all while they are safely on the ground. This system is not limited to medical capability and can be expanded to support multiple training and operational capabilities.

This military medical mixed reality (MR) simulator was developed for the Australian Defence Force (ADF) through funding from a Defence Innovation Hub contract and is currently in use by the ADF. 

Blended spaces

A blended space is a space in which a physical environment and a virtual environment are deliberately integrated in a close knit way. The aim of blended space design is to provide people with the experience of feeling a sense of presence in the blended space, acting directly on the content of the blended space. Examples of blended spaces include augmented reality devices such as the Microsoft HoloLens and games such as Pokémon Go in addition to many smartphone tourism apps, smart meeting rooms and applications such as bus tracker systems.

The idea of blending comes from the ideas of conceptual integration, or conceptual blending introduced by Gilles Fauconnier and Mark Turner.

Manuel Imaz and David Benyon introduced blending theory to look at concepts in software engineering and human-computer interaction.

The simplest implementation of a blended space requires two features. The first required feature is input. The input can range from tactile, to changes in the environment. The next required feature is notifications received from the digital spaces. The correspondences between the physical and digital space have to be abstracted and exploited by the design of the blended space. Seamless integration of both the spaces is rare. Blended spaces need anchoring points or technologies to link the spaces.


A well designed blended space advertises and conveys the digital content in a subtle and unobtrusive way. Presence can be measured using physiological, behavioral, and subjective measures derived from the space.

Conceptual Blending in Mixed Reality Spaces

There are two main components to any space. They are:

  1. Objects – The actual distinct objects which make up the medium/space. The objects thus effectively describe the space.
  2. Agents – Correspondents/users inside the space who interact with it through the objects.


For presence in a blended space, there must be a physical space and a digital space. In the context of blended space, the higher the communication between the physical and digital spaces, the richer the experience. This communication happens through the medium of correspondents which relay the state and nature of objects.
For the purpose of looking at blended spaces, the nature and characteristics of any space can be represented by these factors:

  1. Ontology – Different types of objects present in the space the total number of objects and the relationships between objects and the space.
  2. Topology – The way objects are placed and positioned.
  3. Volatility – Frequency with which the objects change.
  4. Agency – Medium of communication between the objects, and between the objects and users. Agency also encompasses the users inside the space.


Physical Space – Physical spaces are spaces which afford spatial interaction. This kind of spatial interaction greatly impacts the user's cognitive model.
Digital Space – Digital space (also called the information space) consists of all the information content. This content can be in any form.

Remote working

Mixed reality allows a global workforce of remote teams to work together and tackle an organization's business challenges. No matter where they are physically located, an employee can wear a headset and noise-canceling headphones and enter a collaborative, immersive virtual environment. As these applications can accurately translate in real time, language barriers become irrelevant. This process also increases flexibility. While many employers still use inflexible models of fixed working time and location, there is evidence that employees are more productive if they have greater autonomy over where, when, and how they work. Some employees prefer loud work environments, while others need silence. Some work best in the morning; others work best at night. Employees also benefit from autonomy in how they work because of different ways of processing information. The classic model for learning styles differentiates between Visual, Auditory, and Kinesthetic learners.

Machine maintenance can also be executed with the help of mixed reality. Larger companies with multiple manufacturing locations and a lot of machinery can use mixed reality to educate and instruct their employees. The machines need regular checkups and have to be adjusted every now and then. These adjustments are mostly done by humans, so employees need to be informed about needed adjustments. By using mixed reality, employees from multiple locations can wear headsets and receive live instructions about the changes. Instructors can operate the representation that every employee sees, and can glide through the production area, zooming in to technical details and explaining every change needed. Employees completing a five-minute training session with such a mixed-reality program have been shown to attain the same learning results as reading a 50-page training manual. An extension to this environment is the incorporation of live data from operating machinery into the virtual collaborative space and then associated with three dimensional virtual models of the equipment. This enables training and execution of maintenance, operational and safety work processes, which would otherwise be difficult in a live setting, while making use of expertise, no matter their physical location.

Functional mockup

Mixed reality can be used to build mockups that combine physical and digital elements. With the use of simultaneous localization and mapping (SLAM), mockups can interact with the physical world to gain control of more realistic sensory experiences  like object permanence, which would normally be infeasible or extremely difficult to track and analyze without the use of both digital and physical aides.

Healthcare

Smartglasses can be incorporated into the operating room to aide in surgical procedures; possibly displaying patient data conveniently while overlaying precise visual guides for the surgeon. Mixed reality headsets like the Microsoft HoloLens have been theorized to allow for efficient sharing of information between doctors, in addition to providing a platform for enhanced training. This can, in some situations (i.e. patient infected with contagious disease), improve doctor safety and reduce PPE use. While mixed reality has lots of potential for enhancing healthcare, it does have some drawbacks too. The technology may never fully integrate into scenarios when a patient is present, as there are ethical concerns surrounding the doctor not being able to see the patient. Mixed reality is also useful for healthcare education. For example, according to a 2022 report from the World Economic Forum, 85% of first-year medical students at Case Western Reserve University reported that mixed reality for teaching anatomy was “equivalent” or “better” than the in-person class.

Product content management

Product content management before the advent of Mixed Reality consisted largely of brochures and little customer-product engagement outside of this 2-dimensional realm. With mixed reality technology improvements, new forms of interactive product content management has emerged.  Most notably, 3-dimensional digital renderings of normally 2-dimensional products have increased reachability and effectiveness of consumer-product interaction.

Human-in-the-loop operation of robots

Recent advances in mixed-reality technologies have renewed interest in alternative modes of communication for human-robot interaction. Human operators wearing mixed reality glasses such as HoloLens can interact with (control and monitor) e.g. robots and lifting machines on site in a digital factory setup. This use case typically requires real-time data communication between a mixed reality interface with the machine / process / system, which could be enabled by incorporating digital twin technology.

Business firms

Mixed reality allows sellers to show the customers how a certain commodity will suit their demands. A seller may demonstrate how a certain product will fit into the homes of the buyer. The buyer with the assistance of the VR can virtually pick the item, spin around and place to their desired points. This improves the buyer’s confidence of making a purchase and reduces the number of returns.

Architectural firms can allow customers to virtually visit their desired homes.

Display technologies and Products

While Mixed Reality refers to the intertwining of the virtual world and the physical world at a high level, there are a variety of digital mediums used to accomplish a mixed reality environment. They may range from handheld devices to entire rooms, each having practical uses in different disciplines.

Cave Automatic Virtual Environment

A user standing in the middle of a Cave Automatic Virtual Environment

The Cave Automatic Virtual Environment (CAVE) is an environment, typically a small room located in a larger outer room, in which a user is surrounded by projected displays around them, above them, and below them. 3D glasses and surround sound complement the projections to provide the user with a sense of perspective that aims to simulate the physical world. Since being developed, CAVE systems have been adopted by engineers developing and testing prototype products. They allow product designers to test their prototypes before expending resources to produce a physical prototype, while also opening doors for "hands-on" testing on non-tangible objects such as microscopic environments or entire factory floors. After developing the CAVE, the same researchers eventually released the CAVE2, which builds off of the original CAVE's shortcomings. The original projections were substituted  for 37 megapixel 3D LCD panels, network cables integrate the CAVE2 with the internet, and a more precise camera system allows the environment to shift as the user moves throughout it.

Head-up display

Photograph of the Head-up display of a F/A-18C.

Head-up display (HUD) is a display that projects imagery directly in front of a viewer without heavily obfuscating their environment. A standard HUD is composed of three elements: a projector, which is responsible for overlaying the graphics of the HUD, the combiner, which is the surface the graphics are projected onto, and the computer, which integrates the two other components and computes any real-time calculations or adjustments. Prototype HUDs were first used in military applications to aid fighter pilots in combat, but eventually evolved to aid in all aspects of flight - not just combat. HUDs were then standardized across commercial aviation as well, eventually creeping into the automotive industry. One of the first applications of HUD in automotive transport came with Pioneer's Heads-up system, which replaces the driver-side sun visor with a display that projects navigation instructions onto the road in front of the driver. Major manufacturers such as General Motors, Toyota, Audi, and BMW have since included some form of head-up display in certain models.

Head-mounted display

An Augmented reality head-mounted display

A head-mounted display (HMD), worn over the entire head or worn in front of the eyes, is a device that uses one or two optics to project an image directly in front of the user's eyes. Its applications range across medicine, entertainment, aviation, and engineering, providing a layer of visual immersion that traditional displays cannot achieve. Head-mounted displays are most popular with consumers in the entertainment market, with major tech companies developing HMDs to complement their existing products. However, these head-mounted displays are virtual reality displays and do not integrate the physical world. Popular augmented reality HMDs, however, are more favorable in enterprise environments. Microsoft's HoloLens is an augmented reality HMD that has applications in medicine, giving doctors more profound real-time insight, as well as engineering, overlaying important information on top of the physical world. Another notable augmented reality HMD has been developed by Magic Leap, a startup developing a similar product with applications in both the private sector and the consumer market.

Mobile devices

Mobile devices, including smartphones and tablets, have continued to increase in computing power and portability. Many modern mobile devices come equipped with toolkits for developing augmented reality applications. These applications allow developers to overlay computer graphics over videos of the physical world. The first augmented reality mobile game with widespread success was Pokémon GO, which released in 2016 and accumulated 800 million downloads. While entertainment applications utilizing AR have proven successful, productivity and utility apps have also begun integrating AR features. Google has released updates to their Google Maps application that includes AR navigation directions overlaid onto the streets in front of the user, as well as expanding their translate app to overlay translated text onto physical writing in over 20 foreign languages. Mobile devices are unique display technologies due to the fact that they are commonly equipped at all times.

Pythagoras

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Pythagoras   Pythagoras Bust of Pythago...