A team from Rensselaer Polytechnic Institute has proven that computer software
Glycosaminoglycans - a complex repertoiresequences, like a work of Shakespeare - a complex set of letters. It takes an expert to write them, just as it takes an expert to read them. We trained the machine to quickly read the equivalent of four-letter words such as ababab or bcbcbc. These are simple sequences that have no meaning. However, they showed that a machine can be taught to read. If we scale up and develop this technology, it has the potential to sequence glycans or even proteins in real time without taking years.
Robert Linhardt, lead researcher and professor. in chemistry and chemical biology at Rensselaer Polytechnic Institute
Commercial sequencing devicesnanopores are used for DNA sequencing. It is made up of four nucleic acid units, known as the letters A, C, G, and T, linked together in an infinite variety of configurations. The device uses an ionic current through a hole in the membrane only a few billionths of a meter wide. DNA strands are placed on one side of the hole and pulled through it with current. Each nucleic acid blocks the hole to some extent as it passes, disrupting the current and giving a specific signal associated with that nucleic acid. The devices now being used for field research are just one of several relatively fast and automated DNA sequencing methods.
Glycosaminoglycans (GAG) area structurally complex class of glycans. These are essential sugars found in living organisms. They have multiple functions in cell growth and signaling, anticoagulation, and wound healing. Today, glycosaminoglycans are extracted from slaughtered animals and used as medicines and nutraceuticals.
Like DNA, they can be divided intotheir constituent disaccharide sugar units. But while DNA consists of only four letters in a linear string, glycans have dozens of basic units. Some of them have sulfate, acid and amide groups attached. For example, even a relatively small naturally occurring heparan sulfate molecule of six sugar units may have 32,768 possible sequences. Glycan sequencing remains cumbersome, relying on painstaking laboratory work and complex analysis using techniques such as liquid chromatography and tandem mass spectrometry and nuclear magnetic resonance spectroscopy.
Nanopore and imaging software can sequence sulfated glycosaminoglycan in real time. Credit: Rensselaer Polytechnic Institute.
Scientists have developed a synthetic version of the common blood-thinning heparin. He is sequencing the GAG to understand naturally occurring forms and to develop synthetic variants.
The team of scientists skipped every heparan sulfatethrough the nanopores and built a graph showing the output voltage of the device versus time. Each of the four variants passed through the device more than 2,000 times, which increased the statistical probability of accurate reading, taking into account the elementary design of the experimental nanopore.
The device sequenced the simplest heparan sulfate in real time and created a pattern that scientists can easily recognize for each of the four samples at once. It is immediately clear that they are different.
To provide an objective analysis, the teamuploaded the results to free machine learning and image recognition software. They used Google's deep neural network to train software to distinguish four different patterns and identify each variant of heparan sulfate. The most successful model gave an analysis with an accuracy of almost 97%.
GAG sequence information contentcan significantly exceed the same amount of DNA or RNA. This means that the ability to read them quickly opens up a new window for understanding the complex biochemistry of life. Proof-of-concept research links innovative nanoscale detection techniques to state-of-the-art machine learning tools.
Decreasing the rate at which glycosaminoglycanspass through the nanopores, will increase the accuracy, and the device can be trained on more complex sequences. However, scientists have already reduced the time required for sequencing key GAG molecules from a few years to minutes.
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Glycosaminoglycans, mucopolysaccharides —the carbohydrate part of proteoglycans, polysaccharides, which include amino sugars-hexosamines. In the body, glycosaminoglycans are covalently bound to the protein part of proteoglycans and are not found in free form.
NMR spectroscopy - spectroscopic methodresearch of chemical objects using the phenomenon of nuclear magnetic resonance. The NMR phenomenon was discovered in 1946 by the American physicists F. Bloch and E. Persel.
Liquid chromatography and tandem mass spectrometry is a widely used method of chemical analysis that combines the physical separation of liquid chromatography with mass spectrometry.