Sunday reading (27.03)
Review of scientific periodicals for March 21-27
Ksenia Morozova, PCR.news
Intercellular communication
1. Extracellular vesicles are the most important pathway of intercellular signaling, their study is of great interest. The authors of the article published in Current Biology have developed a method for labeling the contents of extracellular vesicles in the nematode body Caenorhabditis elegans and carried out extensive work to isolate them. Comparing the data of proteomic and transcriptomic analyses, they found out that a significant part of the contents of vesicles produced by nerve cells are RNA molecules and RNA-binding proteins. They also showed that extracellular vesicles are heterogeneous in composition, and identified four proteins that are most commonly found in the vesicles of nerve cells. elegans, among them the phosphatase ENPP-1 and the double-stranded RNA transporter SID-2. Extracellular vesicles in the human brain can carry proteins associated with the development of Alzheimer's disease, their study can help in the development of new therapies, the authors note.
Stem cells
2. Scientists from the Guangzhou Institute of Biomedicine and Healthcare of the Chinese Academy of Sciences, together with colleagues from the UK and Bangladesh, for the first time in the world described a fast and controlled method for obtaining totipotent stem cells from pluripotent ones without the use of transgenic technologies. They are similar to cells formed at the stage of an 8-cell embryo during zygote fragmentation, and have a potential for differentiation greater than that of the pluripotent cells described earlier. The discovery was facilitated by advances in the field of multiomic profiling of individual cells: the authors identified key molecular events and genes associated with the transition to totipotence, and activated the expression of these genes. The authors suggest that it will be possible to grow organs from the obtained cells for the needs of transplantology.
Artificial intelligence
3. The use of artificial intelligence systems has made it possible to take another step towards the effective automation of gene editing. The system for automatic electroporation NFP-E (Nanofountain Probe Electroporation) developed by scientists from the USA uses deep learning to accurately detect cell nuclei and control the position of the probe generating electrical impulses. As the authors note, most methods either provide a good yield, but require millions of cells, or allow selective action on individual cells with a sufficiently low efficiency; it is difficult to achieve selectivity and high yield at the same time. The new method ensures high efficiency of transfection and at the same time allows you to work with small amounts of cells without loss.
4. Scientists from the Research Institute of the New York Stem Cell Foundation (NYSCF Research Institute) together with Google Research have developed a platform for phenotypic profiling of cell cultures - The NYSCF Global Stem Cell Array. It uses a unique technique of multiple cell staining Cell Painting and deep learning neural networks to process the resulting images. The effectiveness of the platform for the isolation and classification of fibroblasts from healthy donors and patients with Parkinson's disease (91 people) was demonstrated; the authors generated the largest array of Cell Painting staining data with a volume of 48 TB. The neural network was able to identify both individual features of fibroblasts of each patient, and features specific to two forms of Parkinson's disease. According to the authors, the platform will greatly simplify the development of medicines.
5. Artificial intelligence systems can be used not only for automation of biomedical research. A common area of AI research is the analysis of images obtained by computed tomography (CT). The authors of the article published in The Lancet Digital Health analyzed CT angiography data to simplify the assessment of plaque formation in patients' vessels. The neural network was trained on a dataset from the results of CT angiography of 921 patients already described by doctors: on average, it takes a specialist 25-30 minutes to do this, and the new algorithm copes in a few seconds. The neural network predicted the risk of a heart attack fairly accurately, which was tested on data from 1,611 patients obtained as part of the SCOT-HEART study. The authors expect that the algorithm will allow to estimate the probability and approximate timing of myocardial infarction, based on CT images of plaques in blood vessels.
Biomarkers
6. After the discovery of biomarkers of the disease, it is necessary to check their clinical significance for different cohorts of subjects. Thus, the level of certain substances in the blood may be associated with the risk of developing dementia and Alzheimer's disease. Researchers from Texas analyzed blood samples from 745 Mexican Americans to assess the reliability of such an analysis. The panel included 6 biomarkers previously associated with an increased risk of neurodegenerative diseases, however, the study showed that only the content of glial fibrillary acidic protein (GFAP) can reliably predict the likelihood of developing dementia in the selected group. The authors note that additional validating studies will be required before this biomarker, alone or in combination with those not yet studied, finds application in clinical practice.
7. Significant progress has been made in the treatment of cancer in children, but patients in remission often develop diseases more characteristic of older age groups. Having obtained data from genome-wide sequencing of more than 6,000 patients who survived childhood cancer as part of the St. Jude Hospital Cohort Study from Memphis, USA (St. Jude Lifetime Cohort Study, SJLIFE), scientists identified genetic variants characteristic of patients with accelerated epigenetic aging. One of these variants turned out to be the rs732314 allele of the SELP gene: other studies have described an association of increased SELP expression with the risk of developing Alzheimer's disease. Another variant was associated with the HLA locus. The authors hope that their work will help identify patients more susceptible to accelerated epigenetic aging, as well as identify targets for preventing the development of diseases. For example, an inhibitor is already known for p-selectin, a product of the SELP gene, which is used in the treatment of other diseases.
8. Idiopathic pulmonary fibrosis is a serious disease of often unclear origin, in which lung damage leads to the formation of scar tissue. Is known. that one of the causes of fibrosis may be the pro-apoptotic peptide corizine, which is secreted by staphylococci in lung infections, and a group of researchers from the United States suggested that antibodies to this peptide can improve the prognosis for patients. They injected synthetic corisine into mice and identified monoclonal antibodies that proved to be the most effective, mAb 21A. They also showed that the level of corizine in the blood is elevated in patients with fibrosis, and its determination can be a safe alternative to collecting bronchoalveolar lavage — a more invasive method of diagnosing fibrosis. Staphylococci can also transmit the corizine gene to bacteria that are part of the microflora of the lungs and intestines by horizontal transfer, which creates additional difficulties in treatment. Corizine is dangerous not only for the lungs, but also for other tissues and organs.
Infections (host-targeted therapy)
9. The proteins of the host cell are necessary for the effective operation of the polymerase of the Ebola virus. Scientists from the USA investigated the interaction of viral particles with cells and identified two proteins that inhibit the work of viral polymerase at the initial stages of infection: GSPT1, a translation termination factor, and UPF1, involved in splicing. However, it turned out that switching occurs at later stages of the disease: GSPT1 begins to participate in the normal termination of viral RNA transcription, which leads to positive transcription regulation. GSPT1 has not previously been associated with viral infections. The authors also showed that when cells are treated with CC-90009, which leads to the degradation of GSPT1, the reproduction of the virus slows down. This substance was first described as a potential drug for patients with acute myeloid leukemia. The authors hope that studies of CC-90009 or other drugs with a similar effect will open the way to a cure for the Ebola virus.
10. Drugs targeting host cell proteins can be effective not only in the treatment of viral diseases. Researchers from Canada have shown that exposure to PPM1A phosphatase can significantly reduce the survival of Mycobacterium tuberculosis in macrophages and lungs of infected mice. Normally, PPM1A suppresses selective autophagy in infected cells. The authors used biomimetic approaches and functionally-oriented synthesis to obtain and test more than 500 artificially created drugs and identify a PPM1A inhibitor with potential for use in therapy. Such an inhibitor turned out to be SMIP-30, a small molecule that is not toxic to cells. The use of SMIP-30 made it possible to activate selective autophagy and more effectively protect the body from the development of tuberculosis. According to the authors, the development of drugs focused on interactions with host proteins is especially important for the treatment of infections caused by antibiotic-resistant pathogens.
Personalized drug development
11. Personalized cancer vaccines can become a reality thanks to an international group of researchers who have proposed a method for selecting and isolating the most immunogenic peptides on the surfaces of tumor cells. The resulting antigens are recognized by T cells and cause a powerful and specific immune response. The authors identified more than 8000 potential peptide targets from the CT26 colorectal cancer cell line and selected the most promising ones using RNA sequencing and special software. After all the selection stages, oncolytic adenovirus vaccines were created based on the six remaining peptides, which were tested on mice with vaccinated tumors. One of the vaccines proved to be effective not only when injected into the tumor area, but also in the treatment of a tumor located on the opposite side from the injection site — this result indicates the formation of immunity. The adenovirus vector has already passed clinical trials and can be used as a platform for a wide range of peptides, and the selection methods proposed by the authors will allow the development of oncolytic vaccines quickly and efficiently.
12. A new method of computer modeling of protein-protein interactions will help simplify the development of drugs that bind to protein targets in cells. Researchers from the USA and Belgium used de novo development of protein ligands to 12 target proteins based on their three-dimensional structure. The resulting sequences of up to 65 amino acids were characterized by high stability. The authors resolved the crystal structure of five ligand-target complexes and showed that it coincides fairly accurately with the simulation results. The algorithm is able to search for potential interaction sites, generate protein sequences targeted at these sites, and select the most optimal candidates. Among the analyzed targets were proteins of varying complexity from cellular receptors to virus envelope proteins.
Neurons for making informed decisions
13. When making decisions, we take into account both potential benefits and risks: it turns out that there is a special group of neurons in the striatum of the brain for this. It was discovered by scientists from the Massachusetts Institute of Technology. They developed a special test, during which the mice had to try to get as much reward as possible with the least risk. The mice rotated the wheel, and each turn could, with varying probability, bring a reward – sweetened water — or negative reinforcement (a small trickle of air into the nose). Observing the calcium activity of neurons using two-photon microscopy during the training of mice, the researchers isolated populations of cells associated with reward and punishment systems when making decisions, and found that some neurons are activated with both positive and negative results. Studying the activity of these cells will help to get an idea of the decision-making process that is disrupted in mental illnesses such as depression, obsessive-compulsive disorder and others. Potential methods of their treatment may be aimed at the stage of encoding information about the results of decision-making.
Phase transitions in the cell and embryogenesis
14. Phase transitions in biosystems play an important role in the dynamics of lipid membranes and can affect the functions of membrane proteins, but this is not the only area where this physical process is involved. Scientists have shown the importance of the transition from liquid to solid phase in condensed ribonucleoprotein droplets containing oskar mRNA – an important factor in embryogenesis in drosophila. These droplets are not surrounded by membranes, and when their contents are in a liquid state, mRNA molecules can be embedded in them, and during the transition to the crystalline state, embedding is impossible. This makes it possible to limit the space inside the cell in which Oskar translation is carried out: a violation of the structure of the drop, in which it became liquid again, led to serious violations in embryonic development. This method of compartmentalization of cellular contents is described for the first time.
Company news
15. Oxford Nanopore Technologies plans to develop clinical diagnostic tools with the help of a newly created subsidiary of Oxford Nanopore Diagnostics. On Tuesday, at a teleconference dedicated to the company's financial results for 2021, Oxford Nanopore CEO Gordon Sangera spoke about the applications of nanopore sequencing in clinical translational research, including infectious diseases, oncology, rare hereditary diseases and rapid sequencing in intensive care. OND is a separate technical and commercial team, Sanger told investors, adding that its goal is to sell nanopore technologies to "traditional big players to see where the traction will be."
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