Sunday reading (22.05)
Review of scientific periodicals for May 16-22
Anastasia Gorshkova, PCR.news
Aging1. A research team from Cambridge studied the relationship of the epigenetic clock with other markers of cellular aging on the primary culture of human fibroblasts.
Epigenetic age is calculated by the degree of methylation of the CpG islands of differentiated cells, it coincides in all human somatic cells and increases with biological age. In tumor cells, the epigenetic age is noticeably reduced. Epidemiological studies have linked the acceleration of epigenetic aging with a variety of causes. Thus, the state of health, lifestyle, mental state and even environmental factors affect aging. To describe in more detail the mechanisms of counting epigenetic age, scientists have tested how epigenetic aging is associated with the manifestation of other signs of aging. The study showed that nutrient availability, mitochondrial activity, depletion of the stem cell pool and changes in intercellular communication affect epigenetic aging, while cellular aging, telomere shortening and genomic instability do not affect. As part of the new work, experiments were conducted only on primary cultures of human fibroblasts, so in the future the authors plan to investigate the relationship of these mechanisms in mouse models.
2. Another article about aging, published in the journal Nature Aging, demonstrated that the induction of mitochondrial autophagy increases life expectancy in fruit flies. It is known that the level of mitophagy, or autophagy of non-functional mitochondria, decreases with age, and its activation should help reduce the level of reactive oxygen species and reduce neuroinflammation. Therefore, the ways of influencing mitophagy are a promising target for the search for drugs that slow down aging and the progression of neurodegenerative diseases. Scientists from the USA have found that overexpression of the BNIP3 protein in drosophila brain cells induces mitophagy and prevents the accumulation of non-functional mitochondria in the aging brain. To do this, they used a genetically modified line of fruit flies expressing the desired protein in neurons. BNIP3 has an atypical location for proteins of its family — on the outer membrane of mitochondria, and also participates in proapoptotic signaling pathways, which explains the revealed effect. It is important to note that the induction of BNIP3-mediated mitophagy also increased life expectancy and improved health in flies. Thus, BNIP3 is a promising target for the creation of a drug against cellular aging.
Genetics and aging
3. One of the most common and significant health consequences of aging is hearing impairment and loss. An international team of scientists conducted a GWAS using data from 723,300 people and identified 48 genetic loci affecting the development of pathology, ten of them were new. This full—genome meta-analysis in the field of hearing genetics is one of the largest to date. Further, by sequencing single brain cells and the mouse auditory system, the scientists saw that many pathogenic variants are expressed in the cells of the cochlea vascular strip, but not in the brain. This indicates the importance of the influence on hearing loss of processes that occur directly with sensory hair cells, for example, such as the organization of the cytoskeleton,
Oncology
4. Breast cancer in men is much less common than in women. To date, its relationship with reproductive functions has not been studied well enough, despite the well-known association of this cancer with sex hormones. The authors from the Institute of Cancer Research in London studied the link between infertility or lack of children and the risk of breast cancer in men. Scientists interviewed 1998 men under the age of 80 who were diagnosed with breast cancer between 2005 and 2017. The control group included 1,597 men who were not blood relatives of any of the experimental group. A measure of the relationship of a potential cause with a disease for such studies is the odds ratio (OR, odd ratio). The risk of breast cancer in men was statistically significantly associated with male infertility (OR = 2.03). The risk was higher for men who had no children (OR = 1.50) compared to fathers. These associations were found only for invasive tumors. The authors write that it is necessary to further investigate the cause of the revealed link between breast cancer and male infertility.
5. A new study by scientists from the USA and Germany has shown that in acute lymphoblastic leukemia (ALL), an unusually high level of methylation of the genome of cancer cells is observed. The researchers conducted genome-wide bisulfite sequencing of cancer cells obtained from 82 children with ALL. They found that CpG hypermethylation persists despite the cancer cell phenotype. For a long time it was believed that hypomethylation always accompanies oncogenesis, but in T-cell leukemia, the distribution of DNA methylation patterns is comparable to the distribution in healthy T-cell precursors. Next, the researchers analyzed the activity of genes associated with epigenetic regulation. It turned out that the promoter of the TET2 gene was hypermethylated in more than a quarter of T-cell ALL samples, and the expression of this gene was reduced. DNMT3B, the gene encoding DNA methyltransferase, on the contrary, was expressed more strongly in this type of leukemia. Based on these results, the authors suggest that the study of the methylome will help to better understand the general epigenetic changes in cancer.Cardiovascular diseases
6. Scientists have discovered a protein in cardiomyocytes that regulates heart stiffness, which could potentially lead to the discovery of a new therapy for cardiovascular diseases. For optimal contraction and relaxation, it is necessary to maintain a certain level of stiffness of the heart muscle. Aging, stress, hypertension and obesity can lead to increased stiffness, and the heart will not be able to effectively relax and fill with blood, which will lead to diastolic dysfunction. The scientists found that the stiffness of myofibrils was increased in mice knocked out by the histone deacetylase 6 (HDAC6) gene. These mice also developed diastolic dysfunction and hypertension. The use of a selective HDAC6 inhibitor on the primary culture of myocytes of healthy adult mice also caused an increase in the stiffness of myofibrils. Conversely, overexpression of HDAC6 in cardiomyocytes and their treatment with recombinant protein ex vivo led to a decrease in the stiffness of myofibrils. Proteomic analysis showed that HDAC6 in cardiomyocytes functions as a sarcomeric protein deacetylase and is responsible for deacetylation of the PEVK domain of titin, the largest mammalian protein. The results of the study showed that HDAC6 deacetylase controls the function of myocardial stiffness and is a potential target for manipulating the elastic properties of the heart in the treatment of cardiovascular diseases.
7. Analysis of chromatin availability (ATAC-seq) at the level of single cells allowed scientists from the USA to find out the molecular basis of coronary heart disease. Coronary heart disease (CHD) is a complex inflammatory disease, in the pathogenesis of which different types of cells are involved. Earlier, with the help of GWAS, it became clear that most of the mutations that increase the risk of coronary heart disease are in non-coding DNA sequences. The authors of the new study analyzed chromatin available for transposase in 28,316 nuclei isolated from frozen preparations of coronary artery segments from 41 patients with various stages of coronary artery disease. The analysis revealed 14 cell clusters, as well as several variants significant for the progression of the disease. According to the data obtained, the key regulators of the pathogenesis of the disease are transcription factors PRDM16 and TBX2, and scientists tested this using immunohistochemical staining on PRDM16. Its expression did noticeably increase with the progression of coronary heart disease. The authors hope that their research will be the key to the discovery of new drugs for coronary heart disease.Molecular Biology
8. PNAS published an article describing the mechanisms of crossing in the nematode C. elegans. Meiotic recombination begins with the formation of numerous double-stranded DNA breaks, but only a few eventually pass through the crossover. For a long time it remained unclear how this process is regulated to ensure that each pair of homologous chromosomes forms at least one recombination site. Scientists have shown that CDK-2 kinase interacts with the cyclin-like protein COSA-1 and promotes the formation of a crossover chromosome through phosphorylation and activation of the MutSy complex. The target of phosphorylase is a MutSy component called MSH-5. It has an unordered C-terminal domain, which contains 13 potential phosphorylation sites and is necessary for the concentration of crossing-promoting proteins in recombination sites. The scientists also described the regulation of crossing-over as a positive feedback model, where the process depends on the phosphorylation of MutSy. The concentration of factors contributing to crossing over may be a universal mechanism for regulating this process in eukaryotes.
9. For a long time there was a debate about the existence of metal chaperones that bind zinc ions and distribute them throughout the cell. The fact is that, unlike many other metal ions, zinc does not interact with oxygen and does not form active forms, which means that the cell does not need to protect itself from it. On the other hand, the function of metal chaperones is also to ensure the interaction of metal ions with proteins that need them in conditions of ion deficiency. The dispute ended with the discovery of GTP-dependent zinc transferase Zng1 in yeast, binding zinc ions and transferring them to Map1p aminopeptidase. In colonies knocked out by the ZNG1 gene, Map1p activity decreased, and the negative effect increased in an environment with a low zinc content. In vitro experiments on isolated proteins have shown that Map1p does not work in the absence of zinc. But the protein did not start working even when Zng1 and zinc were added to the solution. The authors have shown that Zng1 needs to be activated using GTP.Genetic engineering
10. Scientists from the USA have created a high-performance automatic platform for the assembly of plasmids called PlasmidMaker. The user-friendly interface of the program allows you to assemble a plasmid and send an order to the iBioFAB company, which accepts the order, manufactures structures and checks their quality. The assembly is carried out by a robotic platform, thanks to which the entire process of building plasmids becomes automated. The platform works on the basis of a new method of assembling several DNA fragments into a plasmid using artificial restriction enzymes (ARE) based on Pyrococcus furiosus Argonaute (PfAgo). The peculiarity of the use of these restrictases is that they introduce a gap in the gene region complementary to their guide DNA added from the outside. Theoretically, they can cut any DNA fragment anywhere, and in a very specific way. The scientists tested the assembly of 101 plasmids and showed that the new method allows synthesizing fragments with a GC content of up to 77% and accurately assembling plasmids up to 27 t.n. in size, including those containing multiple repeats.
Company news
11. Merger of three partner companies: BC Platforms, Euformatics and Oncompass Medicine, has won a contract to develop a standardized NGS protocol for the treatment of oncology in seven Central European hospitals. Companies will also integrate, standardize and analyze the results of oncogenes testing, pharmacogenomic testing and drug databases to support decision-making by doctors. The contract is partially financed within the framework of the European Union Horizon 2020 project in the amount of 8 million euros. The BC, Euformatics and Oncompass Medicine platforms will start working immediately and should present preliminary results by August, after which a consortium of hospitals will evaluate the services and decide whether they should continue working.
12. On Wednesday, Illumina announced that it has started a collaboration with Allegheny Health Network to evaluate the possibility of using genomic profiling kits at home to select a cancer treatment strategy. Companies will find out in which cases testing of tissue and blood samples may be useful when choosing a therapy. Financial and other details were not disclosed. The project will last one year with the possibility of expanding the range of clinical trials.Personalized medicine
13. A study published in the journal Nature Medicine has shown that molecular profiling of rheumatoid arthritis-affected joint tissue can significantly improve understanding of whether specific medications will be effective for treating a patient. Scientists conducted a clinical study involving 164 patients with arthritis, during which their reaction to rituximab or tocilizumab, two drugs for the treatment of rheumatoid arthritis, was tested. Rituximab is a monoclonal antibody to CD20, and tocilizumab is to the IL6 receptor. Histological analysis of inflamed joint tissue, as well as RNA-seq cells of synovial fluid was performed. The results showed that only 12% of patients with a low content of synovial B cells had a response to rituximab, and a response to tocilizumab was observed in 50% of patients. In subjects with a high content of B cells, these two drugs turned out to be approximately the same in effectiveness. Based on histological and molecular data, the researchers applied machine learning techniques to develop computer algorithms that could predict the response to the drug in individual patients by complex signatures. The model successfully predicts whether each of the two drugs will be effective for treating the patient, or whether he will be immune to both.
Microscopy and neural networks
14. A new technology called Deep Visual Proteomics allows you to describe the proteome of a cell in an unusual way. The technology combines the analysis of images of cancer cells or tumor slices with the results of mass spectrometry of single cells or nuclei. Scientists have also created the BIAS software, which coordinates scanning and laser microdissection (LMD) microscopes. This technology is applicable to the analysis of archival biobank tissues fixed in formalin and placed in paraffin (FFPE). The artificial intelligence selects cellular and subcellular objects either independently or with the help of instructions, and then the area of interest is automatically cut out and sent for proteomic profiling using mass spectrometry. The data obtained and compared with each other can be used to detect protein signatures affecting the cell phenotype, while preserving complete spatial information. For example, using this technology, the authors described changes in the proteome as normal melanocytes transition into invasive melanoma and identified the molecular pathways that contribute most to the progression of cancer.
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