Sunday reading (05.06)
Review of scientific periodicals for May 30 — June 5
Elizaveta Minina, PCR.news
Genetics1. Scientists from the UAE and Jordan conducted genetic profiling of 45 patients of Arab or Asian origin suffering from multisystem inflammatory syndrome in children (multisystem inflammatory syndrome in children, MIS-C).
The results of the work are published in the J AMA Network Open. The authors of the study managed not only to identify variants that are associated with MIS-C in residents of the Middle East, but also to identify a link between some genes and the time of onset of the disease, as well as resistance to therapy for this pathology. In particular, 19 subjects were found to have potentially harmful mutations in the genes TLR3, TLR6, IL22RA2, IFNB1 and IFNA6 associated with the immune system.
2. A large international team studied the population dynamics of chimpanzees. The results of the study are published on the pages of Cell Genomics. For the analysis, chromosome 21 sequences obtained from fecal samples from 828 animals were used. Samples were taken in different regions of Africa. Scientists have confirmed the division of the chimpanzee species (Pan troglodytes) into four subspecies, between which genes have been exchanged since the late Pleistocene. According to the data obtained, chimpanzees, unlike humans, did not undergo periods of long migrations. Based on the genetic variants characteristic of each region, the authors of the work created a catalog with the help of which it is possible to trace the origin of chimpanzees who have fallen into shelters.
3. The results of the next GWAS conducted on the data contained in the UK Biobank are published in Nature Genetics. The purpose of GWAS was to identify genes associated with the risks of aneurysm and aortic dissection. The study included cross-sectional images of the aorta obtained for 36,021 people. The diameter of the aorta was calculated automatically from these images. It was possible to identify 41 loci, variants of which affect the risk of aneurysm and aortic dissection. In particular, the genes HAND2 and TBX20 associated with the development of the cardiovascular system turned out to be risk loci.
Antimicrobial therapy4. Researchers from Spain and the USA presented an improved version of a fundamentally new approach to antibacterial therapy.
The work is published in Science Advances. The basis of the new method is the "nanodrel" — an artificial molecular complex. Their structure includes a fixed stator and a rotor, which, when activated, can rotate at a speed of 2-3 million rpm. Moreover, due to the chemical properties of the stator, the molecules themselves detect target cells and are specifically fixed on their surface. The rotor is drilled through the cell membranes, which in itself can cause the death of bacteria, but they are most effective in combination with an antibiotic. The first version of "nanodrels" activated by ultraviolet light. This limited their use, since ultraviolet light is harmful to mammals. The new generation of molecules is activated by visible violet light (wavelength 405 nm). In in vitro and in vivo experiments, scientists have shown that "nanodrels" destroy both gram-negative and gram-positive bacteria in a few minutes, including methicillin-resistant Staphylococcus aureus. At the same time, resistance to molecules did not develop.
Physiology5. With age, clonal expansion of cells in the human body, due to the acquisition of somatic mutations, occurs more and more often.
This is also observed in the hematopoietic system. Scientists from the UK and Italy have been tracking the dynamics and natural history of human clonal hematopoiesis for a long time. The results of the work are published in Nature. The authors of the study analyzed 697 clones of hematopoietic cells using sequencing, which were taken from 385 people aged at least 55 years for an average of thirteen years. According to the data obtained, 92.4% of the clones showed uniform exponential growth. At the same time, various somatic mutations affected the growth rate. For example, the number of cells with mutations in DNMT3A and TP53 increased by 5%, with the SRSF2 P95H mutation — by more than 50% per year.
Vaccines6. Scientists from the Karolinska Institute (Sweden) have created a vaccine against pneumococcus with a new principle of action and told about it on the pages of PNAS.
The vaccine is administered intranasally — this method simulates a natural infection with pneumococcus through inhaled air. The vaccine is based on the so—called membrane particles - vesicles obtained from bacteria during cultivation in biofilms reproducing colonization of the nasopharynx. Membrane particles contain antigens — conservative lipoproteins of pneumococcus MalX and PrsA. The results of a study of the vaccine in mice showed that the vaccine provides protection against all serotypes of pneumococcus.
Molecular Biology7. The authors of a paper published this week in Cell have shown that in humans, non-coding 7S RNA regulates mitochondrial transcription activity both in the cell-free system and in living cells.
Using cryo-electron microscopy, scientists have found that 7S RNA, interacting with molecules of mitochondrial RNA polymerase POLRMT, induces their dimerization. Dimerization of POLRMT interferes with transcription of mitochondrial genes. Scientists suggest that 7S RNA is a component of the negative feedback loop regulating transcription in mitochondria.
Developmental biology8. Polycomb 2 complex (PRC2) is one of the key repressive factors of chromatin remodeling.
The authors of a new paper published in the journal Nature Cell Biology have shown that PRC2 prevents the differentiation of pluripotent stem cells during early human development, preventing them from dividing into mesoderm and trophectoderm cells. Quantitative epigenomic profiling has shown that the maintenance of a naive undifferentiated state of pluripotent cells is accompanied by a wide spread of the H3K27me3 label in their genome. The suppression of PRC2 leads to the activation of pluripotent cells and the start of their differentiation.
9. The development of the digestive system requires the formation of a functional intestinal barrier. As reported in a new paper published in Cell Stem Cell, the formation of the intestinal barrier in the first weeks after birth is carried out by stromal cells. These cells are characterized by the LTBR+PDGFRa High molecular phenotype. When the intestinal barrier matures, a transcriptomic shift occurs in them, limiting the stem characteristics of cells and directing them towards differentiation.
Oncology10. Therapy of melanoma with MAPK kinase inhibitors leads to the accumulation of PD-L1/2 — ligand molecules of the immunological checkpoint PD-1 on the surface of tumor cells.
Thanks to this protein, malignant cells escape from antitumor immunity and quickly acquire resistance to therapy. The authors of a new study published in Cancer Discovery found that ITCH ubiquitin ligase binds and ubiquitinates PD-L1/2 on the cell surface. Overexpression of this protein in the tumor reduces the amount of PD-L1/2, which activates the cytolytic action of CD8+ T cells against melanoma. In vivo experiments, a small molecule, the activator of ITCH, suppressed the acquired resistance of melanoma to MAPK inhibitors.
11. Scientists from the USA have proposed a new approach to the treatment of triple-negative breast cancer, as reported on the pages of Nature Cancer. They considered lysosomal acid lipase (LIPA) as a target. Scientists have selected a small molecule ERX-41, which specifically binds LIPA, induces stress of the endoplasmic reticulum and thereby causes the death of malignant cells. The authors emphasize that the effect of ERX-41 is not related to the activity of LIPA, but to its localization in the endoplasmic reticulum.
12. Checkpoint inhibitor therapy has made significant progress in the treatment of many types of cancer, but in the case of lung cancer it is not always effective. A new study conducted on patients has shown that a liquid biopsy is better suited to predict the effectiveness of immunotherapy than a tumor biopsy. The results are published in the Journal of Experimental & Clinical Cancer Research. The authors of the study analyzed extracellular vesicles contained in the patients' blood. They showed that the most important predictive biomarker of the effectiveness of immunotherapy in non-small cell lung cancer is the level of PD-L1 on the surface of extracellular vesicles.
Company news13. The South Korean company Genome Insight, specializing in the analysis and interpretation of genome-wide sequencing data, has announced that it is ready to enter the US market.
The company recently received $23 million in Series B funding. The company was founded in 2020 and specializes in analyzing genome-wide sequencing data obtained from tumor samples.
Molecular diagnostics14. The Dutch system of noninvasive prenatal diagnostics TRIDENT-2 allows detecting trisomies on chromosomes 21, 18 and 13.
A recent study showed that the system also detects rarer trisomies, as well as structural abnormalities in chromosomes. It turned out that one of the 275 women who used the system revealed disorders other than the most common trisomies. In about 10% of cases, it is not possible to find out the origin of chromosomal aberrations. About a quarter of the remaining 90% are due to fetal abnormalities, more than a quarter come from the mother and in about half of the cases the findings are associated with placental mosaicism.
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