Sunday reading (03.04)
Review of scientific periodicals for March 28 — April 3
Ilya Sklyar, PCR.news
Molecular Biology
1. Researchers from the University of Texas Southwestern Medical Center have shown the ability of several genes to control the assembly of ribosomes. The results are published in Cell Reports. To study the biogenesis of ribosomes in human cells, scientists used a combination of several techniques: genome-wide screening with gene knockout, as well as the Ribo-SNAP technique specially created for this study, which allows differentiating the labeling of new and existing ribosomes. The technique developed by the researchers also allows you to compare the levels of existing and new ribosomes, as well as to assess the degree of their assembly. The study revealed four key genes for ribosome biogenesis — C1ORF109, SPATA5, SPATA5L1 and CINP. The product of these genes is a protein complex involved in ribosome folding. Allelic variants SPATA5, SPATA5L1 and CINP are associated with microcephaly, mental retardation, hearing loss and seizures in humans. Scientists have found out that two allelic variants of SPATA5 disrupt ribosome biogenesis, cause defects in ribosome production and mRNA translation in these conditions. Researchers are wondering why the nervous system is most sensitive to disorders of ribosome biogenesis. This issue may be the subject of further study by the group.
Aging
2. A group of Japanese researchers studied the relationship between daily physical activity and the risk of dementia, leading to a decrease in capacity. The article was published in the JAMA Network. The authors analyzed the data of 43,896 patients aged 50 to 79 years for the year 2000-2003. Statistical analysis showed that the risk of dementia in the group with high physical activity was significantly lower than in the group with low activity, both in men and women. The same pattern persisted in people with moderate to high physical activity, and in people engaged in physical activity from time to time. However, when men who developed dementia within seven years of the starting point of the study and women who developed dementia within eight years were excluded from the statistical sample, these associations disappeared. Significant associations between dementia risk and physical activity are also shown within the group that engaged in physical activity from time to time. The data obtained indicate that a high level of physical activity from medium to high is associated with a reduced risk of dementia leading to disability in men.
Obstetrics and gynecology
3. A group of researchers, led by scientists from the Cincinnati Children's Hospital Medical Center, described the mechanism of chorioamnionitis development. The article was published in Science Translational Medicine. Chorioamnionitis is a complication of pregnancy in which inflammation can lead to an increased risk of respiratory diseases in the fetus. Researchers have shown on an animal model (rhesus monkeys were used for the experiment) that inflammation in a pregnant female leads to a violation of the development of the inner surface of the fetal lungs, causes significant damage to alveolar structures, in particular, the differentiation of alveolar pneumocytes of the first type and specialized capillary alveolar endothelium is disrupted. RNA sequencing of single cells showed that perinatal inflammation disrupted the genesis of the alveoli, reduced the gas exchange surface of the lungs and, as a result, led to chronic lung diseases in the fetus. Blockade of inflammatory cytokines TNF-α and IL-1β restored key signaling pathways and improved fetal alveogenesis. These data, according to the researchers, allow us to take a fresh look at the pathophysiology of the development of lung damage.
New drugs
4. A group of scientists from the Karolinska Institute and other European researchers have identified a new means to combat diabetes, which prevents an increase in blood glucose and preserves the activity of insulin-producing beta cells. The article was published in Science Translational Medicine. In diabetes, beta cells must produce large amounts of insulin, which leads to hypoxia. Hypoxia increases the level of HIF-1a protein, which, in turn, reduces the activity of beta cells. In an animal model, it was shown that the HIF-1α PX-478 inhibitor (an experimental cancer drug) prevents an increase in glycemia and the progression of diabetes by maintaining a normal concentration of insulin in blood plasma. In mice with streptozocin-induced diabetes, PX-478 improved the restoration of glucose homeostasis. Isolated Langerhans islets from these mice showed increased expression of genes involved in beta cell functionality, inhibition of dedifferentiation markers, and formation of mature insulin granules. Increased insulin secretion in response to the use of PX-478 was confirmed by experiments on organoids derived from human cells. Researchers believe that PX-478 may be a more successful drug for the treatment of type 2 diabetes, as it supports the work of beta cells with increased metabolic activity.
5. The joint work of scientists from the USA and Canada is devoted to the mechanism of possible effects of therapeutic drugs on non-coding RNAs. The study is published in Nature. A group from the Massachusetts General Hospital, under the leadership of which the study was conducted, has been studying the role of RNA in the inactivation of the X chromosome for a long time. According to a new study, it is possible to prevent the inactivation of the X chromosome by using chemical compounds. The study focused on the non-coding RNA Xist, which is responsible for the silencing of genes on the X chromosome. The researchers analyzed 50,000 compounds that can interact with the Xist molecule, and found the compound X1. X1 prevents the binding of the Xist site, called RepA, and the proteins PRC2 and SPEN, which is necessary for the inactivation of the X chromosome. As a result, inactivation becomes impossible. Normally, the RepA site can be formed into 16 conformations, but binding to X1 causes the adoption of one universal conformation. Conformational changes prevent RepA from contacting PRC2 and SPEN. The study can help both in the treatment of genetic diseases associated with mutations in X chromosome genes (Rett syndrome, brittle X chromosome syndrome), and in the development of other drugs targeting RNA.
Inflammation
6. An article on the effect of obesity on the body's immune system was published in Nature. A large team of scientists from the USA, Australia, China and South Korea has revealed a fundamental difference in the mechanism of the inflammatory process in obese mice and "thin" mice. Mice with atopic dermatitis were used for the study. In autoimmune diseases and allergies, overactivation of T-helpers (TH1, TH2, and TH17) occurs. Scientists have found that in mice with atopic dermatitis and obesity, TH17 cells are active during inflammation, whereas in non-obese mice with atopic dermatitis, TH2 cells are activated. Thus, in obese animals, the level of inflammation is not higher, but a different mechanism is involved. This fact also affects the therapy of the disease. Thus, therapy working for "thin" mice led to a deterioration in the condition of obese mice. Single cell RNA sequencing and genome-wide analysis showed that obese mice had reduced activity of the peroxisome proliferator-activated gamma receptor (PPARy) in TH2 cells compared to "lean" mice. PPARy is necessary, among other things, in order to prevent aberrant inflammation not caused by TH2. The use of the PPARy agonist molecule reduced the development of inflammation caused by TH17 in obese mice, which made it possible for therapy to work normally.
7. An article in Nature from American and Japanese scientists describes a new approach to the treatment of cardiovascular diseases. The researchers found that deletions of the gene encoding the protein TRPM2 (Ca2+-permeable transient receptor potential melastatin 2) in Apoe−/− mice led to a decrease in the level of atherosclerosis. Lack of expression Trpm2 reduced the level of absorption of oxidized low-density lipoproteins by macrophages, which, in turn, reduced the infiltration of macrophages, the formation of "foam cells" (macrophages with lipid granules) and the inflammatory response. Activation of the oxidized low—density lipoprotein receptor — CD36 - induces TRPM2 activity and vice versa. In macrophage cell culture, it was shown that TRPM2 is activated by ligands of oxidized low-density lipoproteins acting on CD36 and thrombospondin-1, and deletion of Trpm2 or inhibition of the activity of its product (TRPM2) suppresses the CD36 signaling cascade. A new object of the scientists' research was the expression of Trpm2 in monocytes (precursors of macrophages) and the correlation of this expression with cardiovascular diseases in humans. Trpm2 can become both a new marker of the disease and a potential therapeutic target, the researchers believe.
Oncology
8. A study by a group of scientists from the USA and Europe has shed light on the mechanisms of mesothelioma. The article is published in Nature Communications. Mesothelioma is a cancer of the mesothelium (the tissue lining the inner surface of many organs, for example, the pleura or pericardium), a common cause of which is inhalation of asbestos. The researchers used model animals (danio fish and mice), as well as human mesothelioma cell lines. They found that the mechanism of oncogenesis involved the "inclusion" of the expression of the hand2 gene, a key protein necessary during embryogenesis for the formation of mesothelium. In the case of adult animals, reactivation of HAND2 leads to the growth of mesothelial cells and their migration, as it happened in the embryo, the researchers believe. Scientists have also shown that not all cases of mesothelioma involve activation of HAND2. The possibility of therapy aimed at HAND2 will become a further object of the group's research.
9. Scientists from Denmark have published an article in Nature Communications in which they describe the movement of filopodia cells. Filopodia are structures on the surface of eukaryotic cells based on the protein actin. They help the cell to explore the environment and provide chemical signaling. The article shows that filopodia explore the three-dimensional extracellular space by combining growth and compression with axial twisting and bending. The main mechanism of filopodia movement is twisting of the actin rod. The researchers tracked entire filopodia in three-dimensional space, and also measured the actin rod inside the filopodia. To do this, they used special fluorescent beads coated with vitronectin, which provided binding directly to integrin. The integrin, in turn, connected these beads to the actin rod. Images were obtained using a confocal microscope. The movements of the filopodia, according to the researchers, resemble the movements of the tentacles of an octopus. The authors also believe that studying the mechanism of movement of filopodia cells may be important in cancer therapy, since filopodia can help cancer cells to study the environment, avoid therapy and spread in the body.
10. Scientists from Europe and the USA have published an article in eLife on the link between aging and cancer risk. It is known that epigenetic markers affecting the regulation of chromatin change with age. DNA methylation patterns correlate best with age. In the new study, the researchers used models called "epigenetic clocks," which are based on changes in DNA methylation with age. Four models were selected, two "first generation" models that link methylation patterns with chronological age, and two "second generation" models that use markers associated with an increased risk of age-related diseases. Genome—wide analysis using epigenetic clock models showed that the levels of acceleration of epigenetic aging (acceleration of epigenetic aging is a phenomenon in which the biological age of an individual is higher than chronological) are associated with an increased risk of colorectal cancer.
Microbiology
11. A fundamental work devoted to rethinking the mechanisms of DNA repair in bacteria has been published in Nature. Until now, it was believed that the repair combined with transcription (provided by RNA polymerase, is a special case of excision repair) does not play a significant role in the overall DNA repair. In the new work, the authors refute this statement and prove that excision repair of nucleotides in bacteria is in most cases associated with RNA polymerase. The authors claim that early studies could not provide a complete picture, since they attempted to recreate the interactions of protein complexes outside a living cell. In the new study, the authors used mass spectrometry technology to map the distances between chemically bound proteins and determine the interaction of protein complexes of excisional nucleotide repair in living cells. The obtained data were loaded into specially created computer simulations to obtain realistic structural models. The study showed that it is RNA polymerase that serves as the primary sensor of DNA damage, as well as a platform for recruiting proteins involved in excision repair of nucleotides. uvrA and UvrD monomers are permanently bound to RNA polymerase, and when DNA damage is detected, another UvrD monomer is recruited, forming a dimer with helicase activity. uvrA and UvrB are recruited to initiate the repair process. According to the study, this mechanism prevails in most cases of DNA repair. The study also showed that this mechanism is not as dependent on the Mfd molecule as previously thought.
12. Portuguese researchers in collaboration with American colleagues have discovered a new mechanism by which the lifetime of RNA molecules can be extended. Scientists have found that the RNA of variant surface glycoproteins (VSG) in the microorganism Trypanosoma brucei, which causes African trypanosomiasis, has a significant amount of N6-methyladenosine in its composition. At the same time, 50% of all N6-methyladenosine falls on the poly(A) tail of RNA molecules. The inclusion of N6-methyladenosine in the poly(A) tail of VSG transcripts is due to a 16-dimensional motif in the 3'-untranslated region of VSG genes. Removal of this motif resulted in transcripts with a poly(A)tail without N6-methyladenosine. The inclusion of N6-methyladenosine in the poly(A) tail of the RNA molecule allows it to last longer in the cell, because before deadenylation and degradation of mRNA, it is necessary to remove N6-methyladenosine. Researchers believe that the regulation of RNA stability is one of the determinants of T. brucei virulence and that a similar mechanism may take place in human cells.
13. Researchers from the University of Minnesota, together with colleagues from China, studied the movement of bacteria in complex non-Newtonian fluids. The study is published in Nature. It has been experimentally shown that bacteria with flagella show almost the same motor activity in colloidal solutions and in polymer solutions. Moreover, the rate of bacteria increased in colloidal solutions and varied depending on the particle size of colloids. The velocity could increase by 80% in solutions with particles with a radius of 500 nm. The researchers believe that when the bacteria swim, the resistance created by the passage of particles allows the flagella to align better with their bodies, which ultimately helps them move faster. The discovery will help to understand the mechanism of movement of bacteria in complex fluids, including in the human body.
Molecular diagnostics
14. Thermo Fisher Scientific announced on Tuesday that it received the CE-IVD marking for the integrated Ion Torrent Genexus Dx sequencer in March and makes the platform commercially available for diagnostic testing and clinical research. Garrett Hampton, President of Clinical NGS and Oncology, said that now, thanks to the integrated Genexus Dx sequencer, any hospital in the United States, including regional and community hospitals, can implement next-generation sequencing, providing clinicians with access to timely and comprehensive genomic profiling results. The company said it is also developing a sample-to-report diagnostic workflow and a portfolio of clinically validated assays for Genexus, including comprehensive genomic profiling and hematooncological assays.
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