Sunday reading (20.02)
Review of scientific periodicals for February 14-20
Anastasia Gorshkova, PCR.news
Neurodegenerative diseases1. Neuroscientists from the USA found out that the P522R mutation in the PLCG2 gene reduces the risk of developing Alzheimer's disease.
PLCG2 is a component of the TREM2 signaling pathway, changes in which increase the risk of Alzheimer's disease, and both of these genes are expressed in microglia. PLCG2 belongs to the phospholipase family, and the P522R variant has been shown to increase enzyme activity. Ultimately, this mutation increases the concentration of calcium in the microglial cell, activates phagocytosis, chemotaxis and induces the expression of certain genes. Scientists used induced pluripotent human stem cells, from which microglia were obtained for transplantation to wild-type mice and mice with a predisposition to Alzheimer's disease. Next, they sequenced the total RNA and RNA of single cells, and also performed histological analysis. The PLCG2-P522R variant in microglia significantly increased the expression of human leukocyte antigen (HLA), as well as many antigen presentation induction genes, chemokine signaling and T cell proliferation pathways, the expression of which is reduced in Alzheimer's disease. The next step of the study may be the search for drugs that increase the activity of the PLCG2 enzyme and stimulate the protective functions of microglia.
2. For several years, an international team of scientists collected nasal mucosa biopsy samples from healthy people and patients with Alzheimer's disease and sequenced the RNA of single cells from these samples. It turned out that in Alzheimer's disease, the secretion of beta-amyloid increases in the neurons of the olfactory epithelium, and the expression of 240 genes associated with the disease also changes. In addition, changes in the expression of mitochondrial genes in olfactory epithelial cells in patients were confirmed by functional analyses. The authors demonstrated a change in mitochondrial respiration and a decrease in ATP production. The results demonstrated the importance of obtaining transcriptomic data at the level of single cells for the study of molecular and cellular mechanisms of Alzheimer's disease.
Sequencing technologies3. RNA sequencing at the level of single cells has some limitations.
So, it takes thousands of cells to create a library, which makes it difficult to study small organisms and histological preparations. Scientists from Lausanne have come up with an elegant way to circumvent this limitation and have developed DisCo — "a deterministic system of droplet capture of mRNA and joint encapsulation of cells." This system requires less than 500 cells. Her work is based on a computer vision algorithm for actively detecting cells, capturing them and enclosing them in oil droplets containing balls with adapters. The system is characterized by high capture efficiency (more than 70%) and a throughput capacity of up to 350 cells per hour. To demonstrate the principle of the method, the authors of the article analyzed intestinal organoids at different stages of development. They found previously undescribed clusters of specific cell types, as well as stem cells.
Genetics4. Researchers and law enforcement agencies in the United States use genetic analysis to identify criminal networks of ivory traffickers.
Scientists analyzed the tusks of 4,320 savanna (Loxodonta africana) and forest elephants (L. cyclotis), which were seized from poachers in the period from 2002 to 2019 during 49 different law enforcement operations. The African savanna elephant is endangered, and the African forest elephant is recognized as an endangered species. Previously, scientists compiled a genetic tree of African elephants by collecting and analyzing their feces. This tree was used to determine which elephant population each tusk belongs to. It turned out that the tusks of the same elephant sometimes fell into different shipments, and this information was used to determine the ports where the poachers worked. In their new work, the researchers expanded genetic analysis to study family relationships between animals.
5. Exome sequencing helped to identify the genes responsible for the occurrence of a severe form of male infertility called non-obstructive azoospermia. In this form of infertility, a man's ejaculate does not contain sperm. The exomes of 96 people with non-obstructive azoospermia were sequenced, in which conventional genetic tests did not find the cause of the disease. The defect that causes the disease was detected in 16 genes in 22 people (23%). Six of the genes found had not been previously described in humans (DDX25, HENMT1, MCMDC2, MSH5, REC8, TDRKH), and the remaining ten were already known (C14orf39, DMC1, FANCM, GCNA, HFM1, MCM8, MEIOB, PDHA2, TDRD9, TERB1). Seven people had mutations in the genes of DNA repair pathways, three in the genes of post—meiotic maturation, and 12 in the genes controlling meiosis. Some of the de novo identified mutations are associated with infertility in women and in mouse models. The researchers hope that the data obtained can be used for the diagnosis and treatment of non-obstructive azoospermia.
Neuroscience6. MIT scientists and collaborators have compiled a transcriptomic atlas of brain vascular cells of healthy and sick people of various ages.
Despite the fact that these cells make up only 0.3% of all brain cells, they form a blood-brain barrier, which normally prevents pathogens and toxins from entering the brain from the blood, while passing nutrients and signaling molecules. The study was conducted on 100 postmortem fixed samples of human brain tissue and 17 samples of living brain tissue removed during surgery for the treatment of epilepsy. Scientists sequenced RNA from more than 16,000 cerebrovascular cells and classified them into 11 different subtypes. When comparing the tissues of healthy people and people with Huntington's disease, they also found that in the cells of patients there was a decrease in the expression of the MFSD2A gene, a key lipid transporter across the blood-brain barrier. The loss of this vector can contribute to an increase in the permeability of the barrier and worsen the course of the disease.
Infectious diseases7. Administration of hematopoietic stem cells to mice increased their survival rate in sepsis caused by staphylococcus infection.
Scientists began with studies of the effects of sepsis in mice after infection with the bacterium Streptococcus pyogenes. They observed a sharp decrease in the number of hematopoietic stem cells (HSPC, HSC) in the bone marrow of animals. Next, the scientists transfused a suspension of healthy new HSPCs to mice with sepsis about 24 hours after infection. Treatment increased the survival rate of animals by 50-60% compared to the control group. The infusion of HSPC did not reduce the number of bacteria, but it contributed to an increase in the population of immune cells of mice suppressing inflammation. These data suggest that HSPCs play an important immunomodulatory role, and this may already lead to new therapeutic strategies for sepsis.
Oncology8. Researchers from Spain have developed the METPlatform platform for screening drugs against brain metastases on organotypic cultures.
About a quarter of cancer patients are at risk of tumor metastasis to the brain. There is no specific therapy for this type of metastasis, so the likelihood of this complication is a serious and growing public health problem. To use the platform, you must first create organotypic cultures: as soon as samples of brain tissue affected by metastases are received from hospitals, they are processed in a specific way, which allows them to be cultured in the laboratory. Further, the METPlatform screening platform is applied to these cultures, which simultaneously analyzes the effect of hundreds of compounds on the tumor. This screening method is very simple and easily applicable in the laboratory and does not require complex technologies: results can be obtained in seven days. During the application of the platform, researchers have already discovered several promising drugs against brain metastases. Among them are HSP90 inhibitors, which have already been tested on various types of tumors, but never on metastatic brain tumors.
Transplantology9. With the help of two enzymes, scientists from Canada have learned how to turn donor lungs with blood group A into donor lungs with blood group O ex vivo.
The experiment was the first to use the Ex Vivo Lung Perfusion (EVLP) system, which perfuses nutrient fluids through donor organs, allowing them to heat up to body temperature. Human lungs from donors with blood group A were placed in an EVLP circuit. One lung was treated with the enzymes FpGalNAc-deacetylase and Fp-galactosaminidase to clean the organ surface from antigens, and the other lung of the same donor remained untreated. The researchers then tested the effectiveness of the procedure by adding group O blood (with high concentrations of anti-A antibodies) to the circuit to simulate a graft incompatible by blood type. Treatment of donor lungs with enzymes minimized antibody binding, deposition of complement system proteins and antibody-mediated damage compared to control lungs. The results show that the use of enzymes to convert any donor lungs into lungs with a universal blood type can be achieved using the EVLP system.
DNA Methylation10. Using bisulfite sequencing, scientists from the University of California analyzed placental methylome and discovered new biomarkers of predisposition to autism spectrum disorders (ASD).
The detection of genetic risk factors for the development of ASD is complicated by the interaction of the genome and the environment during the perinatal period of development. Epigenetic modifications, such as DNA methylation, reflect the molecular memory of intrauterine events during fetal development. The researchers analyzed 92 placenta samples taken during childbirth, of which 46 developed ASD, and 46 did not. Scientists have discovered a previously uncharacterized risk gene LOC105373085, subsequently renamed NHIP. Of the 134 differentially methylated regions associated with ASD, cluster 22q13.33 corresponds to a hypomethylated block of 118 t.n. In this locus, NHIP is functionally characterized as a transcript encoding a nuclear peptide with a high level of expression in the brain. Overexpression of NHIP increases cell proliferation and alters the expression of other genes that are already known to affect the development of ASD.
Aging11. Using UK Biobank data, scientists linked the length of leukocyte telomeres with age, gender and ethnic origin.
Telomeres shorten with each cell division, so it is believed that their length reflects cellular age and may even be a biomarker of biological age. Using data from 474,074 people from UK Biobank, the authors of the article in Nature Aging confirmed the known data that older age and belonging to the male sex are associated with shorter telomeres. In addition, they noted the relationship between ethnic origin and the age of the father at birth and the length of leukocyte telomeres, and also determined the individual variability of telomere length over five years.
Population genetics12. Researchers have found traces of Indian genetic origin in the population of modern Thailand.
In the first millennium AD, Indian culture influenced the creation of states in Southeast Asia, and evidence of this influence is still reflected in the genome of the inhabitants of Thailand. An international team of researchers analyzed the SNP of ten separate ethnic groups in Thailand. The analysis showed that many groups have not only historical ties with India, but are also genetically related to the Bengali population. Some isolated Southeast Asian groups, meanwhile, had no evidence of genetic heritage from South Asia.
Molecular diagnostics13. Biopharmaceutical company Zogenix has announced the sponsorship of a free genetic testing program for the diagnosis of mitochondrial diseases in the United States.
The experimental project is designed to help any patient to diagnose a suspected mitochondrial disease for free. Participation in the program must be initiated by patients: they will fill out an online questionnaire with symptoms, and the patient will be sent a home kit to test a saliva sample. Zogenix is interested in studying mitochondrial diseases, as it is currently testing MT1621, a drug for the treatment of late-stage thymidine kinase 2 deficiency. The company also recently became a partner of Invitae as part of its free genetic testing program for Duchenne myodystrophy.
14. The FDA has announced that Base10 Genetics is withdrawing its sample collection kits for testing for RNAstill MTM viral infections. The kit is designed for collecting, transporting, inactivating, stabilizing and long-term storage of smears from the nasopharynx or oropharynx for testing for pathogens, including SARS-CoV-2, influenza virus and bacterial infections. Base10 kits were produced without proper premarking from the FDA, as there is not enough data on how well the product inactivates and stabilizes viruses during transportation and storage. If the smears are stored incorrectly, this can lead to false negative results or to the spread of the virus in the diagnostic laboratory. The kits were delivered to institutions where employees were not trained to work with the kit's transport environment, which contains dangerous chemicals. The company and the agency recommend to stop using the product and return unused kits.
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