nature
● The new editing method can correct 89% of pathogenic DNA.
In the latest research, the team of David R. Liu of Harvard University reported a genome editing method that does not require DNA double-strand breaks and donor DNA. 20 19 10 2 1, Nature published related papers online.
The researchers described a method called prime editing, which is a universal and accurate genome editing method. It uses Cas9, which is destroyed by engineering reverse transcriptase, to write new genetic information directly into the designated DNA site, and uses the chief editor to guide RNA programming, both of which specify the target site and code the required editing.
Researchers have edited 175 times in human cells, including targeted insertions, deletions and all point mutations of 12 types, without double-strand breaks or donor DNA templates.
Using the main editing function in human cells, the researchers effectively corrected the main genetic causes of sickle cell disease and Tay-Sachs disease, and added protective transformation to PRNP gene, while adding a small amount of by-products, and accurately inserted various tags and epitopes into the target site.
Four human cell lines and primary mitotic mouse cortical neurons support major editing with different efficiency.
Compared with base editing, primer editing has advantages, complementary advantages and disadvantages in the efficiency and product purity of homologous arm-mediated repair, and the off-target editing at known Cas9 off-target sites is much lower than Cas9 nuclease.
Prime editing greatly expands the scope and ability of genome editing, and in principle, it can correct about 89% of known human genetic variation.
It is reported that most of the genetic mutations that cause diseases are difficult to be effectively corrected, and at the same time, there are too many side effects.
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● FSP 1 protein inhibits cell iron death.
James A. Olzmann's research team at the University of California, Berkeley, found that coenzyme Q oxidoreductase FSP 1 was involved in inhibiting cell iron death in a way parallel to GPX4 protein. Related papers were published online in Nature on 2065438+2009 65438+2 1.
Using synthetic lethal CRISPR_Cas9 screening, the researchers identified iron death inhibitory protein 1 as an effective iron death resistance factor.
The data showed that the acylation of nutmeg recruited FSP 1 to the plasma membrane, where it was used as an oxidoreductase, thus reducing coenzyme Q 10 and producing lipophilic free radical capture antioxidants, thus preventing the diffusion of lipid peroxides.
The researchers further found that the expression of FSP 1 was positively correlated with iron death resistance in hundreds of cancer cell lines, and FSP 1 mediated iron death resistance in cultured lung cancer cells and mouse tumor xenografts.
Therefore, these data confirm that FSP 1 is the key component of non-mitochondrial CoQ antioxidant system, which works in parallel with the classical GPX4 pathway based on glutathione.
These findings define a new method to inhibit rust, and indicate that the pharmacological inhibition of FSP 1 may provide an effective strategy to make cancer cells sensitive to iron death-induced chemotherapy.
It is reported that iron death is a regulated form of cell death, which is caused by iron-dependent lipid peroxidation. Glutathione-dependent lipid catalase-glutathione peroxidase 4 can prevent hypertrophy by converting lipid peroxide into nontoxic lipid alcohol.
Iron death is related to cell death, which is the basis of several degenerative diseases. Inhibition of GPX4 can be used as a therapeutic strategy to induce cancer cell death.
However, the sensitivity of cancer cell lines to GPX4 inhibitors varies greatly, which indicates that other factors determine the resistance to iron death.
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Nature-methodology
● Deep learning helps protein project.
The research team of George M. Church of Harvard University unified the modeling of reasonable protein engineering design by using sequence-based depth representation learning. 101October 2 1 day, the internationally renowned academic journal Nature-Methodology published this achievement online.
Researchers applied deep learning to unlabeled amino acid sequences, and refined the basic features of protein into statistical expressions, which are rich in semantics and have a solid foundation in structure, evolution and biophysics.
Researchers show that the simplest model based on this unified representation can be widely used and can be extended to invisible areas in sequence space.
This data-driven method can compete with the latest methods to predict the stability of natural and de novo protein and the quantitative function of molecular diversity mutants.
UniRep can also improve the efficiency by two orders of magnitude in protein engineering task. UniRep is a generalization of protein's basic functions, which can be used in protein's engineering informatics.
According to reports, a reasonable protein project needs a comprehensive understanding of protein's functions.
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Natural genetics
● Scientists draw genetic maps of subcortical brain structures.
Researchers such as M. Arfan Ikram of Erasmus Medical Center in the Netherlands and Claudia L. Satizabal of San Antonio Health Center of the University of Texas described the genetic structure of subcortical brain structure of 388,565,438+0 individuals. On 20 191October 2 1 day, the internationally renowned academic journal Nature-Genetics published this achievement online.
Using nearly 40,000 individuals in the databases of CHARGE, ENIGMA and British Biobank, researchers conducted genome-wide association studies, and identified common genetic variations related to nucleus accumbens, amygdala, brain stem, caudate nucleus, globus pallidus, putamen and thalamus.
The researchers found that the variability of subcortical volume is heritable and identified 48 significantly related loci.
Using the data of gene expression, methylation and neuropathology to annotate these loci, the researchers determined that 199 genes may be related to neural development, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to nervous system diseases.
This group of genes significantly enriched the orthologous genes related to neurodevelopmental phenotype in Drosophila, indicating an evolutionary conservation mechanism.
These findings reveal new biological mechanisms and potential drug targets of brain development and diseases.
It is reported that the subcortical brain structure is indispensable for exercise, consciousness, emotion and learning.
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Nature-immunology
● Scientists of the Chinese University of Science and Technology found that * * * virus maintains intestinal homeostasis.
China University of Science and Technology School of Basic Medicine, Key Laboratory of Natural Immunity and Chronic Diseases of China Academy of Sciences, Professor Zhou Rongbin, Jiang Wei and Stephany of Hefei National Research Center for Micro-scale Material Science jointly found that enteroviruses maintain intestinal intraepithelial lymphocytes through non-classical RIG-I signals. Related papers were published online in Nature-Immunology on1October 2 1.
Researchers have shown that * * * virus is very important for the homeostasis of lymphocytes in intestinal epithelial cells. Mechanically speaking, RIG-I, a cytoplasmic virus RNA receptor in antigen presenting cells, can recognize * * * virus and maintain IEL in a way independent of type I interferon.
IEL recovered by administration of interleukin 15 reversed the sensitivity of virus-reduced mice to colitis caused by dextran sodium sulfate.
Generally speaking, these results show that * * * virus maintains IEL through non-classical RIG-I signal, thus maintaining intestinal homeostasis.
It is reported that people are generally concerned about the role of * * bacteria in health and diseases, but the role of * * * virus has not been fully studied.
Although metagenomics analysis shows that there are various viruses in the intestines of healthy people and animals, and the disorder of these viruses may be related to inflammatory diseases, there is still a lack of causal data and potential mechanisms to understand the physiological functions of * * * viruses in the intestines.
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● Mitochondrial fragmentation limits the tumor killing ability of NK cells.
The cooperation between Hemingway and Tian Zhigang in the School of Life Science of China University of Science and Technology reveals that mitochondrial breakage limits tumor immune monitoring mediated by natural killer cells. Related papers were published online in Nature-Immunology on 20 19, 10, 2 1.
Natural killer cells play a key role in tumor monitoring. The researchers found that there were small and broken mitochondria in the cytoplasm of NK cells infiltrating tumor in human liver cancer, while normal large tubular mitochondria were found in NK cells outside tumor and surrounding NK cells.
This fragmentation is related to the decrease of cytotoxicity and the loss of NK cells, which leads to the tumor escaping from NK cell-mediated monitoring, which indicates that the survival rate of patients with liver cancer is very low.
Hypoxia tumor microenvironment drives the mechanical target of rapamycin-GTpase dynamic protein-related protein 1 in NK cells to be continuously activated, resulting in excessive mitochondrion division into fragments.
The inhibition of mitochondrial breakage improves the metabolism and survival of mitochondria and the anti-tumor ability of NK cells.
These data reveal an immune escape mechanism, which may be targeted and can stimulate cancer treatment based on NK cells.
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● Fibroblasts promote T cell metabolism and survival.
Researchers such as Shannon J. Turley, W. Nicholas Haining and Arlene H. Sharpe of Harvard Medical School of Dana Farber Cancer Institute found that fibroblast reticular cells promote T cell metabolism and survival through epigenetic remodeling. Related papers were published online in Nature-Immunology 20 19,10,21.
The researchers found that exposure to FRC enhanced the production of cytokines and reconstructed the accessibility of chromatin in newly activated CD8 positive T cells through interleukin -6.
These epigenetic changes promote metabolic reprogramming and amplify the activity of survival pathway through differential transcription factor activity. Therefore, the regulation of FRC significantly enhanced the persistence of virus-specific CD8 positive T cells in vivo, and enhanced their differentiation into tissue resident memory T cells.
This study shows that FRC can not only limit the expansion of T cells, but also affect the fate and function of CD8 positive T cells.
According to reports, lymph node FRC responds to the signal of activating T cells by releasing nitric oxide, inhibits the proliferation of T cells and limits the size of the expanded T cell pool.
It is not clear whether the interaction with FRC also supports the function or differentiation of activated CD8 positive T cells.
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Natural medicine
● Enterovirus may be related to acute flaccid myelitis.
Michael R. Wilson's team at the University of California, San Francisco found that pan-virus serology showed that enterovirus was related to the onset of acute flaccid myelitis. Related papers were published online in Nature-Medicine on 20 19, 10, 2 1.
Using phage display libraries expressing 48 1966 overlapping peptides from all known vertebrates and arboviruses, the researchers studied intrathecal antiviral antibodies in cerebrospinal fluid of control children with AFM and other pediatric neurological diseases.
The researchers also sequenced the metagenome of the next generation AFM CSF RNA.
Using VirScan, compared with the control, the virus family with significantly enriched CSF in AFM cases belongs to picornaviridae, and the most enriched peptide in picornaviridae belongs to enterovirus.
EV VP 1 ELISA test confirmed this discovery. MNGS did not detect other EV RNA.
Although EV RNA is rarely detected, compared with the control group, pan-virus serology often recognizes high levels of CSF EV-specific antibodies in AFM, which provides further evidence for the causal role of non-polio EV in AFM.
According to the researchers, the AFM of American children has soared every two years since 20 12. Epidemiological evidence shows that non-polio EV is a potential cause, but EV RNA is rarely detected in cerebrospinal fluid.
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● mTORC2 can inhibit or treat nervous system diseases caused by Pten deletion.
Mauro Costa-Mattioli of Baylor Medical College recently found that therapeutic inhibition of mTORC2 can save behavioral and neurophysiological abnormalities related to Pten deficiency. Related papers were published online in Nature-Medicine 20 19,10,21.
The researchers said that the imbalance of mammalian rapamycin signal transduction targets was mediated by two complexes with different structures and functions, mTORC 1 and mTORC2, which involved a variety of nervous system diseases.
Individuals with functional mutations of phosphatase and tensin homologous genes are prone to megacephaly, autism spectrum disorder, epilepsy and mental retardation.
It is generally believed that the neurological symptoms associated with PTEN deletion and other mTOR diseases are caused by the overactivation of protein synthesis mediated by mTORC 1.
Using molecular genetics, researchers unexpectedly found that the deletion of mTORC2 gene prolonged life span, inhibited seizures, saved ASD-like behavior and long-term memory, and normalized metabolic changes in the brain of mice lacking Pten.
In a more therapeutic method, the researchers found that antisense oligonucleotides targeting Rictor (a definite component of MTO RC2) can specifically inhibit the activity of MTORC2 and reverse the behavioral and neurophysiological abnormalities of adolescent Pten-deficient mice.
Generally speaking, these findings indicate that mTORC2 is the main driver of neuropathophysiology related to Pten deficiency, and its therapeutic reduction may become a promising, widely effective conversion therapy for nervous system diseases with mTOR signal disorder.
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