December 13, 2019 Science journal essence

December 21, 2019 / BIOON / - -- a new issue of Science Journal (December 13, 2019) will be published this week What are the highlights of its research? Let Xiaobian come together The picture is from science journal 1 A decade long scientific dispute is finally settled! Two science papers revealed that human annexin is a chromosomal multi subunit adenosine triphosphatase complex, which is composed of DOI: 10.1126/science.aaz3418, DOI: 10.1126/science.aaz4475 When loaded onto a chromosome, it produces a DNA loop to regulate the function of the chromosome It has been proposed that annexins can be assembled by ring extrusion, but there is no direct evidence to support this In the first new study, Jan Michael Peters, director of the Institute of molecular pathology (IMP), Vienna biological center, Austria, and his team confirmed for the first time that a molecular machine can actively and purposefully fold DNA through "loop extrusion", thus realizing a variety of important functions in interphase cells This new insight into the process of DNA looping has changed the old view about how genomes are assembled in cells This discovery clarifies the basic mechanism of life and solves a decade long scientific dispute The relevant research results were published in the Science Journal on December 13, 2019, with the title of "DNA loop extension by human cohesin" The Peters team, including Iain Davidson, a senior postdoctoral researcher at the Peters lab, was able to reconstruct the function of adhesins in a simplified system in vitro As a result, Davidson was able to see how a single binding protein molecule quickly compresses a single piece of DNA into a DNA ring His discovery has profound influence and changed the whole understanding of genome in many ways: (1) genome is not static, but highly dynamic structure; (2) genome DNA folding is a process of active regulation, which involves the formation of DNA molecules into rings through extrusion, and many DNA rings are constantly moving; (3) the formation of DNA rings is mediated by adhesion proteins, because The binding protein must be a kind of molecular motor, similar to other motor proteins such as myosin; (4) the binding protein molecules form a hook ring structure around the DNA, and must be dynamically connected to the DNA through multiple binding sites, so as to be able to fold the DNA; as found last year, the condensation protein must also be so In a second new study, researchers from the University of Texas Southwestern Medical Center and the University of Texas at Austin used single-molecule imaging to reveal that the recombinant human annexin-nipbl complex compresses the naked and nucleosome bound DNA by squeezing the DNA ring The relevant research results were published in the Science Journal on December 13, 2019, and the paper title is "human cohesin compacts DNA by loop extension" The corresponding authors of the paper are Dr Hongtao Yu from the University of Texas Southwestern Medical Center and Dr Ilya J Finkelstein from the University of Texas at Austin This DNA compression carried out by annexins requires ATP hydrolysis and is pressure sensitive This compression process processes tens of thousands of bases at an average rate of 0.5 KB per second The compression of double stranded DNA by annexin indicates that the dimer of annexin compresses the DNA ring in two directions These results indicate that the binding protein nipbl complex is an ATP driven molecular motor capable of DNA ring extrusion All in all, these two new studies show that unlike the way in which adhesins regulate the attachment of sister chromatids, the proteins do not appear to capture DNA on topology during ring extrusion These results provide direct evidence for the cyclic extrusion model of chromatin assembly and indicate that the genome structure is highly dynamic 2 Science: a new method to identify the metabolite molecules produced by intestinal microbiome doi: 10.1126/science.aav1282; doi: 10.1126/science.aaz4164 intestinal microflora produced hundreds of high-level molecules in the blood circulation, their levels vary greatly among different people These molecules are a promising starting point for the study of the interaction between intestinal microbiome and host; a few of the molecules described in detail have strong immunoregulatory or metabolic regulatory activities and are ligands of G-protein-coupled receptors or nuclear hormone receptors However, in most cases, the production of these molecules has not been associated with specific bacterial strains or metabolic pathways, and it is difficult to understand the contribution of each molecule to host biology In a new study, researchers from Stanford University and other research institutions in the United States described a crispr-cas9-based method for reliably constructing bacterial mutants that do not need to be labeled to produce specific metabolite molecules in model symbiotic Clostridium sporogenes This method can construct a variety of mutant Clostridium sporogenes strains Relevant research results were published in the Science Journal on December 13, 2019, and the title of the paper is "completion of microbiome derived molecules in the host using Clostridium genetics" By using this method to knock out 10 kinds of molecules produced by Clostridium sporogenes - trimethylamine, 5-aminovalerate, tryptamine, indolpropic acid, isovaleric acid, 2-Methylbutyric acid, isobutyric acid, isohexanoic acid, propionic acid and butyric acid, they showed its practicability; we verified the corresponding metabolites in the extracts of Clostridium sporogenes cultured in vitro by liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry The lack of each knockout to verify the success Then, they planted wild-type Clostridium sporogenes or some of the five mutants of Clostridium sporogenes lacking corresponding metabolites into sterile mice The results showed that in the mice planted with wild-type Clostridium sporogenes, the products of these metabolic pathways accumulated in the host tissue, but each metabolite could be eliminated by planting corresponding metabolic pathway mutants By comparing the mice inoculated with wild-type Clostridium sporogenum and the mice inoculated with Clostridium sporogenum mutants lacking in producing branched short chain fatty acids - isobutyric acid, 2-Methylbutyric acid or isovaleric acid, they found that these abundant intestinal microbiome derived molecules had a previously unknown activity of regulating immunoglobulin A (IGA) plasma cells 3 Science: the new research reveals that the human microbiome is a potential new antibacterial drug, DOI: 10.1126/science.aax9176; Doi: 10.1126/science.aaz4164 just as gold prospectors in the gold rush used to mine this shiny precious metal on the mountains of Northern California, bioprospectors are also looking for new awards: potential antimicrobial molecules, and they are looking for them in the human microbiome For nearly two decades, scientists have been unveiling the mystery of these microbial communities that use the human body as their home Today, they see the human microbiome as an untapped source of molecules that could help fight infection and potentially treat other diseases In a new study, Dr Yuki Sugimoto of Princeton University and his colleagues combined bioinformatics with synthetic biology to identify bioactive molecules with similar drug functions By using their new algorithm, they were able to elucidate DNA fingerprints of potentially effective antimicrobial molecules The related research results were recently published in the journal Science The title of the paper is "a metric strategy for harnessing the chemical repertoire of the human organism" The corresponding author is Mohamed Donia, a molecular biologist at Princeton University Sugimoto is a postdoctoral researcher at Donia lab Sugimoto and his colleagues describe the human microbiome as an unparalleled resource for identifying the chemical structure of new drugs "We found that members of a class of clinically used molecules are widely encoded in the human microbiome and play an effective antibacterial role against neighboring microorganisms," they wrote in the paper Our approach paves the way for the systematic discovery of the chemical molecular library encoded by the human microbiome " In the search process, the researchers rely on their customized method, a computer algorithm that allows them to search a large number of molecular fragments This bioinformatics method, known as metabgc (metagenomic biosynthetic gene cluster), enables them to discover molecules from the human microbiome that have never been reported before They focused on samples from the mouth, intestines and skin, which are rich in microbial flora They found a variety of new enzymes in these three sites, namely, type II polyketide synthetase BGC, or tii-pks BGC for short Because a tii-pks enzyme is an important component of adriamycin, an antibiotic active anticancer drug, tii-pks is widely known In addition to its role in cancer treatment, adriamycin is also used as a test method for screening environmental bacteria To test the importance of their discovery of the tii-pks BGC molecule, Sugimoto and his team tested samples from around the world - the United States, Denmark, Spain, Fiji and China They found that people have genes that synthesize these molecules regardless of their geographical location, suggesting that they are common in people 4 Science: the low-temperature electron microscopic structure of ost-a and ost-b was analyzed Doi: 10.1126/science.aaz3505 glycosylation is a common modification of eukaryotic secretory protein Asparagine linked sugar chains attach to many protein substrates when they are transferred to the endoplasmic reticulum Ram í rez et al Analyzed the low temperature electron microscopic structure of ost-a and ost-b The catalytic subunits of these two complexes bind to chaperones, which guide the glycosylation of specific protein substrates (ost-a) in translation or after the protein substrates (ost-b) are completely folded The high-resolution structure of the active site and the binding protein substrate in one of the two complexes reveals the important characteristics of such enzymes in human body 5 Science: the new research revises the mechanism of action of breast cancer drug paboxenil doi: 10.1126/science.aaw2106; doi: 10.1126/science.aaz4043 the crystal structure of the active form of cyclin dependent kinase 4 (CDK4) can reveal the regulation of cell cycle and the mechanism of action of drugs for breast cancer treatment P27 has been considered as a CDK inhibitor Guiley et al Carried out structural analysis of the active complex of CDK4 with cyclin D1 (cycd1) and p27 The results showed that when p27 was phosphorylated on tyrosine (phosp27), p27 actually remolded the active site of CDK4, thus realizing the full activation of the latter In addition, they found that the breast cancer drug, palbociclib, is a CDK4 inhibitor and does not actually interact with the active phosp27-cdk4-cycd1 trimer Instead, the clinically promising drug appears to bind to inactive CDK4 monomers and block the interaction between the monomers and p27 6 Science: new technology can identify cell types in neural circuits doi: 10.1126/science.aax8055; doi: 10.1126/science.aaz8969 in many cases, single molecular marker is not enough to identify specific cell types