A new carrier to improve the effectiveness of mRNA vaccines! Stem cell therapy improves heart function!

In the past year, many researches have made new breakthroughs and clarified new biological and drug targets Here are some exciting research in 2019 that has driven biomedical development Recently, American scientists alexinott, inger Holtman and so on have mapped the regulatory elements of the main cell types of human brain through a scientific research to help clarify the transcription mechanism of their development and functional characteristics in health and disease It is known that most of the disease-related genetic variation exists in the noncoding region of the genome, and many pathogenic variants play their role by influencing gene expression regulation In this study, astrocytes, microglia, neurons and oligodendrocyte nuclei were isolated from cortical brain tissues of 6 different individuals and analyzed by transposable and chromatin sequencing (ataC-seq) to determine the open chromatin regions in 200000 specific nuclei In addition, 500000 nuclei were analyzed by chromatin immunoprecipitation, and then histone 3-labeled lysine 27 acetylation (h3k27ac) and lysine 4 trimethylation (h3k4me3) were sequenced (chip SEQ) to determine the active promoter and enhancer in each cell type Scientists have found a "one to many relationship between promoters and enhancers," as previously determined Compared with most active promoters shared among cell types, the number of overlapping active enhancers among different cell types is quite small This finding indicates that cell type specificity is mainly regulated by enhancers The linkage disequilibrium analysis was applied to the whole genome association analysis (GWAS), and the heritability based on SNP was summarized to determine the relationship between neuron specific variants in transcriptional enhancers or promoters and mental illness or behavioral characteristics In contrast, Alzheimer's disease risk variants are most prominent among microglial specific enhancers These patterns of brain cell type specific enhancers and promoters will serve as a useful resource for identifying cell types that affect genes and their functions in neurological and psychiatric disorders Original: https://science.sciencemag.org/content/366/6469/1134 In the past 50 years, the incidence of antibiotic discovery has declined sharply, while the incidence of drug resistance has risen sharply The decline in antibiotic efficacy is one of the biggest health threats of our time In response, the World Health Organization released a list of bacteria in urgent need of new antibiotics Two recent studies have reported that new compounds may help fight antibiotic resistance The two reports of Imai, y, Meyer, K from the United States and tomaszl.czarny, omarm.el-halfawy from Canada have been published in nature Imai, Meyer et al Found a new antibiotic that selectively kills gram-negative bacilli In their study, it was demonstrated that useful compounds may exist in symbionts that need to produce antibiotics, such as resistance to alien invasive species, and they are non-toxic to the host In order to study the growth inhibition of E coli in vitro, a library of Photobacterium and nematophilus was screened An inhibitory region was produced by the concentrated extract of photoelastic algae, and its effective part was identified by HPLC The structure of the active compound was confirmed by MS and NMR It was named darobactin In another study, El halfawy et al found an antiviral compound in methicillin-resistant Staphylococcus aureus (MRSA) that can reverse β - lactam resistance Antiviral compounds are promising antibiotic substitutes or adjuvants because they do not create the pressure that leads to increased resistance Researchers screened 45000 compounds from Staphylococcus aureus with high-throughput cells to identify molecules that can both weaken virulence and reverse antibiotic resistance Finally, an effective compound (mac-545496) was identified, which can reverse the resistance to various β - lactam antibiotics (i.e reduce the minimum inhibitory concentration), including penicillin, cephalosporins and carbapenems Mac-545496 can inhibit the virulence of the larva of S.aureus, inhibit the formation of biofilm in macrophage and reduce the survival rate of S.aureus Therefore, mac-545496 has certain application value in the treatment of MRSA infection Together, these studies highlight the importance of investing in discovery research as they can discover new sources of much-needed antimicrobial drugs Original text: 1、https://www.nature.com/articles/s41586-019-1791-1 2、https://www.nature.com/articles/s41589-019-0401-8 In a recent study published in the New England Journal of medicine by jinkuk Kim and others from the United States, a custom-designed antisense oligonucleotide was used to treat a patient's unique Barton's disease This study set a precedent for the rapid development of individualized therapy based on gene sequencing The study was led by Yu Timothy of Boston Children's Hospital, who met a six-year-old girl through social media She was diagnosed with Barton's disease, an autosomal recessive genetic disorder; her symptoms include vision loss, falls, dysarthria, dysphagia, seizures, and atrophy of the brain and cerebellum Gene test showed that there was a mutation in the mfsd8 gene of the little girl, which was related to Barton's disease However, when a recessive disease appears, a second mutation is also expected, although it has not yet been found Based on the background of the whole exome and genome sequencing and analysis, yutimothy and colleagues started to carry out molecular diagnosis Whole genome sequencing revealed an intron mutation that had not been detected before This mutation changed the splicing of mfsd8 and reduced the expression of normal gene products The biological basis of this mutation is similar to the causal mutation of spinal muscular atrophy On this basis, the researchers developed a customized oligonucleotide based on the principle of nosinogenase sodium The team designed multiple oligonucleotide targeted splicing variants of mfsd8 and selected one of the patients' fibroblasts that most effectively increased normal gene expression The oligonucleotide, known as milasen, was developed for clinical use and has been approved by the FDA for clinical research under an expanded trial drug application Original: https://www.nejm.org/doi/full/10.1056/nejmoa1813279 Cancer vaccines are designed for tumor associated antigens, which are preferentially expressed or specific to tumor cells Although mRNA vaccines have many advantages over synthetic peptide vaccines or DNA vaccines, it is a challenge to deliver mRNA between cells and thus induce strong immune activity Now, the research team led by Daniel Anderson has developed a series of new lipid nanoparticles (LNPS), which mediate the transmission of mRNA, and provide targeted immune stimulation through interferon gene stimulation (sting) pathway, improving the effectiveness of mouse anti melanoma vaccine Through the previous study, the team finally targeted two most effective mRNA delivery vectors, a2-iso5-2dc18 (A2) and a2iso5-2dc18 (A12) Then the anti-tumor immune responses of the two vectors were tested in B16F10 melanoma mouse model expressing ovalbumin (OVA) Compared with a12-mva-lnp, a2-mva-lnp showed significant antitumor effect, while a12-mva-lnp had little antitumor effect This antitumor activity is caused by high specific antigen-specific cytotoxic T-lymphocyte (CTL) reaction and IFN - γ secretion, neither of which is mediated by multinucleated cells When a2-mova-lnps was combined with PD1 antibody, the combined therapy significantly delayed tumor growth and improved the overall survival rate This new lipid nanoparticles, which integrate targeted adjuvants into an effective delivery system, may provide a universal vaccination method Original text: https://www.nature.com/articles/s41587-019-0247-3 Despite dozens of clinical trials involving thousands of patients who received stem cell therapy in the hope of regenerating infarcted heart tissue and improving heart function, the efficacy of this approach is still questionable Now, Jeffery molkentin and colleagues report in a paper published in nature that stem cell therapy can indeed improve heart function, but it can trigger an acute inflammatory wound healing response rather than by forming new cardiomyocytes as previously thought The possibility of using bone marrow mononuclear cells (MNC) containing Kit + hematopoietic stem cells to regenerate the heart after myocardial infarction has been studied The basic principle of these clinical trials is to observe that in the animal model of myocardial ischemia injury, the improvement of cardiac function by stem cell therapy is moderate but consistent, but whether this improvement is related to the formation of new cardiac myocytes is unclear "In our 2014 paper in nature, we showed that Kit + adult stem cells do not produce new cardiac myocytes in mouse heart significantly at baseline, during injury or during development This work makes us question the premise of general cardiac cell therapy, whether these cells really become cardiac myocytes after injection into the heart, and the use of Mechanisms of action in all human clinical trials of cell therapy "