Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease.

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP. Following in vitro optimization of the top-performing LNP (C3 LNP) for codelivery of an adenine base editing platform, we improve the biochemical phenotype of a lysosomal storage disease in the neonatal mouse brain, exhibit proof-of-principle mRNA brain transfection in vivo in a fetal nonhuman primate model, and demonstrate the translational potential of C3 LNPs ex vivo in human patient-derived brain tissues. These LNPs may provide a clinically translatable platform for in utero and postnatal mRNA therapies including gene editing in the brain.

Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice.

Neutrophils are critical mediators during the early stages of innate inflammation in response to bacterial or fungal infections. A human hematopoietic system reconstituted in humanized mice aids in the study of human hematology and immunology. However, the poor development of human neutrophils is a well-known limitation of humanized mice. Here, we generate a human granulocyte colony-stimulating factor (hG-CSF) knockin (KI) NOD/Shi-scid-IL2rgnull (NOG) mouse in which hG-CSF is systemically expressed while the mouse G-CSF receptor is disrupted. These mice generate high numbers of mature human neutrophils, which can be readily mobilized into the periphery, compared with conventional NOG mice. Moreover, these neutrophils exhibit infection-mediated emergency granulopoiesis and are capable of efficient phagocytosis and reactive oxygen species production. Thus, hG-CSF KI mice provide a useful model for studying the development of human neutrophils, emergency granulopoiesis, and a potential therapeutic model for sepsis.

Rnf20 deficiency in adipocyte impairs adipose tissue development and thermogenesis

RNF20, an E3 ligase critical for monoubiquitination of histone H2B at lysine 120 (H2Bub), has been implicated in the regulation of various cellar processes; however, its physiological roles in adipocytes remain poorly characterized. Here, we report that the adipocyte-specific knockout of Rnf20 (ASKO) in mice led to progressive fat loss, organomegaly and hyperinsulinemia. Despite signs of hyperinsulinemia, normal insulin sensitivity and improved glucose tolerance were observed in the young and aged CD-fed ASKO mice. In addition, high-fat diet-fed ASKO mice developed severe liver steatosis. Moreover, we observed that the ASKO mice were extremely sensitive to a cold environment due to decreased expression levels of brown adipose tissue (BAT) selective genes, including uncoupling protein 1 (Ucp1), and impaired mitochondrial functions. Significantly decreased levels of peroxisome proliferator-activated receptor gamma (Pparγ) were observed in the gonadal white adipose tissues (gWAT) from the ASKO mice, suggesting that Rnf20 regulates adipogenesis, at least in part, through Pparγ. Rosiglitazone-treated ASKO mice exhibited increased fat mass compared to that of the non-treated ASKO mice. Collectively, our results illustrate the critical role of RNF20 in control of white and brown adipose tissue development and physiological function.

influence of Qufeng Xuanbi Formula on ICAM-1 of Asthma Guinea Pig / 浙江中医药大学学报

[Objective]To discuss the functional mechanism of Qufeng Xuanbi(remove wind and apoplexy)Formula(Pingxiao Heji) on bronchia asthma.[Method]Make bronchia asthma animal model with guinea pig sensitized by egg albumen,treat it with Qufeng Xuanbi Formula,observe the changes of cell adhesion molecular(ICAM-1)in animal plasma.[Result]When experimental guinea pig was attacked by asthma,the ICAM-1 was obviously more than that in normal control group,the formula could markedly lower ICAM-1(95% of the believable zone 20.387～53.834u/ml)(P

Correlation between the levels of vascular endothelial growth factor and its receptor Flt-1 and KDR in human brain glioma / 肿瘤研究与临床

Objective To evaluate the serum changes in glioma patients, and in relations with clinicopathalogy parameters response to treatment and survival in patients with glioma via the examination of the significance of serum VEGF, Flt-1 and KDR levels. Methods Serum VEGF,Flt-1 and KDR levels were analyzed in patients of glioma before and after treatment, and patients with brain metastasis, as well as in healthy controls. Serum VEGF, Flt-1 and KDR levels were assessed by Enzyme-Linked Immunosorbent Assay(ELISA) and the data were processed by SPSS 11.5 for t-test and relevant analyses. Results Serum VEGF, Flt-1 and KDR levels were higher in patients with glioma than in healthy control (P =0.001, P =0.043 and P =0.045 respectively). Significant difference on levels of VEGF was found (P =0.032) comparing glioma group with brain metastasis group. The pretherapeutic serum levels of VEGF and Flt-1 were significantly different with disease recurrence or persistence after treatment (P =0.026 and P =0.038). There was significant correlation between the serum levels of VEGF correlated and that of Flt-1 and KDR (r =0.456 P