GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines

BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.

CR6-interacting factor-1 contributes to osteoclastogenesis by inducing receptor activator of nuclear factor κB ligand after radiation

BACKGROUND Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury.Receptor activator of nuclear factor κB ligand(RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood.AIM To investigate the role of CR6-interacting factor-1(Crif1) in osteoclastogenesis after radiation and its possible mechanism.METHODS C57 BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of wholebody sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells(BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. Clus Pro and Inter Pro Surf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate(c AMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt(WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BMMSCs, and Vero cells.RESULTS Crif1 expression increased in bone marrow cells after radiation in mice.Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression,resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A(PKA)agonist(forskolin) and inhibitor(H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the c AMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the c AMP/PKA pathway.CONCLUSION Crif1 promotes RANKL expression via the c AMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.

Transmission patterns of COVID-19 in the mainland of China and the efficacy of different control strategies: a data-and model-driven study

Background:The coronavirus disease 2019(COVID-19)outbreak has seriously endangered the health and lives of Chinese people.In this study,we predicted the COVID-19 epidemic trend and estimated the efficacy of several intervention strategies in the mainland of China.Methods:According to the COVID-19 epidemic status,we constructed a compartmental model.Based on reported data from the National Health Commission of People's Republic of China during January 10-February 17,2020,we estimated the model parameters.We then predicted the epidemic trend and transmission risk of COVID-19.Using a sensitivity analysis method,we estimated the efficacy of several intervention strategies.Results:The cumulative number of confirmed cases in the mainland of China will be 86763(95%CI:86067-87460)on May 2,2020.Up until March 15,2020,the case fatality rate increased to 6.42%(95%CI:6.16-6.68%).On February 23,2020,the existing confirmed cases reached its peak,with 60890 cases(95%CI:60350-61431).On January 23,2020,the effective reproduction number was 2.620(95%CI:2.567-2.676)and had dropped below 1.0 since February 5,2020.Due to governmental intervention,the total number of confirmed cases was reduced by 99.85%on May 2,2020.Had the isolation been relaxed from February 24,2020,there might have been a second peak of infection.However,relaxing the isolation after March 16,2020 greatly reduced the number of existing confirmed cases and deaths.The total number of confirmed cases and deaths would increase by 8.72 and 9.44%,respectively,due to a 1-day delayed diagnosis in non-isolated infected patients.Moreover,if the coverage of close contact tracing was increased to 100%,the cumulative number of confirmed cases would be decreased by 88.26%on May 2,2020.Conclusions:The quarantine measures adopted by the Chinese government since January 23,2020 were necessary and effective.Postponing the relaxation of isolation,early diagnosis,patient isolation,broad close-contact tracing,and strict monitoring of infected persons could effectively control the COVID-19 epidemic.April 1,2020 would be a reasonable date to lift quarantine in Hubei and Wuhan.