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In drilling engineering, it is extremely challenging to drill a prescribed wellbore over several thousand meters. One of the main difficulties arises from accurately predicting and controlling the directional drilling performance, caused by the complex nonlinear dynamics of the slender drilling assembly and its interactions with the surrounding rocks. Nowadays, the simplified analytical geometry method, which has been adopted as the industry standard, can merely offer a rough estimation of the drilling direction, while the high-accuracy finite element method is computationally inefficient. This study is intended to provide a straightforward prediction of the drilling direction for a long drilling distance accurately and efficiently by proposing a dynamical simulation method based on the flexible multibody approach. Three techniques were adopted to achieve the critical objective of the paper. First, an Arbitrary Lagrangian–Eulerian formulation was used to provide a new approach to balance the efficiency and accuracy. Additionally, it can perfectly simulate the realistic drilling operation that drill pipes are continuously added to the drill string one by one through dynamically inserting new beam elements into the existing model. Second, the whole drill string and its interaction with the wellbore were all considered to carry out a high-fidelity simulation. Finally, the bit–rock interaction model was introduced to offer a straightforward way of evaluating the steerability of drilling assemblies. The presented method and model were validated by the consistency between the simulated wellbore trajectory and the in-field experimental data and are ready to be applied in drilling tools design, real-time drilling simulation, and drilling direction control.

Results: relationship between the changes of each microvascular variable and basal microvascular parameters.

Microcirculatory measurements and analysis: detailed microcirculatory measurements and analysis.

Search strategy for the Cochrane database. Table S2 Search strategy for other databases. (DOCX 63 kb)

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N(6)-methyladenosine (m(6)A) modification has been implicated in various biological processes. However, the role of m(6)A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m(6)A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m(6)A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m(6)A-regulated FMT process. m(6)A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m(6)A modification in pulmonary fibrosis. Manipulation of m(6)A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.

Yu-Jie Wu, 1 Li-xia Li, 2 Lu Liu, 1 Si-shu Zhao, 1 Hai-rong Qiu, 1 Hui Wang 1 1Department of Hematology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210029, Jiangsu Province, People’s Republic of China; 2Department of Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People Hospital), Nanjing 210011, Jiangsu Province, People’s Republic of ChinaCorrespondence: Yu-Jie Wu Email wuyujie123456@163.comBackground: Mixed lineage leukemia (MLL) fusion protein alone exhibits poor histone lysine methyltransferase (HKMT) activity in catalyzing histone H3 Lys4 trimethylation (H3K4me3) in MLL-rearranged acute leukemia.Methods: To explore the HKMT effect of another regulatory protein within the complex of proteins associated with Set 1 (COMPASS), we analyzed the H3K4me3 modification of the HOXC8 promoter under the action of ASH2L regulation. Small interfering RNA of ASH2L, chromatin immunoprecipitation, real-time-PCR (RT-PCR), and Western blotting were used to detect the expression of specific regions of the HOXC8 promoter, RBBP5, WDR5, MLL, and BRTF in two MLL-rearranged acute leukemia cell lines (RS4:11 and THP-1 cells).Results: The gene and protein expression levels of HOXC8 were significantly downregulated upon treatment with ASH2L-siRNA (as analyzed by targeting specific regions of the HOXC8 promoter located 0 and 3 kb (– 3.0 kb) upstream of the transcriptional start site in RSH:11 cells; and – 3.0 and – 2.0 kb upstream of the transcriptional start site, and +1.4 kb downstream of the transcriptional start site in THP-1 cells). The expression levels of the BRTF, RBBP5, WDR5, and MLL genes were significantly downregulated from the different transcriptional start sites of the HOXC8 promoter in the RSH:11 cell line (P < 0.05). Furthermore, the BPTF and RBBP5 genes were downregulated from the HOXC8 promoter in the THP-1 cell line (P < 0.05).Conclusion: Based on these results, we suggest a new concept of histone modification of the ASH2L protein in MLL-rearranged acute leukemia, which cannot carry out methyltransferase activity independently. The protein–protein interactions of ASH2L with other COMPASS members, such as MLL, WDR5, RBBP5, and chromatin remodeling factor BRTF, appear to be essential for its role in the activation of HOXC8 gene transcription.Keywords: MLL-rearranged acute leukemia, HOXC8 gene, ASH2L, COMPASS complex, H3K4 trimethylation &nbsp