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Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

The method developed in our previous work (Wang et al., AIChE J. 2020; 66(8): e16257), was used to study the influence of the mass‐transfer direction and flux on the dynamic interfacial tension (DIFT) in a pulsed column. The breakup frequency was the highest near the entrance of the dispersed droplet, corresponding to the lowest interfacial tension and highest mass transfer flux. The decrease in the interfacial tension was proportional to the square root of mass‐transfer flux, and this difference is defined as a new parameter, named interfacial relaxation. When the mass‐transfer direction was changed from the dispersed phase to continuous phase to the opposite direction, the proportion of binary breakage was decreased from ~80% to ~40% and the interfacial relaxation was more sensitive to the mass‐transfer flux. A DIFT model was finally established based on the interfacial relaxation parameter, which predicted the experimental results with an error of ±10%. [ABSTRACT FROM AUTHOR]

It was reported that the Wnt/β‐catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/β‐catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg‐AD mice were treated with ICA. HT22 cells, the Aβ25‐35 peptide and Dickkopf‐1 (DKK1) agent (a specific inhibitor of the Wnt/β‐catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti‐AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg‐AD mice back to wild‐type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aβ25‐35. However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg‐AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/β‐catenin pathway. [ABSTRACT FROM AUTHOR]

Objective: To establish ulcerative colitis (UC) rat model of spleen deficiency and dampness, and to explore effect of Jianpi-Huazhu pill and its different deconditions on TLR-4/MyD88/NF-κB pathway. Methods: A total of 64 Wistar rats were randomly divided into normal control group (n=8) and model group (n=56). UC rat model was established by traditional Chinese medicine syndrome combined with ethanol-2, 4, 6-trinitrobenzene sulfonic acid enema method. After successfully modeling, rats were randomly divided into model group (M), Mesalazine group (A), Jianpi-Huazhi pill group (B), Jianpi-Qinghua decoction group (C), Jianpi-Qinghua-Huoxue decoction group (D), Jianpi-Qinghua-Daozhi decoction group (E) and Qinghua-Daozhi-Huoxue decoction group (F), with 8 rats in each group, given corresponding drugs by gavage for 4 weeks. At end of course of treatment, all rats were sacrificed and samples were taken. Changes of body weight, disease activity and pathological changes of colon were observed. TNF-α expression in colon tissue was detected by ELISA and immunohistochemistry. RT-PCR and Western blot were used to detect mRNA and protein expressions of TLR-4, MyD88 and NF-κB in rat colon tissue. Results: Rats weight in Jianpi-Huazhi pill group, Jianpi- Qinghua decoction group, Jianpi-Qinghua-Huoxue decoction group and Jianpi-Qinghua-Daozhi decoction group were obviously higher than that of model group (P<0.01), all treatment groups could obviously improve UC model rat pathological damage and disease activity index in colon tissue, and Jianpi-Huazhi pill group and Jianpi-Qinghua-Huoxue group showed better efficacy. All treatment groups could inhibit mRNA and protein expressions of TLR-4, MyD88 and NF-κB in colon tissue (P<0.001). Mesalazine group, Jianpi-Huazhi pill group, Jianpi-Qinghua-Daozhi group and Qinghua-Daozhi-Huoxue group were significantly better than Jianpi-Qinghua group and Jianpi-Qinghua-Huoxue group in reducing NF-κB mRNA and protein expressions (P<0.05). All groups could reduce expression of TNF-α in colon tissue (P<0.001), and there was no significant difference between groups (P>0.05). Conclusion: Jianpi- Huazhi pill and its various deconditions may play roles through TLR-4/MyD88/NF-κB pathway. Among them, Coptid-Rhizoma coptifolia, stews woody incense, Fengwei herb and gung ginger may be core drugs of this recipe, which has certain guiding significance for clinical practice. [ABSTRACT FROM AUTHOR]

This manuscript introduces a symmetrical gripping mechanism, a significant piece of robotic equipment, adept at adjusting to the variable dimensions of disparate objects within an extensive range. The innovative mechanism presented in this treatise has dual degrees of freedom (DOF), and its parameters can be customized to satisfy diverse requirements. Symbolic computation is employed to dissect both the forward and inverse kinematics of the mechanism. Furthermore, the requisite driving force of the mechanism, when paired with parameterized objects, is discussed. Ultimately, a methodology is suggested for discerning the mechanism's parameters in relation to variously grasped widths and forces. The article concludes with the introduction of a prototype construction process. Experimental results substantiate the effectiveness and functionality of the proposed mechanism. [ABSTRACT FROM AUTHOR]

It is in urgent requirement to directly measure the droplet coalescence frequency for the application of the population balance model. In this study, a method was firstly developed to directly measure the droplet coalescence frequency in turbulent flow field by using a specially designed mixing tank and a high‐speed camera. The effects of the rotating speed and holdup fraction on the droplet coalescence frequency were quantitatively investigated. The increasing of rotation speed promotes first and then inhibits the coalescence, while the holdup fraction has little influence on the coalescence frequency function. The droplet collision frequency was also counted and the coalescence efficiency was calculated. The models in the literature were tested with our experimental data and were found failing to predict the coalescence frequency in the stirring tank. Empirical correlation was finally proposed and good agreement was found between the prediction results and the experimental data. [ABSTRACT FROM AUTHOR]