M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s

Background Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC). Results We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family. Conclusion Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent

Developing a Volume Model Using South NTS-372R Total Station without Tree Felling in a Populus canadensis Moench Plantation in Beijing, China

Volume table preparation using the traditional method and a collection model requires the harvest of approximately 200–300 trees of individual species. Although high precision could be achieved using that method, it causes huge damage to the forest. To minimize these losses, in this study, a South NTS-372R total station with a precise angle and distance measurement mode was used to measure 507 trees of Populus canadensis Moench without single tree felling. Moreover, the C# programming language was used in this study and the collected volume data were inserted in the total station. Using this method, a real-time precise measurement of volume could be achieved. After data collection, the optimal binary volume model of Populus canadensis Moench could be obtained through a comparative analysis. It turns out that the Yamamoto model is the optimal binary volume model (also known as two predictor variable model), with 0.9641 as the coefficient of determination (R2) and 0.19 m3 as the standard deviation of estimated value (SEE), which presents a good imitative effect. Moreover, it showed relative stability with the general relative error (TRE) of –0.12% and the mean system error (MSE) of –1.24%. The mean predicted error (MPE) of 1.18% and the mean predicted standard error (MPSE) of 9.25% showed high estimated precision of the average and individual tree volumes. The model has only three parameters, so it is suitable for volume table preparation. Finally, this study will present some new technical methods and means for volume modeling for further application in forestry

PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells

The biggest challenge in the field of gene therapy is how to effectively deliver target genes to special cells. This study aimed to develop a new type of poly(D,L-lactide-co-glycolide) (PLGA)-based nanoparticles for gene delivery, which are capable of overcoming the disadvantages of polyethylenimine (PEI)- or cationic liposome-based gene carrier, such as the cytotoxicity induced by excess positive charge, as well as the aggregation on the cell surface. The PLGA-based nanoparticles presented in this study were synthesized by emulsion evaporation method and characterized by transmission electron microscopy, dynamic light scattering, and energy dispersive spectroscopy. The size of PLGA/PEI nanoparticles in phosphate-buffered saline (PBS) was about 60 nm at the optimal charge ratio. Without observable aggregation, the nanoparticles showed a better monodispersity. The PLGA-based nanoparticles were used as vector carrier for miRNA transfection in HepG2 cells. It exhibited a higher transfection efficiency and lower cytotoxicity in HepG2 cells compared to the PEI/DNA complex. The N/P ratio (ratio of the polymer nitrogen to the DNA phosphate) 6 of the PLGA/PEI/DNA nanocomplex displays the best property among various N/P proportions, yielding similar transfection efficiency when compared to Lipofectamine/DNA lipoplexes. Moreover, nanocomplex shows better serum compatibility than commercial liposome. PLGA nanocomplexes obviously accumulate in tumor cells after transfection, which indicate that the complexes contribute to cellular uptake of pDNA and pronouncedly enhance the treatment effect of miR-26a by inducing cell cycle arrest. Therefore, these results demonstrate that PLGA/PEI nanoparticles are promising non-viral vectors for gene delivery

HINT1 Is Involved in the Chronic Mild Stress Elicited Oxidative Stress and Apoptosis Through the PKC ε/ALDH-2/4HNE Pathway in Prefrontal Cortex of Rats

Major depressive disorder (MDD) is a severe, highly heterogeneous, and life-threatening psychiatric disease which affects up to 21% of the population worldwide. A new hypothesis suggests that the mitochondrial dysfunction causing oxidative stress (OS) and dysregulation of apoptosis in brain might be one of the key pathophysiological factors in MDD. Histidine triad nucleotide binding protein 1 (HINT1), which was first supposed to be protein kinase C (PKC) inhibitor, has been gradually demonstrated to be involved in diverse neuropsychiatric diseases. It still remains elusive that how HINT1 involves in depression. The present study utilized a rat model exposed to chronic mild stress (CMS) to explore the involvement of HINT1 in depression. Face validity, construct validity and predictive validity of CMS model were comprehensive evaluated in this study. Behavioral tests including sucrose preference test, open field test, and elevated plus maze and forced swimming test revealed that stressed rats displayed elevated level of anxiety and depression compared with the controls. CMS rats showed a significant decrease of superoxide dismutase, and a marked increase malondialdehyde levels in prefrontal cortex (PFC). We also found the CMS rats had elevated expression of HINT1, decreased levels of phosphorylated-PKC ε and aldehyde dehydrogenase-two (ALDH-2), and accumulated 4-hydroxynonenal (4HNE) in PFC. Moreover, CMS increased the levels of cleaved caspase-3 and Bax, and decreased the level of Bcl-2 in PFC. The alterations in behavior and molecule were prevented by antidepressant venlafaxine. These results demonstrated that HINT1 was involved in the CMS elicited OS and apoptosis in PFC, probably through the PKC ε/ALDH-2/4HNE pathway. The results suggest that the suppression of HINT1 might have potential as a novel therapeutic strategy for depression

Locate and Beamform: Two-dimensional Locating All-neural Beamformer for Multi-channel Speech Separation

Recently, stunning improvements on multi-channel speech separation have been achieved by neural beamformers when direction information is available. However, most of them neglect to utilize speaker's 2-dimensional (2D) location cues contained in mixture signal, which limits the performance when two sources come from close directions. In this paper, we propose an end-to-end beamforming network for 2D location guided speech separation merely given mixture signal. It first estimates discriminable direction and 2D location cues, which imply directions the sources come from in multi views of microphones and their 2D coordinates. These cues are then integrated into location-aware neural beamformer, thus allowing accurate reconstruction of two sources' speech signals. Experiments show that our proposed model not only achieves a comprehensive decent improvement compared to baseline systems, but avoids inferior performance on spatial overlapping cases.Comment: Accepted by Interspeech 2023. arXiv admin note: substantial text overlap with arXiv:2212.0340