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

Effect of non-invasive ventilator in combination with tiotropium bromide on pulmonary function and sleep quality of patients with chronic obstructive pulmonary disease complicated with obstructive sleep apnea-hypopnea syndrome

Purpose: To study the influence of non-invasive ventilator and tiotropium bromide on pulmonary function and sleep quality of patients with chronic obstructive pulmonary disease (COPD) combined with obstructive sleep apnea-hypopnea syndrome (OSAHS).Methods: One hundred and twenty patients with COPD-OSAHS were selected and randomly assigned to control group (CG) and treatment group (TG), with 60 subjects in each group. Non-invasive ventilator therapy was used in both groups, based on conventional therapy, while tiotropium bromide was added in TG. Treatment effectiveness in the two groups was evaluated and compared.Results: Total effectiveness was significantly higher in TG than in CG. Post-therapy arterial oxygen saturation (SaO2) and oxygen partial pressure (PaO2) were increased, while partial pressure of carbon dioxide (PaCO2) and lactic acid (Lac) were decreased in both groups (p < 0.05). Post-treatment values of indices of lung function, viz, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were higher than the corresponding pre-treatment levels, and also values were significantly higher in TG than in CG (p < 0.05). Average sleep time, apnea and hypopnea index (AHI) and mechanical ventilation time of TG were less than those of CG. There were lower levels of Creactive protein (CRP), procalcitonin (PCT) and interleukin-17 (IL-17) in TG than in CG. During the treatment, no obvious adverse reaction was seen in both groups.Conclusion: Non-invasive ventilator, in combination with tiotropium bromide, is more effective in the treatment of COPD-OSAHS than the use of non-invasive ventilator alone. However, further clinical trials are required before its adoption in clinical practice

Targeted DNA Damage at Individual Telomeres Disrupts Their Integrity and Triggers Cell Death

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising \u3c1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage

Leaf senescence exhibits stronger climatic responses during warm than during cold autumns

A warmer world could extend the growing seasons for plants. Changes in spring phenology have been studied, yet autumn phenology remains poorly understood. Using >500,000 phenological records of four temperate tree species between 1951 and 2013 in Europe, we show that leaf senescence in warm autumns exhibits stronger climate responses, with a higher phenological plasticity, than in cold autumns, indicating a nonlinear response to climate. The onset of leaf senescence in warm autumns was delayed due to the stronger climate response, primarily caused by night-time warming. However, daytime warming, especially during warm autumns, imposes a drought stress which advances leaf senescence. This may counteract the extension of growing season under global warming. These findings provide guidance for more reliable predictions of plant phenology and biosphere–atmosphere feedbacks in the context of global warming

Location patterns of urban industry in Shanghai and implications for sustainability

China’s economy has undergone rapid transition and industrial restructuring. The term “urban industry” describes a particular type of industry within Chinese cities experiencing restructuring. Given the high percentage of industrial firms that have either closed or relocated from city centres to the urban fringe and beyond, emergent global cities such as Shanghai, are implementing strategies for local economic and urban development, which involve urban industrial upgrading numerous firms in the city centre and urban fringe. This study aims to analyze the location patterns of seven urban industrial sectors within the Shanghai urban region using 2008 micro-geography data. To avoid Modifiable Areal Unit Problem (MAUP) issue, four distance-based measures including nearest neighbourhood analysis, Kernel density estimation, K-function and co-location quotient have been extensively applied to analyze and compare the concentration and co-location between the seven sectors. The results reveal disparate patterns varying with distance and interesting co-location as well. The results are as follows: the city centre and the urban fringe have the highest intensity of urban industrial firms, but the zones with 20–30 km from the city centre is a watershed for most categories; the degree of concentration varies with distance, weaker at shorter distance, increasing up to the maximum distance of 30 km and then decreasing until 50 km; for all urban industries, there are three types of patterns, mixture of clustered, random and dispersed distribution at a varied range of distances. Consequently, this paper argues that the location pattern of urban industry reflects the stage-specific industrial restructuring and spatial transformation, conditioned by sustainability objectives

A Transient Stability Numerical Integration Algorithm for Variable Step Sizes Based on Virtual Input

In order to reduce the online calculations for power system simulations of transient stability, and dramatically improve numerical integration efficiency, a transient stability numerical integration algorithm for variable step sizes based on virtual input is proposed. The method for fully constructing the nonhomogeneous virtual input for a certain integration scheme is given, and the calculation method for the local truncation error of the power angle for the corresponding integration scheme is derived. A step size control strategy based on the predictor corrector variable step size method is proposed, which performs an adaptive control of the step size in the numerical integration process. The proposed algorithm was applied to both the IEEE39 system and a regional power system (5075 nodes, 496 generators) in China, and demonstrated a high level of accuracy and efficiency in practical simulations compared to the conventional numerical integration algorithm

Effects of Sample Preparation Methods on Permeability and Microstructure of Remolded Loess

To explore the influence of sample preparation methods on the permeability and microstructure of remolded loess, remolded loess collected from Heifangtai was taken as the research object. A total of 40 sets of falling-head permeability tests were conducted using two commonly used sample preparation methods, and five different dry density and four initial water content conditions. Additionally, the electrical conductivity of the leachate and the microscopic structure of the samples were analyzed. The results demonstrate that compared to the transfer wetting method, the homogeneity of samples prepared using the pre-wetting method is inferior. This difference is particularly evident when the initial water content is high. Due to the long duration of the permeability test, the pore structure is prone to change, resulting in relatively higher permeability coefficients. Moreover, the total dissolved solids (TDS) of the leachate exhibit a significant decrease with increasing seepage time, indicating the loss of soluble salts. Microscopic structural analysis reveals that samples prepared using the pre-wetting method exhibit a greater number of large pores and aggregates, which are intrinsic factors contributing to the observed differences in permeability between the two sample preparation methods. Furthermore, it should be noted that the impact of the sample preparation method on the permeability of remolded loess is more significant when the dry density is relatively low (specifically, less than 1.45 g/cm3). Conversely, when the dry density is higher, the influence becomes less pronounced