Connexin43 hemichannels contributes to the disassembly of cell junctions through modulation of intracellular oxidative status

AbstractConnexin (Cx) hemichannels regulate many cellular processes with little information available regarding their mechanisms. Given that many pathological factors that activate hemichannels also disrupts the integrity of cellular junctions, we speculated a potential participation of hemichannels in the regulation of cell junctions. Here we tested this hypothesis. Exposure of renal tubular epithelial cells to Ca2+-free medium led to disassembly of tight and adherens junctions, as indicated by the reduced level of ZO-1 and cadherin, disorganization of F-actin, and severe drop in transepithelial electric resistance. These changes were preceded by an activation of Cx43 hemichannels, as revealed by extracellular efflux of ATP and intracellular influx of Lucifer Yellow. Inhibition of hemichannels with chemical inhibitors or Cx43 siRNA greatly attenuated the disassembly of cell junctions. Further analysis using fetal fibroblasts derived from Cx43 wide-type (Cx43+/+), heterozygous (Cx43+/-) and knockout (Cx43-/-) littermates showed that Cx43-positive cells (Cx43+/+) exhibited more dramatic changes in cell shape, F-actin, and cadherin in response to Ca2+ depletion, as compared to Cx43-null cells (Cx43-/-). Consistently, these cells had higher level of protein carbonyl modification and phosphorylation, and much stronger activation of P38 and JNK. Hemichannel opening led to extracellular loss of the major antioxidant glutathione (GSH). Supplement of cells with exogenous GSH or inhibition of oxidative sensitive kinases largely prevented the above-mentioned changes. Taken together, our study indicates that Cx43 hemichannels promote the disassembly of cell junctions through regulation of intracellular oxidative status

Post-translational regulation enables robust p53 regulation

The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis

Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis

Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis

The impact of different benefit packages of Medical Financial Assistance Scheme on health service utilization of poor population in Rural China

<p>Abstract</p> <p>Background</p> <p>Since 2003 and 2005, National Pilot Medical Financial Assistance Scheme (MFA) has been implemented in rural and urban areas of China to improve the poorest families' accessibility to health services. Local governments of the pilot areas formulated various benefit packages. Comparative evaluation research on the effect of different benefit packages is urgently needed to provide evidence for improving policy-making of MFA. This study was based on a MFA pilot project, which was one component of Health VIII Project conducted in rural China. This article aimed to compare difference in health services utilization of poor families between two benefit package project areas: H8 towns (package covering inpatient service, some designated preventive and curative health services but without out-patient service reimbursement in Health VIII Project,) and H8SP towns (package extending coverage of target population, covering out- patient services and reducing co-payment rate in Health VIII Supportive Project), and to find out major influencing factors on their services utilization.</p> <p>Methods</p> <p>A cross-sectional survey was conducted in 2004, which used stratified cluster sampling method to select poor families who have been enrolled in MFA scheme in rural areas of ChongQing. All family members of the enrolled households were interviewed. 748 and 1129 respondents from two kinds of project towns participated in the survey. Among them, 625 and 869 respondents were included (age≥15) in the analysis of this study. Two-level linear multilevel model and binomial regressions with a log link were used to assess influencing factors on different response variables measuring service utilization.</p> <p>Results</p> <p>In general, there was no statistical significance in physician visits and hospitalizations among all the respondents between the two kinds of benefit package towns. After adjusting for major confounding factors, poor families in H8SP towns had much higher frequency of MFA use (β = 1.17) and less use of hospitalization service (OR = 0.7 (H8SP/H8), 95%CI (0.5, 1.0)) among all the respondents. While calculating use of hospital services among those who needed, there was significant difference (p = 0.032) in percentage of hospitalization use between H8SP towns (46%) and H8 towns (33%). Meanwhile, the non-use but ought-to-use hospitalization ratio of H8SP (54%) was lower than that of H8 (67 %) towns. This indicated that hospitalization utilizations had improved in H8SP towns among those who needed. Awareness of MFA detailed benefit package and presence of physician diagnosed chronic disease had significant association with frequency of MFA use and hospitalizations. There was no significant difference in rate of borrowing money for illness treatment between the two project areas. Large amount of medical debt had strong association with hospitalization utilization.</p> <p>Conclusions</p> <p>The new extended benefit package implemented in pilot towns significantly increased the poor families' accessibility to MFA package in H8SP than that of H8 towns, which reduced poor families' demand of hospitalization services for their chronic diseases, and improved the poor population's utilization of out-patient services to some degree. It can encourage poor people to use more outpatient services thus reduce their hospitalization need. Presence of chronic disease and hospitalization had strong association with the presence of large amount of medical debt, which indicated that: although establishment of MFA had facilitated accessibility of poor families to this new system, and improved service utilization of poor families to some degree, but its role in reducing poor families' medical debt resulted from chronic disease and hospitalization was still very limited. Besides, the following requirements of MFA: co-payment for in-patient services, ceiling and deductibles for reimbursement, limitations on eligibility for diseases reimbursement, also served as most important obstacles for poor families' access to health care.</p> <p>Therefore, there is great need to improve MFA benefit package design in the future, including extending to cover out-patient services, raising ceiling for reimbursement, removing deductibles of MFA, reducing co-payment rate, and integrating MFA with New Rural Cooperative Medical Scheme more closely so as to provide more protection to the poor families.</p

Research on Method of Trajectory Prediction in Aircraft Flight Based on Aircraft Performance and Historical Track Data

Traditional 4D trajectory prediction based on aircraft performance models and flight procedures does not consider control handover rules. Meanwhile, method based on historical data mining cannot accurately couple with real-time conditions such as weather and also cause computational efficiency problems. This project collected a large amount of historical data to form a control experience database and mined the historical database to obtain control experience and flight intention. On the basis of the traditional aircraft performance model, this paper puts forward the aircraft maneuver mode using strategy and introduces the high-altitude wind information from the weather information into the aircraft 4D model to optimize the aircraft 4D trajectory calculation model. By comparing the flight forecast time with the real crossing time, it is found that the average error of the improved 4D forecast crossing time is less than 5% of the flight time, which is obviously better than that before optimization. It is proved that the optimized method based on historical track data is effective and reliable, and the accuracy of 4D track prediction is improved greatly

An Integrated Wireless Wearable Sensor System for Posture Recognition and Indoor Localization

In order to provide better monitoring for the elderly or patients, we developed an integrated wireless wearable sensor system that can realize posture recognition and indoor localization in real time. Five designed sensor nodes which are respectively fixed on lower limbs and a standard Kalman filter are used to acquire basic attitude data. After the attitude angles of five body segments (two thighs, two shanks and the waist) are obtained, the pitch angles of the left thigh and waist are used to realize posture recognition. Based on all these attitude angles of body segments, we can also calculate the coordinates of six lower limb joints (two hip joints, two knee joints and two ankle joints). Then, a novel relative localization algorithm based on step length is proposed to realize the indoor localization of the user. Several sparsely distributed active Radio Frequency Identification (RFID) tags are used to correct the accumulative error in the relative localization algorithm and a set-membership filter is applied to realize the data fusion. The experimental results verify the effectiveness of the proposed algorithms