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ShcA is an important mediator of ErbB2- and transforming growth factor β (TGF-β)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-β stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling.

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

One of the effective methods for energy conservation and emission reduction in coal mines is to utilize waste heat recovery technology to recover mine return air waste heat. The gravity heat pipe is widely used in mine return air waste heat recovery due to its sustainable and economic advantages, but its heat transfer is a complex process influenced by multiple parameters. A single-tube heat transfer resistance model and a heat transfer calculation model based on enthalpy difference were established for the heat exchange tubes. Four typical application cases of a low flow rate and a low number of tube rows were selected, and their heat transfer characteristics were tested onsite and analyzed. It was found that there were problems such as a low overall heat transfer efficiency, a low fresh air outlet temperature, and a risk of icing in the final tube section. The effects of the gravity heat pipe parameters on the heat transfer performance were studied, such as the tube outer diameter, tube spacing, and the finned tube outer diameter. It was found that the air-resistant force of the heat exchanger increased with the increase of the tube spacing and the finned tube outer diameter, the heat transfer resistance increased with the increase of the tube spacing and the decrease of the finned tube outer diameter, and the heat transfer coefficient first increased and then decreased with the increase of the tube outer diameter. A configuration improvement scheme with a high flow rate and a high number of tube rows is proposed here. Taking Case 2 as an example, the temperature distribution of the heat tube before and after improvement is compared and analyzed. The results show that the heat transfer performance of the heat exchange system significantly improved. Without increasing the air resistance of the heat tube, the temperature of the return air outlet after improvement was reduced to 1.1 °C, 4.1 °C lower than that before improvement, further recovering the waste heat of the mine return air. The temperature of the condensate water film was greater than 0.5 °C, avoiding the icing problem of the condensate tube section, the fresh air outlet temperature reached 5.2 °C, an increase of 7.8 °C compared to that before improvement, and the overall heat transfer efficiency increased from 56.7% to 66%. [ABSTRACT FROM AUTHOR]

Based on the analysis of transmission mechanism of rod-gear type Pulse Continuously Variable Transmission（ P-CVT）,the closed vector equations of equivalent plane six-bar mechanism is built,and the kinematic mathematical model of angular displacement,angular velocity and angular acceleration of connecting rod,rocker and meshing point to input shaft axis of single phase transmission mechanism is constructed by the matrix method. At last,by using software Matlab,the simulation analysis of the effects of speed-adjusted style,phase number and eccentricity on the speed-variation characteristics,the main speed regulating mode and the optimal phase number are the determined,the advantages of large variable speed ratio range and small pulsation rate the transmission mechanism are proved. The reference for improving the design theory and engineering implementation of the transmission is provided.

Based on the analysis of transmission mechanism of rod-gear type Pulse Continuously Variable Transmission（ P-CVT）,the closed vector equations of equivalent plane six-bar mechanism are built. The kinematic mathematical model of angular displacement,angular velocity and angular acceleration of connecting rod,rocker and meshing point to input shaft axis of single phase transmission mechanism is constructed by the matrix method. At last,the kinematics simulation of three key components of connecting rod,rocker and output shaft plate is carried out by using MATLAB program. The results show that the rod-gear type CVT has the advantages of large variable speed range and low pulse rate,it also has the disadvantages of large inertia force of rod,rocker and large impact of output shaft disc etc.

As a multi-linkage mechanism with multi-degree of freedom,the two-leg shield hydraulic support is comprised of beams,fore and rear links and hydraulic cylinders.It can realize supporting roof,protecting coal wall and moving forward under the function of hydraulic power,and plays an important role in coal mining.According to structure and operating characteristics of the two-leg shield hydraulic support,the geometrical relationship and calculations about rear link angle and shield beam angle for the supporting height,head distance,leg length and balance cylinder length are deduced.The differential equation of motion for the hydraulic support is established by the Lagrangian theory,and the support type of ZY17300/32/70 is calculated and analyzed.The relationship between angle displacement and velocity for the rear link angle and shield beam angle along with the motion characteristic of supporting height is obtained.The response characteristics of motion velocity and acceleration for top beam are discussed during the working process of lifting up and down.

In order to realize the functions of remote control cutting coal and rock,and intelligent remember shaping,it is necessary to study the kinematic characteristics of cutting tooth of EBH300 A roadheader during operation.According to the engineering design of EBH300 Aroadheader prototype,the 3Dsolid model and virtual prototype are built with Pro/E software.The mechanical system dynamic analysis software is used to simulate the displacement,movement based on the parameters of the EBH300 Aroadheader,in which,the motion displacement,velocity and acceleration of cutting tooth on the cutting head are provided.

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases (1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX(α-thalassaemia/mental retardation syndrome X-linked) (5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres (6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis., Brain tumours are currently the leading cause of cancer-related mortality and morbidity in children. Glioblastoma multiforme (GBM) is a highly aggressive brain tumour and the first cancer to be comprehensively [...]