YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation [preprint]

The YAP and TAZ paralogues are transcriptional co-activators recruited to target sites, primarily by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB and STAT3, key factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, co-occupy many target sites in vivo via AP-1 and (to a lesser extent) STAT3 sequence motifs, and stimulate transcriptional activation by AP-1 proteins. A few target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes. YAP/TAZ, JUNB, and STAT3 directly regulate a common set of target genes that overlap, but are distinct from, those regulated by YAP/TAZ and TEADs. The set of genes regulated by YAP/TAZ, STAT3, and JUNB is associated with poor survival in breast cancer patients with the triple-negative form of the disease

YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation

The YAP and TAZ paralogs are transcriptional co-activators recruited to target sites by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB (a member of the AP-1 family) and STAT3, key transcription factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, and they stimulate transcriptional activation by AP-1 proteins. JUNB, STAT3, and TEAD co-localize at virtually all YAP/TAZ target sites, yet many target sites only contain individual AP-1, TEAD, or STAT3 motifs. This observation and differences in relative crosslinking efficiencies of JUNB, TEAD, and STAT3 at YAP/TAZ target sites suggest that YAP/TAZ is recruited by different forms of an AP-1/STAT3/TEAD complex depending on the recruiting motif. The different classes of YAP/TAZ target sites are associated with largely non-overlapping genes with distinct functions. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes from shared YAP/TAZ target sites. Genes containing either the AP-1 or TEAD class of YAP/TAZ sites are associated with poor survival of breast cancer patients with the triple-negative form of the disease

Clinical spectrum and gene mutations in a Chinese cohort with anoctaminopathy

Recessive mutations in anoctamin-5 (ANO5) are causative for limb-girdle muscular dystrophy (LGMD) 2L and non-dysferlin Miyoshi-like distal myopathy (MMD3). ANDS mutations are highly prevalent in European countries; however it is not common in patients of Asian origin, and there is no data regarding the Chinese population. We retrospectively reviewed the clinical manifestations and gene mutations of Chinese patients with anoctaminopathy. A total of five ANDS mutations including four novel mutations and one reported mutation were found in four patients from three families. No hotspot mutation was found. Three patients presented with presymptomatic hyperCKemia and one patient had limb muscle weakness. Muscle imaging of lower limbs showed preferential adductor magnus and medial gastrocnemius involvement. No hotspot mutation has been identified in Chinese patients to date. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Objective: To expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment. Methods: Whole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays. Results: Common clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that de- fective KARS function is responsible for the phenotypes in these individuals. Conclusions: Our results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease

Investigation on the Vibration Effect of Shock Wave in Rock Burst by In Situ Microseismic Monitoring

Rock burst is a physical explosion associated with enormous damage at a short time. Due to the complicity of mechanics of rock burst in coal mine roadway, the direct use of traditional investigation method applied in tunnel is inappropriate since the components of surrounding rock are much more complex in underground than that of tunnel. In addition, the reliability of the results obtained through these methods (i.e., physical simulation, theoretical analysis, and monitoring in filed application) is still not certain with complex geological conditions. Against this background, present experimental study was first ever conducted at initial site to evaluate the effect of shock wave during the rock burst. TDS-6 microseismic monitoring system was set up in situ to evaluate the propagation of shock wave resulting in microexplosions of roadway surrounding rock. Various parameters including the distance of epicentre and the characteristic of response have been investigated. Detailed test results revealed that (1) the shock wave attenuated exponentially with the increase of the distance to seismic source according to the equation of E=E0e-ηl; particularly, the amplitude decreased significantly after being 20 m apart from explosive resource and then became very weak after being 30 m apart from the seismic source; (2) the response mechanics are characteristic with large scatter based on the real location of surrounding rock despite being at the same section. That is, the surrounding rock of floor experienced serious damage, followed by ribs, the roof, and the humeral angles. This in situ experimental study also demonstrated that microseismic monitoring system can be effectively used in rock burst through careful setup and data investigation. The proposed in situ monitoring method has provided a new way to predict rock burst due to its simple instalment procedure associated with direct and reasonable experimental results

Behaviour of Foam Concrete under Impact Loading Based on SHPB Experiments

This paper presents an innovative method for using foam concrete as a typical building material for soft structures in underground coal mines subjected to dynamic loading. To understand the behaviour of foam concrete under impact loading, a total of 30 specimens with a diameter of 50 mm and a height of 50 mm were experimentally tested using a 75 mm diameter split Hopkinson pressure bar (SHPB) device. The key parameters investigated in the present study included the type of foam concrete (fly ash and sand), the density of foam concrete (1000, 1200 and 1400 kg/m3), and the impact velocity (3.0, 4.0, 5.0, 6.0, and 7.0 m/s). Six specimens were also tested under static loading for comparison. The stress-strain curve of foam concrete under impact loading showed three stages, started with a linear elastic stage, followed by a yield stage and ended with a pore wall destruction stage. The test results also indicated that the dynamic increase factor, ultimate compressive strength, tenacity, and specific energy absorption increase with the strain rate under the same density. In particular, both the failure model and the behaviour of foam concrete were affected by the impact velocity. The findings of this research provide a reference for further research on the application of foam concrete in underground coal mines

Dynamic Response Characteristics of Roadway Surrounding Rock and the Support System and Rock Burst Prevention Technology for Coal Mines

Anchor cables (bolts) act as the main support system and play an important role in improving the rock burst resistance and stability of the roadway surrounding the rock. In this study, the dynamic response characteristics of the roadway surrounding the rock and the support system under different shock intensities were investigated. The following findings were obtained. The stress wave propagation process under dynamic shock was divided into a stress vibration initiation stage, a stress fluctuation stage, and a stress adjustment stage. In the stress vibration initiation stage, the surface mass of the roadway surrounding the rock started to vibrate, and the pretension of the anchor cables (bolts) was reduced; in the stress fluctuation stage, the failure of the roadway surrounding the rock intensified, and the anchor cables (bolts) were damaged to some extent; and in the stress adjustment stage, the roadway deformation of the surrounding rock and the axial forces of the anchor cables (bolts) tended to stabilize. As the dynamic shock intensity increased, the vibration velocity, displacement increment, and acceleration amplitude of the mass of the roadway surrounding the rock increased exponentially. The critical shock energy of the roadway surrounding the rock was 105 J, above which the damage to the rock was aggravated. The larger the pretension of the anchor cables (bolts) was and the higher the dynamic shock intensity was, the more severe the damage to the anchor cables (bolts) was. Given the dynamic response characteristics of the roadway surrounding the rock and support elements under shock, a full anchor cable yielding support technology is proposed to effectively control the stability of the roadway surrounding the rock under dynamic shock, providing a reference for the construction of the support systems for preventing rock bursts in similar roadways

Deformation mechanism and optimum design for large cross-sectional longwall installation roadway under compound roof

Both the deformation characters and the failure mode of the large cross-sectional longwall installation roadway under compound roof are becoming an emergent issue than ever before due to the rapid development of modern mining equipment. Various engineering applications have revealed that the insufficient design and inappropriate support technology are the main reasons for the fatal accidents associated with the sudden roof fall attributed to the separation of the overlying compound strata. The present research work, therefore, starts with a case study using the conventional support technology in order to demonstrate the importance of this issue followed by a summarization of the typical failure mode of the longwall installation roadway under compound strata with varied thicknesses. Then a simplified theoretical model is proposed and set up aiming at a better understanding of the distribution of the elastic-plastic zones as well as the effects of different caving procedures. The finite element analysis software program FLAC3D is adopted to evaluate the effect of the caving method and the reinforcement provided by an additional support. Then a case study conducted at a typical coal mine with compound roof condition is presented to verify the advantages of the proposed design. The results obtained show that the optimized design presented in this research work is effective to control the deformation of the surrounding rock, particularly in terms of separation of the overlying compound strata

A Study on the Mechanical Properties and Bursting Liability of Coal-Rock Composites with Seam Partings

Geological tectonic movements, as well as complex and varying coal-forming conditions, have led to the formation of rock partings in most coal seams. Consequently, the coal in coal-rock composites is characterised by different mechanical properties than those of pure coal. Uniaxial compression tests were performed in this study to determine the mechanical properties and bursting liability of specimens of coal-rock composites (hereinafter referred to as “composites”) with rock partings with different dip angles θ and thicknesses D. The results showed that as θ increased, the failure mode of the composite changed from tensile and splitting failure to slip and shear failure, which was accompanied by a decrease in the brittleness of the composite and an increase in its ductility as well as a decrease in the extent of fragmentation of the coal in the composite. Additionally, as θ increased, the uniaxial compressive strength σu, elastic modulus E, and bursting energy index Ke of the composite decreased. The rock parting in the composite was the key area in which elastic energy accumulated. As D increased, σu, E, and Ke of the composite increased. In addition, as D increased, the ductility of the composite decreased, and the brittleness and extent of coal fragmentation in the composite increased. Notably, the curve for the cumulative acoustic emission (AE) counts of the composite corresponding to the stress-strain curve could be divided into four regimes: pore compaction and closure, a slowly ascending linear elastic section, prepeak steady crack propagation, and peak unsteady crack propagation. The experimental results were used to propose two technologies for controlling the stability of coal-rock composites to effectively ensure safe and efficient production at working faces

Mechanism and Procedure of Repeated Borehole Drilling Using Wall Protection and a Soft Structure to Prevent Rockburst: A Case Study

With the increasing mining depth of coal mines, the occurrence of rockburst, especially in mine roadways, is becoming critical as a severe dynamic disaster. This paper explores the stability control of deep mine roadways and solves the contradiction between the support and pressure relief of roadways by studying the use of an internal steel pipe for wall protection and a soft structure for energy absorption during repeated borehole drilling. Numerical simulations are performed to examine the effects of active support technology on the support structure during repeated drilling. Internal steel pipes can effectively prevent the support structure from being damaged. When the soft structure cracks, the energy transmitted from the rockburst to the roadway is significantly reduced. According to the deformation and failure characteristics of the surrounding rock of the 21170 roadway, the combination of anchor active support, hydraulic lifting shed support, and soft structure energy absorption is proposed. An engineering case study shows that the support method can effectively maintain the stability of the surrounding rock and ensure the safe mining of the working face. The proposed control method can provide reference for the prevention and control of rockburst in mine roadways under similar geological conditions