Lanzhou New District is the first and largest national-level new district in the Loess Plateau region of China. Large-scale land creation and rapid utilization of the land surface for construction has induced various magnitudes of land subsidence in the region, which is posing an increasing threat to the built environment and quality of life. In this study, the spatial and temporal evolution of surface subsidence in Lanzhou New District was assessed using Persistent Scatterer Interferometric Synthetic Aperture radar (PSInSAR) to process the ENVISAT SAR images from 2003–2010, and the Small Baseline Subset (SBAS) InSAR to process the Sentinel-1A images from 2015–2016. We found that the land subsidence exhibits distinct spatiotemporal patterns in the study region. The spatial pattern of land subsidence has evidently extended from the major urban zone to the land creation region. Significant subsidence of 0–55 mm/year was detected between 2015 and 2016 in the land creation and urbanization area where either zero or minor subsidence of 0–17.2 mm/year was recorded between 2003 and 2010. The change in the spatiotemporal pattern appears to be dominated mainly by the spatial heterogeneity of land creation and urban expansion. The spatial associations of subsidence suggest a clear geological control, in terms of the presence of compressible sedimentary deposits; however, subsidence and groundwater fluctuations are weakly correlated. We infer that the processes of land creation and rapid urban construction are responsible for determining subsidence over the region, and the local geological conditions, including lithology and the thickness of the compressible layer, control the magnitude of the subsidence process. However, anthropogenic activities, especially related to land creation, have more significant impacts on the detected subsidence than other factors. In addition, the higher collapsibility and compressibility of the loess deposits in the land creation region may be the underlying mechanism of macro-subsidence in Lanzhou New District. Our results provide a useful reference for land creation, urban planning and subsidence mitigation in the Loess Plateau region, where the large-scale process of bulldozing mountains and valley infilling to create level areas for city construction is either underway or forthcoming.

Geological conditions along the Karakorum Highway (KKH) promote the occurrence of frequent natural disasters, which pose a serious threat to its normal operation. Landslide susceptibility mapping (LSM) provides a basis for analyzing and evaluating the degree of landslide susceptibility of an area. However, there has been limited analysis of actual landslide activity processes in real-time. The SBAS-InSAR (Small Baseline Subsets-Interferometric Synthetic Aperture Radar) method can fully consider the current landslide susceptibility situation and, thus, it can be used to optimize the results of LSM. In this study, we compared the results of LSM using logistic regression and Random Forest models along the KKH. Both approaches produced a classification in terms of very low, low, moderate, high, and very high landslide susceptibility. The evaluation results of the two models revealed a high susceptibility of land sliding in the Gaizi Valley and the Tashkurgan Valley. The Receiver Operating Characteristic (ROC) curve and historical landslide verification points were used to compare the evaluation accuracy of the two models. The Area under Curve (AUC) value of the Random Forest model was 0.981, and 98.79% of the historical landslide points in the verification points fell within the range of high and very high landslide susceptibility degrees. The Random Forest evaluation results were found to be superior to those of the logistic regression and they were combined with the SBAS-InSAR results to conduct a new LSM. The results showed an increase in the landslide susceptibility degree for 2808 cells. We conclude that this optimized landslide susceptibility mapping can provide valuable decision support for disaster prevention and it also provides theoretical guidance for the maintenance and normal operation of KKH.

P38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases that together with ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinases) MAPKs act to convert different extracellular signals into specific cellular responses through interacting with and phosphorylating downstream targets. In contrast to the mitogenic ERK pathway, mammalian p38 MAPK family proteins (alpha, beta, gamma, and delta), with and without JNK participation, predominantly regulate inflammatory and stress response. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and -independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. A selective activation of a stress pathway to block tumorigenesis may be a novel strategy to control human malignancies.

KRAS is mutated in most pancreatic ductal adenocarcinomas (PDAC) and yet remains undruggable. Here, we report that p38γ MAPK, which promotes PDAC tumorigenesis by linking KRAS signaling and aerobic glycolysis (also called the Warburg effect), is a novel therapeutic target. p38γ interacted with a glycolytic activator PFKFB3 that was dependent on mutated KRAS. KRAS transformation and overexpression of p38γ increased expression of PFKFB3 and glucose transporter GLUT2, conversely, silencing mutant KRAS, and p38γ decreased PFKFB3 and GLUT2 expression. p38γ phosphorylated PFKFB3 at S467, stabilized PFKFB3, and promoted their interaction with GLUT2. Pancreatic knockout of p38γ decreased p-PFKFB3/PFKFB3/GLUT2 protein levels, reduced aerobic glycolysis, and inhibited PDAC tumorigenesis in KPC mice. PFKFB3 and GLUT2 depended on p38γ to stimulate glycolysis and PDAC growth and p38γ required PFKFB3/S467 to promote these activities. A p38γ inhibitor cooperated with a PFKFB3 inhibitor to blunt aerobic glycolysis and PDAC growth, which was dependent on p38γ. Moreover, overexpression of p38γ, p-PFKFB3, PFKFB3, and GLUT2 in PDAC predicted poor clinical prognosis. These results indicate that p38γ links KRAS oncogene signaling and aerobic glycolysis to promote pancreatic tumorigenesis through PFKFB3 and GLUT2, and that p38γ and PFKFB3 may be targeted for therapeutic intervention in PDAC. Significance: These findings show that p38γ links KRAS oncogene signaling and the Warburg effect through PFKBF3 and Glut2 to promote pancreatic tumorigenesis, which can be disrupted via inhibition of p38γ and PFKFB3.

Mitogen-activated protein kinases (MAPKs) regulate gene expression through transcription factors. However, the precise mechanisms in this critical signal event are largely unknown. Here, we show that the transcription factor c-Jun is activated by p38γ MAPK, and the activated c-Jun then recruits p38γ as a cofactor into the matrix metalloproteinase 9 (MMP9) promoter to induce its trans-activation and cell invasion. This signaling event was initiated by hyperexpressed p38γ that led to increased c-Jun synthesis, MMP9 transcription, and MMP9-dependent invasion through p38γ interacting with c-Jun. p38γ requires phosphorylation and its C terminus to bind c-Jun, whereas both c-Jun and p38γ are required for the trans-activation of MMP9. The active p38γ/c-Jun/MMP9 pathway also exists in human colon cancer, and there is a coupling of increased p38γ and MMP9 expression in the primary tissues. These results reveal a new paradigm in which a MAPK acts both as an activator and a cofactor of a transcription factor to regulate gene expression leading to an invasive response.

Protein phosphatases are believed to coordinate with kinases to execute biological functions, but examples of such integrated activities, however, are still missing. In this report, we have identified protein tyrosine phosphatase H1 (PTPH1) as a specific phosphatase for p38γ mitogen-activated protein kinase (MAPK) and shown their cooperative oncogenic activity through direct binding. p38γ, a Ras effector known to act independent of its phosphorylation, was first shown to require its unique PDZ-binding motif to increase Ras transformation. Yeast two-hybrid screening and in vitro and in vivo analyses further identified PTPH1 as a specific p38γ phosphatase through PDZ-mediated binding. Additional experiments showed that PTPH1 itself plays a role in Ras-dependent malignant growth in vitro and/or in mice by a mechanism depending on its p38γ-binding activity. Moreover, Ras increases both p38γ and PTPH1 protein expression and there is a coupling of increased p38γ and PTPH1 protein expression in primary colon cancer tissues. These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38γ/PTPH1 complex may be a novel target for Ras-dependent malignancies. Cancer Res; 70(7); 2901–10