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Recurrence of large-scale ancient landslides often manifests as catastrophic events, so it is important to assess their stability by monitoring the deformation process. In this study, the Da'ao ancient landslide along the Jinsha River in China was investigated and analyzed. Field investigation showed that the landslide body is being experienced deforming with many new failures. Three sliding events can be identified according to different main scarps. The Permanent Scatterer Synthetic Aperture Radar Interferometry (PS-InSAR) data further revealed that the most obvious deforming area is in the middle and toe part of the sliding body with the largest cumulative displacement of 55 mm during 2017 to 2021. Additionally, the relatively stable zone and the accelerating deforming zone are divided by displacement rate. This indicates that the Da'ao landslide is becoming unstable. At the same time, the Particle Flow Code (PFC) simulation verified that the risk of landslide recurrence is likely when subjected to strong earthquakes or heavy rainfall, and the resulting sidings could dam the Jinsha River. In addition, the analysis results suggested that the displacement rates were approximately 5 mm/year and 13.3 mm/year before and after the Ms 5.2 earthquake, respectively, which occurred on 04/21/2019. The deformation changed with seasonal variation during 2017–2021 and lagged behind precipitation, while the earthquake can increase the amount and rate of displacement. The results presented here can help us to understand how landslides recur over time and their deformation and failure mechanisms, which is useful for disaster prevention and mitigation. [ABSTRACT FROM AUTHOR]

In order to solve the problems of low magnetic flux density and non-uniformity of magnetic flux density of traditional Lorentz force magnetic bearing (LFMB), a combined magnetic steel single closed magnetic loop magnetic bearing with suction type is designed. Firstly, the magnetic field intensity and magnetic field uniformity of the traditional LFMB are analyzed, and the existing problems of the traditional LFMB are pointed out. Then, a new LFMB structure is designed. The concepts of magnetic field mean value and standard deviation are introduced to describe magnetic field intensity and magnetic field uniformity. By analysis of the 2-D and 3-D magnetic flux characteristics of the proposed LFMB, it can be seen that the magnetic flux density of the new LFMB is 0.67–0.74 T, and the magnetic flux uniformity is 0.009–0.0192. By comparing the conditions of applied current and 0 current, we can see that the structure designed in this paper can reduce the influence of current on the magnetic field uniformity. Finally, by comparing the control effects of the traditional structure and the proposed LFMB structure, it can be concluded that the proposed method can reduce the power consumption and improve the precision of the output torque. [ABSTRACT FROM AUTHOR]

Large earthquake-triggered landslides near a seismogenic fault are usually closely linked to fault slipping. Therefore, it is important to research the relationship between the landslide movement and the deformation pattern of faults to better understand the location and influencing factors related to the large landslides. A large landslide, on the right bank of the Clarence River, New Zealand, was reactivated during the 2016 Mw 7.8 Kaikoura earthquake. The landslide is located in close proximity to the Papatea Fault which ruptured during the earthquake. The special tectonic location of this landslide provided favorable conditions to research the failure mechanism of earthquake-triggered landslides. Field investigation and remote-sensing images revealed that the co-seismic surface rupture zone of the Papatea Fault is relatively complicated and characterized by a wide deformation zone with a width of ~80–170 m. The northern section showed as left-lateral strike-slip and thrust-slip, with a vertical displacement of up to 4–6 m. However, it exhibited thrust motion in the Clarence landslide area. The Clarence landslide was a reactivation of a pre-existing landslide. The thrust faulting of the Papatea Fault produced a wide deformation and fractured zone near the top of the landslide mass, and resulted in over-steepened topography in the landslide area. It should be noted that long-team seismic shaking, especially the main frequency of the seismic acceleration and rapid co-seismic vertical slip of the fault, played the principal role in further accelerating topographic instability during the earthquake. The landslide body thus started to slide along a pre-existing sliding surface under these actions. Our results indicate that the deformation pattern of the seismogenic fault could also play an important role in the occurrence of earthquake-triggered landslides, in addition to geological and geomorphological conditions and local seismic acceleration. [ABSTRACT FROM AUTHOR]

Rising demand for ruminant meat and dairy products in developing countries is expected to double anthropogenic greenhouse gas and ammonia emissions from livestock by 2050. Mitigation strategies are urgently needed to meet demand while minimizing environmental impacts. Here, we develop scenarios for mitigating emissions under local vs global supply policies using data from 308 livestock farms across mainland China, where emissions intensities are ~50% higher than those in developed nations. Intensification of domestic production and globalized expansion through increased trade result in reductions in global emissions by nearly 30% over a business-as-usual scenario, but at the expense of trading partners absorbing the associated negative externalities of environmental degradation. Only adoption of a mixed strategy combining global best-practice in sustainable intensification of domestic production, with increased green-source trading as a short-term coping strategy, can meet 2050 demand while minimizing the local and global environmental footprint of China’s ruminant consumption boom. [ABSTRACT FROM AUTHOR]

The 2015 M 7.8 Gorkha earthquake and its aftershocks caused nearly 9000 deaths and more than 23,000 injuries and triggered thousands of landslides and other mass-wasting effects in the steep, rugged topography of Nepal. In this paper, new slope failures and tension cracks induced by the 2015 Nepal earthquake are documented in steep terrain west of the Tatopani Border Station, which lies along the deeply incised Bhote Koshi River valley, a critical trans-Himalayan transport route between south Asia and Tibet/China. The affected area west of the Tatopani station is the site of a large reactivated paleo-landslide that has experienced repeated failures. The Tatopani station is downslope from the amphitheater-like landslide scar and is constructed on distal landslide debris in a position vulnerable to future landslide and fluvial erosion hazards. We carried out detailed field investigations to document different types of geohazards around the station and present an evolutionary model for past and present landslide development. In addition, a simple numerical model was constructed to evaluate the stability of the large paleo-landslide body under different earthquake conditions. Simulated results suggest that the paleo-landslide body is stable without seismic loading. However, the large paleo-landslide will be remobilized again by large slope failures if the PGA of future earthquake exceeds 0.35 g. We suggest that the results presented in this paper should be taken into consideration during earthquake-resistant design of the border station and other infrastructural development along the Bhote Koshi Valley. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) in NSCLC is a negative prognostic indicator. In the era of EGFR mutations we evaluated the difference between early (≤6 months from diagnosis) versus late BM (>6 months), in EGFR wild type (WT) and mutant (MT) NSCLC patients with respect to radiographic patterns and overall survival (OS). A retrospective study was conducted of referred patients with non-squamous NSCLC with known EGFR mutation status treated for BM from Mar 2010-Dec 2012. Radiographic patterns, treatment and survival were collected. 430 patients were identified: 327 WT (207 early vs. 120 late) and 103 MT (65 early vs. 38 late). Early and late BM radiographic patterns were similar in EGFR WT patients. In EGFR MT there was a trend towards multiple lesions in the late compared to early BM group. OS from initial diagnosis early BM: WT 7.1 months versus MT 19.9 months (p < 0.001). OS from initial diagnosis late BM: WT 24.9 months versus MT 25.6 months (p = 0.51). In multivariate analysis chemotherapy, single lesion and late BM were associated with better survival in WT patients whereas age, and systemic treatment but not BM timing or single lesion were predictive of better outcomes in MT patients. In early BM, EGFR MT have an OS comparable to late BM. In contrast, early BM EGFR WT have a significantly reduced survival compared to late BM. The positive outcome in EGFR MT may be secondary to systemic control and EGFR TKI penetrance across the blood brain barrier. [ABSTRACT FROM AUTHOR]

The 2008 M 7.9 Wenchuan earthquake formed two coseismic surface rupture zones with the trend of N35°E, known as the Beichuan-Yingxiu rupture and the Pengguan rupture. The Beichuan-Yingxiu rupture is the principle one with abundant fault gouge development along its length. In the exploratory trench at the Saba village along the Beichuan-Yingxiu rupture, the new fault gouge zone is only ~3 mm wide, which suggests that fault slip was constrained in a very narrow zone. In this study, we thus carried out detailed microstructural and mineral component analysis on the oriented fault gouge samples from the Saba exploratory trench to understand their features and geological implication. The results show that different microstructures of localized brittle deformation can be observed in the fault gouges, including Y-shear, R1-shear, R2-shear, P-shear as well as tension fracture, bookshelf glided structure and so on. These microstructures are commonly recognized as the product of seismic fault slipping. Furthermore, within the area between two parallel Y-shears of the fault gouge, a few of microstructures of distributed ductile deformations were developed, such as P-foliation, elongation and asymmetrical trailing structure of detrital particles. The microstructure features of fault gouges implicate the thrust movement of the fault during the Wenchuan earthquake. In addition, the fault gouge has less quartz and feldspar and more clay than the surrounding rocks, which indicates that some quartz and feldspar in the surrounding rocks were transformed into clay, whereas the fault gouge has more illite and less illite/montmorillonite mixed layers than the surrounding rocks, which shows that the illite/montmorillonite mixed layer was partly converted into illite due to temperature increasing induced by coseismic fault slipping friction (also being affected partly by the chemical action of solutions). Such microstructures features and mineral component changes recorded the information of fault slip and provide criterions for discussing the genesis of fault gouge and recognition of the direction of fault movement. [ABSTRACT FROM AUTHOR]

Wind tunnel experiments at a model scale have been carried out to investigate the flow characteristics in the near wake of a wind turbine. Time resolved particle image velocimetry (TRPIV) measurements are applied to visualize the wind turbine wake flow. The instantaneous vorticity, average velocities, turbulence kinetic energy, and Reynolds stresses in the near wake have been measured when the wind turbine is operated at tip speed ratios (TSRs) in the range of 3-5. It was found that wind turbine near the wake flow field can be divided into a velocity increased region, a velocity unchanged region, and a velocity deficit region in the radial direction, and the axial average velocities at different TSRs in the wake reach inflow velocity almost at the same radial location. The rotor wake turbulent kinetic energy appears in two peaks at approximately 0.3 R and 0.9 R regions in the radial direction. The Reynolds shear stress is less than the Reynolds normal stresses, the axial Reynolds normal stress is larger than the Reynolds shear stress and radial Reynolds normal stress in the blade root region, while the radial Reynolds normal stress is larger than the Reynolds shear stress and axial Reynolds normal stress in the blade tip region. The experimental data may also serve as a benchmark for validation of relevant computational fluid dynamics (CFD) models. [ABSTRACT FROM AUTHOR]

In 2008, the Wenchuan M 7.9 earthquake triggered a large number of landslides in the Longmenshan area. Among them, the Donghekou landslide is a gigantic one, which buried four villages and one elementary school. During the Wenchuan earthquake, large accelerations, especially vertical, were produced, which should to be taken into account in the dynamic analysis of slope stability. However, the vertical acceleration, which can largely influence the acceleration component normal to the sliding surface, is often overlooked in dynamic analysis of slope stability. In this work, the initiation of the Donghekou landslide is analyzed by using Newmark's sliding block model. Comparative analyses of conditions both with and without an acceleration component normal to the sliding surface, which is contributed mainly by the vertical acceleration, are then conducted to investigate its role in triggering the Donghekou landslide. Research results show that the initiating time of the Donghekou landslide would be earlier considering the acceleration component normal to the slide surface than without it due to larger estimated Newmark displacement. This conclusion is then verified by simulated results on the basis of DEM. It means that initiation of landslides can be influenced significantly by seismic acceleration component normal to sliding surface, especially in the area with large vertical acceleration. [ABSTRACT FROM AUTHOR]

Aerobic granular sludge is a new type of microbe auto-immobilization technology; in this paper, short-cut nitrification and denitrification were effectively combined with the granular sludge technology. Simultaneous nitrification and denitrification granules were developed in a sequencing batch reactor (SBR) using synthetic wastewater with a high concentration of ammonia nitrogen at 25 °C with a dissolved oxygen concentration above 2.0 mg/L and a 15 days sludge retention time. The characteristics of the sludge and the removal efficiency were studied, and the removal mechanisms of the pollutants and the process of short-cut nitrification were analyzed. The average granule diameter of the granular sludge was 704.0 μm. The removal rates of pollutants and the accumulation rate of nitrite in the SBR were studied. During treatment of wastewater with a high concentration of ammonia nitrogen, simultaneous nitrification, and denitrification and the stripping process could contribute to the removal of total nitrogen. The high pH value, the high concentration of free ammonia, and the delamination of granular sludge were the main factors contributing to the short-cut nitrification property of granular sludge in the reaction process. [ABSTRACT FROM AUTHOR]

Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer. [ABSTRACT FROM AUTHOR]

Tsaoling is located in Southwestern Taiwan, 10 km east of the frontal thrusts of the mountain belt. Five large historical landslide events were recorded from 1862 to 1999. No details of the earliest landslide event (1862) are available, thus this paper deals with the 1941 landslide event. Using the Particle Flow Code in two dimensions (PFC 2D) to simulate the mechanism of the Tsaoling landslide in 1941, this study shows that the landslide block developed cracks and slid down 0.2-1.8 m on the sliding plane. The cracks concentrated in certain zones, which corresponded to future landslide detachment planes. During the vibration simulation, the cracks spread from the shear plane to ground surface. Monitoring the variations of the displacements, velocity, and stress during vibration simulation showed that the peak velocity and stress in the transition zones occurred at 3 s. The displacement of the left part of the block exceeded 1.3 m, and the displacement of the right part was less than 1.3 m during vibration simulation. These results suggest that the left part of the block was pushed down by the right part, ultimately inducing a landslide during an earthquake. [ABSTRACT FROM AUTHOR]

In mining areas, vertical ventilating shafts are often threatened by ground movements induced by underground mining. In this paper, damage characteristics related to collapse of the vertical ventilating shaft at the No. 14 exploratory line in Jinchuan Nickel Mine, China are documented. The damage mechanism is then analyzed based on comprehensive consideration of geological conditions and distribution of underground excavations. The results indicate that the high dip angle of the ore body and fault/fissures were responsible for the damage of the shaft when ground movements occurred. Although the damaged shaft was repaired in a short time, its stability and safe usage are still threatened by potential future ground movements, because the shaft is located within a subsiding depression induced by underground mining. This case study indicates that when designing an underground mining operation, it is very important to locate a shaft outside of any area where future mining-induced subsidence may occur. [ABSTRACT FROM AUTHOR]

We report the isolation of a new bacterium species (named as DN-06) that degrades pyridine, a model compound containing both carbon and nitrogen, from the aerobic activated sludge in a coking wastewater treatment plant. DN-06 was identified as Achromobacter sp. using 16S rDNA sequence analysis. In batch culture, more than 95% of pyridine (500 mg/L) was degraded within 18 h by DN-06 grown at 35°C and pH 8 with agitation at 170 rpm. Degradation experiments of pyridine at different initial concentrations (50-4,300 mg/L) revealed that pyridine was an inhibitory substrate, and that neither yield coefficient Y nor endogenous decay coefficient K was a constant. The values of Y and K were 0.55-0.74 and 0.0032-0.0057 h, respectively. Five kinetic models (Haldane, Yano, Aiba, Webb, and Monod) were fitted to the experimental growth kinetic data. Models of Haldane and Yano (correlation coefficient R = 0.929) were the most suitable models. For Haldane kinetic model, the values of μ, K, and K were 0.161 h, 142.6 mg/L, and 4234.8 mg/L, respectively. The large values of Y and K indicated that DN-06 had good tolerance against high pyridine concentrations. These results indicated possible future applications of Achromobacter sp. DN-06 in removing pyridine from industrial wastewaters, as well as in destroying pyridine in concentrated solutions during further treatment of trial water coupling with adsorption technology. [ABSTRACT FROM AUTHOR]

Iron has long been related to the pathological process of alcoholic liver disease (ALD). Liver iron overload is known to accelerate the development of ALD. In the present study we aimed to examine the effect of epigallocatechin-3-gallate (EGCG) on iron overload of ALD and to explore the potential mechanisms involved in its protection against ALD in mice. Male C57BL/6J mice were given alcohol by intragastric administration for 12 weeks. At the end of 8th week, ALD mice were treated for 4 weeks for 10, 20 and 30 mg kg EGCG by intraperitoneal injection. Liver injuries were assessed by histopathologic examination and Serum Alanine Aminotransferase (ALT) levels. Serum iron content, hepatic iron concentration and liver malondialdehyde (MDA) contents were examined. In addition, hepcidin mRNA levels and transferrin (Tf) and transferrin receptor 1 (TfR1) protein levels of liver tissue were also evaluated. Compared with model group, treatment of ALD mice with EGCG ameliorated liver injuries, decreased serum iron level, hepatic iron levels and liver MDA contents, increased hepcidin mRNA level and decreased Tf and TfR1 protein expression in the liver. The results of our study explain a new point of view that the protective effect of EGCG on ALD is associated with its iron-chelating property. The possible mechanisms are that EGCG affects hepatic iron uptake and inhibits iron absorption in the small intestinal. [ABSTRACT FROM AUTHOR]

Abstract  In this paper, we present an adaptive evolutionary Monte Carlo algorithm (AEMC), which combines a tree-based predictive model with an evolutionary Monte Carlo sampling procedure for the purpose of global optimization. Our development is motivated by sensor placement applications in engineering, which requires optimizing certain complicated “black-box” objective function. The proposed method is able to enhance the optimization efficiency and effectiveness as compared to a few alternative strategies. AEMC falls into the category of adaptive Markov chain Monte Carlo (MCMC) algorithms and is the first adaptive MCMC algorithm that simulates multiple Markov chains in parallel. A theorem about the ergodicity property of the AEMC algorithm is stated and proven. We demonstrate the advantages of the proposed method by applying it to a sensor placement problem in a manufacturing process, as well as to a standard Griewank test function. [ABSTRACT FROM AUTHOR]

B3LYP/6-31G(d) hybrid HF/DFT and BLYP/6-31G(d, p) DFT calculations were carried out to determine the structural and electronic properties of the endohedral complex of C60 with Tetrahedral N4 (Td N4), N4@C60. It was demonstrated that N4 was seated in the center of the fullerene cage and the tetrahedral structure of N4 is remained in the cage. The formation of this complex is endothermic with inclusion energy of 37.92 kcal/mol. N4 endohedral doping perturbs the molecular orbitals of C60 not so much, the calculated HOMO–LUMO gaps, the electron affinity (EA) and the ionizational potential (IP) of N4@C60 are similar to that of C60. [ABSTRACT FROM AUTHOR]

The Hawaiian–Emperor volcanic island and seamount chain is usually attributed to a hot mantle plume, located beneath the Pacific lithosphere, that delivers material sourced from deep in the mantle to the surface. The shield volcanoes of the Hawaiian islands are distributed in two curvilinear, parallel trends (termed ‘Kea’ and ‘Loa’), whose rocks are characterized by general geochemical differences. This has led to the proposition that Hawaiian volcanoes sample compositionally distinct, concentrically zoned, regions of the underlying mantle plume. Melt inclusions, or samples of local magma ‘frozen’ in olivine phenocrysts during crystallization, may record complexities of mantle sources, thereby providing better insight into the chemical structure of plumes. Here we report the discovery of both Kea- and Loa-like major and trace element compositions in olivine-hosted melt inclusions in individual, shield-stage Hawaiian volcanoes—even within single rock samples. We infer from these data that one mantle source component may dominate a single lava flow, but that the two mantle source components are consistently represented to some extent in all lavas, regardless of the specific geographic location of the volcano. We therefore suggest that the Hawaiian mantle plume is unlikely to be compositionally concentrically zoned. Instead, the observed chemical variation is probably controlled by the thermal structure of the plume. [ABSTRACT FROM AUTHOR]

The heat shock response is an evolutionarily conserved response to heat and other stresses that promotes the maintenance of key metabolic functions and cell survival. We report that exposure of human prostate (DU-145) and breast (MCF-7) cancer cells to heat (42°C) caused a rapid disappearance of the breast cancer susceptibility gene-1 (BRCA1) protein, starting at approx. 1 h after the onset of heating and slightly lagging behind the increase in heat shock protein 70 (HSP70) levels. The heat-induced loss of BRCA1 occurred at the protein level, since: (1) BRCA1 mRNA expression was unaffected; and (2) the BRCA1 protein loss was also observed in DU-145 cells that expressed exogenous wild-type BRCA1 (wtBRCA1). In addition to heat regulation of BRCA1 protein levels, we also found that BRCA1 could modulate the heat shock response. Thus, wtBRCA1 overexpressing DU-145 cell clones showed significantly decreased sensitivity to heat-induced cytotoxicity; and Brca1 mutant mouse embryo fibroblasts showed increased sensitivity to heat. The DU-145 wtBRCA1 clones also showed increased expression of the small heat shock protein HSP27; and reporter assays revealed that wtBRCA1 stimulated a two to four-fold increase in HSP27 promoter activity, consistent with its ability to upregulate HSP27 mRNA and protein levels. In studies using epitope-tagged truncated BRCA1 proteins, the ability to stimulate the HSP27 promoter and to mediate heat-induced degradation required the amino-terminus but not the carboxyl-terminus of BRCA1. Although the heat-induced loss of BRCA1 appeared to be due to protein degradation, various protein metabolic agents (or combinations) failed to block this event, including: MG132 (a 26S proteasomal inhibitor), N-acetyl-leucyl-leucyl-norleucinal (a calpain inhibitor), z-VAD-fmk (a pan-caspase inhibitor), and ammonium chloride and chloroquine (which stabilize lysosomes). These findings suggest that in addition to its other functions, BRCA1 may participate in... [ABSTRACT FROM AUTHOR]

Unregulated expression of wild-type BRCA1 (wtBRCA1) confers an altered phenotype in cultured human prostate cancer cells, characterized by chemosensitivity, susceptibility to apoptosis, decreased DNA repair activity, and alterations of key cell regulatory proteins. We now report that the expression of truncated or mutant full-length BRCA1 genes can abrogate certain phenotypic characteristics and/or confer the opposite phenotype to the wild-type BRCA1 gene. In particular, several carboxyl-terminal truncated BRCA1 proteins conferred chemoresistance, decreased susceptibility to apoptosis, and decreased ability to suppress in vivo tumor growth. These truncated BRCA1 proteins also blocked the ability of ectopically expressed wtBRCA1 to induce chemosensitivity and to inhibit estrogen receptor transcriptional activity. Studies using epitope-tagged truncated proteins confirmed their expression, nuclear localization, and functionality. On the other hand, in cells with no endogenous wild-type BRCA1 (HCC1937 human breast cancer cells), the wtBRCA1 gene enhanced cellular DNA repair activity and rendered the cells resistant to DNA damage; while truncated BRCA1 proteins blocked the wtBRCA1-induced chemoresistance. Our findings suggest that truncated BRCA1 proteins can inhibit the function of wild-type BRCA1. They raise the possibility that some inherited BRCA1 mutations may actively promote oncogenesis by blocking the function of the remaining wild-type BRCA1 allele, although this hypothesis remains to be proved. Oncogene (2001) 20, 8215–8235. [ABSTRACT FROM AUTHOR]

The tumor suppressor activity of the BRCA1 gene product is due, in part, to functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein. RB binding sites on BRCA1 were identified in the C-terminal BRCT domain (Yarden and Brody, 1999) and in the N-terminus (aa 304–394) (Aprelikova et al., 1999). The N-terminal site contains a consensus RB binding motif, LXCXE (aa 358–362), but the role of this motif in RB binding and BRCA1 functional activity is unclear. In both in vitro and in vivo assays, we found that the BRCA1:RB interaction does not require the BRCA1 LXCXE motif, nor does it require an intact A/B binding pocket of RB. In addition, nuclear co-localization of the endogenous BRCA1 and RB proteins was observed. Over-expression of wild-type BRCA1 (wtBRCA1) did not cause cell cycle arrest but did cause down-regulation of expression of RB, p107, p130, and other proteins (e.g., p300), associated with increased sensitivity to DNA-damaging agents. In contrast, expression of a full-length BRCA1 with an LXCXE inactivating mutation (LXCXE→RXRXH) failed to down-regulate RB, blocked the down-regulation of RB by wtBRCA1, induced chemoresistance, and abrogated the ability of BRCA1 to mediate tumor growth suppression of DU-145 prostate cancer cells. wtBRCA1-induced chemosensitivity was partially reversed by expression of either Rb or p300 and fully reversed by co-expression of Rb plus p300. Our findings suggest that: (1) disruption of the LXCXE motif within the N-terminal RB binding region alters the biologic function of BRCA1; and (2) over-expression of BRCA1 inhibits the expression of RB and RB family (p107 and p130) proteins. Oncogene (2001) 20, 4827–4841. [ABSTRACT FROM AUTHOR]

The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-α] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-α activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-α activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-α in vivo and to bind to ER-α in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-α. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-α binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-α activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-α, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77–87. [ABSTRACT FROM AUTHOR]

Scatter factor (SF) [aka. hepatocyte growth factor (HGF)] (designated HGF/SF) is a multifunctional cytokine that stimulates tumor cell invasion and angiogenesis. We recently reported that HGF/SF protects epithelial and carcinoma cells against cytotoxicity from DNA-damaging agents and that HGF/SF-mediated cytoprotection was associated with up-regulation of the anti-apoptotic protein Bcl-XL in cells exposed to adriamycin. We now report that in addition to blocking apoptosis, HGF/SF markedly enhances the repair of DNA strand breaks caused by adriamycin or gamma radiation. Constitutive expression of Bcl-XL in MDA-MB-453 breast cancer cells not only simulated the HGF/SF-mediated chemoradioresistance, but also enhanced the repair of DNA strand breaks. The ability of HGF/SF to induce both chemoresistance and DNA repair was inhibited by wortmannin, suggesting that these activities of HGF/SF are due, in part, to a phosphatidylinositol-3′-kinase (PI3K) dependent signaling pathway. Consistent with this finding, HGF/SF induced the phosphorylation of c-Akt (protein kinase-B), a PI3K substrate implicated in apoptosis inhibition; and an expression vector encoding a dominant negative kinase inactive Akt partially but significantly inhibited HGF/SF-mediated cell protection and DNA repair. These findings suggest that HGF/SF activates a cell survival and DNA repair pathway that involves signaling through PI3K and c-Akt and stabilization of the expression of Bcl-XL; and they implicate Bcl-XL in the DNA repair process. Oncogene (2000) 19, 2212–2223 [ABSTRACT FROM AUTHOR]

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75–100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly... [ABSTRACT FROM AUTHOR]

In addition to breast and ovarian cancer in women, recent evidence suggests that germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) also confer an increased life-time risk for prostate cancer in male probands. However, it is not known if and how BRCA1 functions in prostate cancer. We stably expressed wild-type (wt) and tumor-associated mutant BRCA1 transgenes in DU-145, a human prostate cancer cell line with low endogenous expression of BRCA1. As compared with parental cells and vector transfected clones, wtBRCA1 clones exhibited: (1) a slightly decreased proliferation rate (doubling time=25 h as compared with 22 h for control cells); (2) a (3–6)-fold increase in sensitivity to chemotherapy drugs (adriamycin, camptothecin, and taxol); (3) increased susceptibility to drug-induced apoptosis; (4) reduced repair of single-strand DNA strand breaks; and (5) alterations in expression of key cellular regulatory proteins (including BRCA2, p300, Mdm-2, p21WAF1/CIP1, Bcl-2 and Bax). Clones transfected with the 5677insA breast cancer-associated mutant BRCA1 (insBRCA1) displayed a similar phenotype to wtBRCA1 clones, except that insBRCA1 clones had a significantly decreased proliferation rate (doubling time=42 h). On the other hand, cells transfected with with 185delAG mutant BRCA1 showed no obvious phenotype as compared with parental or vector transfected cells. These findings suggest that BRCA1 may function as a human prostate tumor suppressor by virtue of its ability to modulate proliferation and various components of the cellular damage response. They also suggest several potential target gene products for a BRCA1 prostate tumor suppressor function. [ABSTRACT FROM AUTHOR]

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6–12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val→ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play... [ABSTRACT FROM AUTHOR]

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. [ABSTRACT FROM AUTHOR]

Health information systems contain extensive amounts of patient data. Information relevant to public health and individuals’ medical histories are both available. In clinical research, the prediction of patient survival rates and identification of prognosis factors are major challenges. To alleviate the difficulties related to these factors, Metadata Utilities was developed to help researchers manage column definitions and information such as import/query/generator Metadata files. These utilities also include an automatic update mechanism to ensure consistency between the data and parameters of the batch produced in the conversion procedure. Survival Metadata Analysis Responsive Tool (SMART) provides a comprehensive set of statistical tests that are easy to understand, including support for analyzing nominal variables, ordinal variables, interval variables or ratio variables as means, standard deviations, maximum values, minimum values, and percentages. In this article, the development of a raw data source and transfer mechanism, Extract-Transform-Load (ETL), is described for data cleansing, extraction, transformation and loading. We also built a handy method for data presentation, which can be customized to the trial design. As demonstrated here, SMART is useful for risk-adjusted baseline cohort and randomized controlled trials. [ABSTRACT FROM AUTHOR]

We investigated the elastic properties of two tin-copper crystalline phases, the ?'-Cu6Sn5 and e-Cu3Sn, which are often encountered in microelectronic packaging applications. The full elastic stiffness of both phases is determined based on strain-energy relations using first-principles calculations. The computed results show the elastic anisotropy of both phases that cannot be resolved from experiments. Our results, suggesting both phases have the greatest stiffness along the c direction, particularly showed the unique in-plane elastic anisotropy associated with the lattice modulation of the Cu3Sn superstructure. The polycrystalline moduli obtained using the Voigt-Reuss scheme are 125.98 GPa for Cu6Sn5 and 134.16 GPa for Cu3Sn. Our data analysis indicates that the smaller elastic moduli of Cu6Sn5 are attributed to the direct Sn-Sn bond in Cu6Sn5. We reassert the elastic modulus and hardness of both phases using the nanoindentation experiment for our calculation benchmark. Interestingly, the computed polycrystalline elastic modulus of Cu6Sn5 seems to be overestimated, whereas that of Cu3Sn falls nicely in the range of reported data. Based on the observations, the elastic modulus of Cu6Sn5 obtained from nanoindentation tests take the microstructure effect that is absent for Cu3Sn. Our analysis of electronic structure shows that the intrinsic hardness and elastic modulus of both phases are dominated by electronic structure and atomic lattice structure, respectively. [ABSTRACT FROM AUTHOR]

Climate change, earthquakes, and human activities are accelerating the degradation of permafrost, leading to loess failures and slope instability. Some engineering corridors (ECs)/infrastructures located on the northeastern margin of the Qinghai-Tibet Plateau (NE-QTP) of China are heavily influenced by landslide phenomena due to being built on permafrost, loess, and seasonally frozen ground. However, few systematic investigations have been carried out in this area. To compile a comprehensive landslide inventory, we visually interpreted 11,914 landslides in GaoFen-6 images taken from 2021 to 2022. We observe that approximately 44.85% of the infrastructures are affected by landslides. Then, based on the ground types and triggering factors, landslides are classified into three types: freeze‒thaw landslides (FTLs), loess landslides (LLs), and general landslides (GLs). More specifically, FTLs are mainly distributed in the boundary regions between permafrost and seasonally frozen ground. The LLs exhibit high-density clustered distribution characteristics. GLs have significant transitional characteristics and commonalities between FTLs and LLs. Furthermore, we apply the geographical detector to determine the controlling factors of the landslides that occurred. We find that the temperature change is the primary controller on the FTLs. The water exhibits a certain correlation with LLs. And the earthquake is the most important factor on the GLs. Our study provides a significant dataset for quantifying the analysis of landslides in NE-QTP. [ABSTRACT FROM AUTHOR]