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The forkhead box transcription factor A2 (FOXA2) is a transcription factor and plays a key role in embryonic development, metabolism homeostasis and tumor cell proliferation; however, its regulatory potential in CRC is not fully understood. Here, it is found that FOXA2 expression is markedly up‐regulated in tumor samples of CRC patients as compared with the normal tissues, which is closely associated with the worse survival in patients with CRC. Notably, a positive correlation between FOXA2 and nuclear factor erythroid 2‐related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) gene expression is observed in CRC patients. Mechanistically, FOXA2 depletion weakens the activation of Nrf2 pathway and decreases GPX4 level in CRC cells, thereby leading to ferroptosis, which is further supported by bioinformatic analysis. More intriguingly, the E3 ubiquitin ligase tripartite motif containing 36 (TRIM36) is identified as a key suppressor of FOXA2, and it is observed that TRIM36 can directly interact with FOXA2 and induce its K48‐linked polyubiquitination, resulting in FOXA2 protein degradation in vitro. Taken together, all the studies demonstrate that FOXA2 mediated by TRIM36 promotes CRC progression by inhibiting the Nrf2/GPX4 ferroptosis signaling pathway, thus providing a new therapeutic target for CRC treatment. [ABSTRACT FROM AUTHOR]

In eukaryotic transcription initiation, a large multi-subunit pre-initiation complex (PIC) that assembles at the core promoter is required for the opening of the duplex DNA and identification of the start site for transcription by RNA polymerase II. Here we use cryo-electron microscropy (cryo-EM) to determine near-atomic resolution structures of the human PIC in a closed state (engaged with duplex DNa), an open state (engaged with a transcription bubble), and an initially transcribing complex (containing six base pairs of DNA-RNA hybrid). Our studies provide structures for previously uncharacterized components of the PIC, such as TFIIE and TFIIH, and segments of TFIIA, TFIIB and TFIIF. Comparison of the different structures reveals the sequential conformational changes that accompany the transition from each state to the next throughout the transcription initiation process. This analysis illustrates the key role of TFIIB in transcription bubble stabilization and provides strong structural support for a translocase activity of XPB., Eukaryotic gene transcription is tightly controlled during the initiation stage, when RNA polymerase II (Pol II) and the general transcription factors (GTFs) (TFIID, TFIIA, TFIIB, TFIIE, TFIIF and TFIIH) assemble [...]

Currently, applying graphene on GaN based electronic devices requires the troublesome, manual, lengthy, and irreproducible graphene transfer procedures, making it infeasible for real applications. Here, a semiconductor industry compatible technique for the in situ growth of patterned graphene directly onto GaN LED epiwafers for transparent heat-spreading electrode application is introduced. Pre-patterned sacrificial Co acts as both an etching mask for the GaN mesa and a catalyst for graphene growth. The Co helps in catalyzing the hydrocarbon decomposition and the subsequent graphitization, and is removed by wet etching afterwards. The use of plasma enhancement in the graphene chemical vapor deposition reduces the growth temperature to as low as 600 °C and improves the graphene quality, where highly crystalline graphene can be obtained in just 2 min of deposition. This method reduces the exposure of the GaN epilayers to high temperature to its limit, avoiding the well-known GaN decomposition and In segregation problems. Importantly, it can directly pattern the graphene without using additional lithographic steps and in doing so avoids any unintentional deleterious doping and damage of graphene from contact with the photoresist. The approach simplifies the fabrication and enables mass production by eliminating the bottlenecks of graphene transfer and patterning procedures. By comparing the GaN LEDs with and without graphene, we find that graphene greatly improves the device optical, electrical and thermal performances, due to the high optical transparency (91.74%) and high heat spreading capability of the graphene electrode. Unlike transferred graphene, this method is intrinsically scalable, reproducible, and compatible with the planar process, and is beneficial to the industrialization of GaN-graphene optoelectronic devices, where the integrated graphene serves as a superior sustainable and functional substitute to other transparent conducting materials such as ITO. [ABSTRACT FROM AUTHOR]

Abstract Background Expressed in embryonic development, matrix metalloprotein-9 (MMP-9) is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM). While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1) and the down stream signaling. Results In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK) and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in part, by boost JNK activation in a way to cooperate the cytokine signaling. Conclusion We identified a novel mechanism for MMP-9 expression in response to injury signals, which is mediated by PAK1 activation and stabilization leading JNK activation.

The paper focuses on the failure process and mechanism of the concrete gravity dam considering different nonlinear models under strong earthquakes. By taking a typical monolith of a concrete gravity dam as a case study, a comparative analysis of the failure process and mechanism of the dam considering the plastic damage model and the dynamic contact model, respectively, is performed using the seismic overload method. Moreover, the ultimate seismic capacity of the dam is evaluated for both of the nonlinear models. It is found that the ultimate seismic capacity of the dam is slightly different, but the failure process has significant distinctions in each model. And, the damage model is recommended when the conditions permit. [ABSTRACT FROM AUTHOR]

There are various uncertainties in the design, construction, and operation of dams. These uncertainties have an important impact on the seismic response and seismic safety evaluation of concrete dams. In this research, a typical nonoverflow monolith of a concrete gravity dam is selected as a case study for the sliding stability analysis. Based on the analysis and demonstration of parameter sensitivity of friction coefficients and cohesion and their influence on the deep antisliding stability of the dam-foundation system, the probabilistic seismic analysis of a gravity dam-foundation system is carried out through Monte Carlo analysis with a large sample number. Damage levels are defined based on the sliding instability failure mode along with the corresponding threshold values of the damage index. Thus, seismic fragility analysis is investigated, and seismic fragility curves are obtained for the vulnerability assessment under earthquake hazards. The overall seismic stability of the gravity dam is evaluated, which provides the basis for the seismic safety evaluation in the probabilistic framework. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death and lung adenocarcinoma is its most common subtype. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations driving lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We found over 32,000 enhancers that appear differentially activated between normal lung and lung adenocarcinoma. Among the identified transcriptional regulators inactivated in lung adenocarcinoma vs. normal lung, NKX2-1 was linked to a large number of silenced enhancers. Among the activated transcriptional regulators identified, CENPA, FOXM1, and MYBL2 were linked to numerous cancer-specific enhancers. High expression of CENPA, FOXM1, and MYBL2 is particularly observed in a subgroup of lung adenocarcinomas and is associated with poor patient survival. Notably, CENPA, FOXM1, and MYBL2 are also key regulators of cancer-specific enhancers in breast adenocarcinoma of the basal subtype, but they are associated with distinct sets of activated enhancers. We identified individual lung adenocarcinoma enhancers linked to CENPA, FOXM1, or MYBL2 that were associated with poor patient survival. Knockdown experiments of FOXM1 and MYBL2 suggest that these factors regulate genes involved in controlling cell cycle progression and cell division. For example, we found that expression of TK1, a potential target gene of a MYBL2-linked enhancer, is associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma epigenomes, highlighting novel potential targets for clinical intervention. Author summary: Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Here we investigated epigenetic alterations that might contribute to lung adenocarcinoma progression. We used a bioinformatics approach called TENET 2.0 to identify key regulators and enhancers altered in lung adenocarcinoma compared to normal lung. We identified NKX2-1 as the transcriptional regulator inactivated in lung adenocarcinoma, linked to a large number of enhancers silenced in cancer. Among the activated transcriptional regulators, CENPA, MYBL2, and FOXM1 were linked to numerous cancer-specific enhancers and high expression of these regulators was observed in a subgroup of lung adenocarcinomas showing poor patient survival. Investigating downstream effects of these key regulators, we also determined individual enhancers associated with survival and their potential target genes, including TK1. Our findings suggest that abnormal expression of key regulators drives epigenetic deregulation in lung adenocarcinoma, promoting future development of novel biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Objective: To explore the sociocultural factors influencing depression in Chinese infertile women in Hunan Province.Methods: A cross-sectional study was carried out. A total of 211 Chinese infertile women completed demographic details, a disease-related information questionnaire, a self-rating depression scale (SDS) and a social support rating scale (SSRS).Results: One hundred and seven (50.71%) of the participants were classified as depressed according to the self-rating depression scale. The average SDS index score was 50.06 ± 10.59. Using analysis of variance (ANOVA), Pearson correlation and a multivariable regression analysis, the results showed family type, feelings of discrimination, social support, feelings of shame and reproductive pressures were influential factors in depression among Chinese infertile women.Conclusion: Sociocultural factors influence depression levels in Chinese female infertile patients. The unique aspects of Chinese culture may have a negative mental impact on the patients, and cultural factors should be taken into consideration in the development of coping strategies for Chinese infertile women. [ABSTRACT FROM AUTHOR]

In this research, seismic stability uncertainty analysis of a high arch dam-foundation system is investigated considering ground motion and modeling parameter uncertainties. Ground motions and modeling parameters of shear strength on the potential sliding block of dam abutment are chosen as random variables in the probabilistic and statistic framework. Taking a high arch dam as a case study, a total number of 1000 nonlinear dynamic analyses are performed using incremental dynamic analysis (IDA) and Latin hypercube sampling (LHS). The peak ground acceleration (PGA) is taken as intensity measure (IM) and the residual sliding displacement and sliding area ratio are adopted as seismic sliding stability performance evaluation indexes, respectively. Comparative analyses are presented to discuss the effect of only modeling parameter uncertainty, only ground motion uncertainty, and both uncertainties on seismic sliding stability of the high arch dam-foundation system. The results reveal that obvious variability of seismic sliding stability of the high arch dam-foundation system is observed due to the existence of ground motion and modeling parameter uncertainties and it is sensitive to PGA. The variability owing to both ground motion and modeling parameter uncertainties is more remarkable compared with that caused by only one single uncertainty. Moreover, the ground motion uncertainty shows a more obvious impact on the variability of residual sliding displacement, while the modeling parameter uncertainty has a more notable effect on the variability of sliding area ratio. Therefore, it is necessary to consider both two kinds of uncertainties for seismic stability safety evaluation of a high arch dam-foundation system in the probabilistic and statistic framework. • A comprehensive approach for seismic stability uncertainty analysis of arch dams is presented. • A comparative analysis is performed to discuss the effect of various uncertainties. • Obvious variability is observed due to uncertainties and it is sensitive to PGA. • Sliding area ratio enlarges and weakens effects of parameter and seismic uncertainty respectively. [ABSTRACT FROM AUTHOR]

Summary Proliferating cell nuclear antigen (PCNA) is a pivotal replication protein, which also controls cellular responses to DNA damage. Posttranslational modification of PCNA by SUMO and ubiquitin modulate these responses. How the modifiers alter PCNA-dependent DNA repair and damage tolerance pathways is largely unknown. We used hybrid methods to identify atomic models of PCNA K107 -Ub and PCNA K164 -SUMO consistent with small-angle X-ray scattering data of these complexes in solution. We show that SUMO and ubiquitin have distinct modes of association to PCNA. Ubiquitin adopts discrete docked binding positions. By contrast, SUMO associates by simple tethering and adopts extended flexible conformations. These structural differences are the result of the opposite electrostatic potentials of SUMO and Ub. The unexpected contrast in conformational behavior of Ub-PCNA and SUMO-PCNA has implications for interactions with partner proteins, interacting surfaces accessibility, and access points for pathway regulation. [ABSTRACT FROM AUTHOR]