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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 this study, a high arch dam-foundation system model with more than ten million degrees of freedom was constructed. The model innovatively incorporates multiple nonlinear couplings of the strength failure of the dam body and stability failure of dam abutment blocks for the first time. A nonlinear dynamic response analysis of the coupling system was performed at different overload coefficients. The maximum damage depth-thickness ratio and sliding area ratio are proposed as performance evaluation indices. The failure mechanism of the model under strong earthquakes was elucidated. The residual displacement of the dam crest relative to the dam bottom in the stream direction is proposed as another performance evaluation index. Sudden changes and rapid growth are suggested as evaluation criteria to assess the ultimate seismic capacity of arch dams based on proposed multi-nonlinear coupled model. The results show that the strength failure of the dam body and stability failure of the dam abutments vary dynamically with the duration and intensity of the earthquake. Earthquake energy can be fully released by only one failure mode at low seismic intensity, whereas it is gradually released by both failure modes as the seismic intensity increases. The overload coefficient corresponding to the ultimate seismic capacity of the dam is concluded to be 2.0. • a finite element model of a high arch dam is constructed considering both strength and stability failures. • two failure modes vary dynamically with the duration and intensity of the earthquake. • earthquake energy may be released by one or both failure modes depending on the seismic intensity. • performance evaluation indices and seismic capacity criteria for high arch dams are proposed. [ABSTRACT FROM AUTHOR]

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]

Background: It has been suggested that peer support intervention may offer an alternative approach to prevent or treat perinatal depression, but little is known about its effectiveness, economics, and satisfaction in the prenatal and postpartum populations. This review summarizes available evidence on the effectiveness, economics, and satisfaction of peer support intervention on perinatal depression.Methods: Multiple electronic databases were searched in five English databases (MEDLINE, Embase, Cochrane Library, Psyc INFO, and CINAHL) and three Chinese databases (Wang Fang, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database) from inception to April 2019. Hand searching of references was also performed. Randomized controlled trials reporting peer support intervention targeting on perinatal depression were included. The quality of evidence was assessed using the Cochrane risk of bias tool.Results: Ten randomized controlled trials met the inclusion criteria and were included in the final analysis. Peer support intervention reduced standardized mean depressive scores (-0.37, 95% CI -0.66 to -0.08) and reduced risk ratio (0.69, 95% CI 0.49-0.96) of depression.Limitations: Clinical heterogeneity was observed among the included studies in peer support intervention, suggesting the existence of potential mediators, such as intensity, frequency, or type of peer support intervention.Conclusion: Peer support intervention may have the potential to effectively prevent perinatal depression or reduce the harm of perinatal depression. Future studies with better design/execution and larger sample size are needed to investigate potential mediators associated with the beneficial effects of peer support intervention on perinatal depression. [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]

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]

Protein arginine methylation is aposttranslational modificationcritical for a variety of biological processes. Misregulation of proteinarginine methyltransferases (PRMTs) has been linked to many pathologicalconditions. Most current PRMT inhibitors display limited specificityand selectivity, indiscriminately targeting many methyltransferaseenzymes that use S-adenosyl-l-methionineas a cofactor. Here we report diamidine compounds for specific inhibitionof PRMT1, the primary type I enzyme. Docking, molecular dynamics,and MM/PBSA analysis together with biochemical assays were conductedto understand the binding modes of these inhibitors and the molecularbasis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan(1, furamidine, DB75), one leading inhibitor, targetsthe enzyme active site and is primarily competitive with the substrateand noncompetitive toward the cofactor. Furthermore, cellular studiesrevealed that 1is cell membrane permeable and effectivelyinhibits intracellular PRMT1 activity and blocks cell proliferationin leukemia cell lines with different genetic lesions. [ABSTRACT FROM AUTHOR]

Abstract: Thermal disruption of protein structure and function is a potentially powerful therapeutic vehicle. With the emerging nanoparticle-targeting and femtosecond laser technology, it is possible to deliver heating locally to specific molecules. It is therefore important to understand how fast a protein can unfold or lose its function at high temperatures, such as near the water boiling point. In this study, the thermal damage of EGF was investigated by combining the replica exchange (136 replicas) and conventional molecular dynamics simulations. The REMD simulation was employed to rigorously explore the free-energy landscape of EGF unfolding. Interestingly, besides the native and unfolded states, we also observed a distinct molten globule (MG) state that retained substantial amount of native contacts. Based on the understanding that which the unfolding of EGF is a three-state process, we have examined the unfolding kinetics of EGF (N→MG and MG→D) with multiple 20-ns conventional MD simulations. The Arrhenius prefactors and activation energy barriers determined from the simulation are within the range of previously studied proteins. In contrast to the thermal damage of cells and tissues which take place on the time scale of seconds to hours at relatively low temperatures, the denaturation of proteins occur in nanoseconds when the temperature of heat bath approaches the boiling point. [ABSTRACT FROM AUTHOR]

An excessive amount of matrix metalloproteinase-9 (MMP-9) has been well documented in inflammatory diseases, including chronic wounds and cancers. Secreted as a zymogen, proMMP-9 can be irreversibly converted to a mature form through cleavage of the N-terminal propeptide domain. Although the converting enzyme for proMMP-9 in human tissues is unknown, we previously found that tumor necrosis factor-α (TNF-α) promotes activation of proMMP-9 in human skin, and characterized the converting activities as tissue-associated chymotrypsin-like proteinases. On the other hand, the pathophysiologic inhibitor to prevent proMMP-9 maturation also remains elusive. In this regard, we observed the presence of the inhibitory property in burn blister fluid that abrogates the skin extract–mediated activation of proMMP-9. Then we determined that α-1-antichymotrypsin (α-ACT), an acute-phase factor abundantly present in the blister, effectively inhibited proMMP-9 activation in human and rodent skin. In contrast, the aminophenylmercuric acetate-induced “cysteine switch” and activation of proMMP-9 were not affected by α-ACT. TNF-α-induced activation of proMMP-9 by the explants of human skin was inhibited by α-ACT but not by related α-1-antitrypsin. α-ACT specifically attenuated maturation of proMMP-9 but not proMMP-2 or proMMP-13. Furthermore, short peptides that mimic the reactive center loop (RCL) of α-ACT were sufficient to inhibit the conversion. Mutation analysis demonstrated that a conserved leucine within the RCL was critical for α-ACT-exerted inhibition. In chronic wounds, a large amount of mature MMP-9 was associated with fragmentation and inactivation of α-ACT. Taken together, these results demonstrate that, to the best of our knowledge, α-ACT is a previously unreported pathophysiologic inhibitor that controls proMMP-9 activation in skin tissue.Journal of Investigative Dermatology (2008) 128, 2334–2342; doi:10.1038/jid.2008.77; published online 10 April 2008 [ABSTRACT FROM AUTHOR]

Abstract: The geometry of dichotomin A, cyclo(-Gly-Thr-Phe-Leu-Tyr-Val-) is optimized at the density functional theory (DFT) with B3LYP parameterization, Hartree–Fock (HF) and our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) levels of theory. The gauge-including atomic orbital (GIAO) methods at both the HF and DFT levels of theory are performed to calculate the 13C chemical shifts of the three optimized geometries. The resulting data show the computing time with HF and ONIOM is much less than DFT and the optimized geometry obtained from HF is the most similar to experimental structure. In the three optimized geometry two β-turns and two hydrogen bonds are formed, which may be the primary factors affecting its activities. Comparing to experiment, the RMS errors for 13C chemical shifts relative to TMS determined using HF with the 6-31G(d) basis set are the smallest among all the methods used here. [Copyright &y& Elsevier]

Abstract: The structural aspects for the complexation of (+)-catechin (CA) and (−)-epicatechin (EC) (an enantiomer) to β-cyclodextrins (CDs) were explored by using a semi-empirical PM3 method. In the β-CD/CA inclusion complex, the orientation in which the aromatic A-ring of CA projects onto the 2-OH/3-OH face of β-CD, and the B-ring projects from the 6-OH face is preferred in the binding energy (BE). In contrast, the inclusion of the B-ring of EC from either the secondary hydroxyl group side or the primary hydroxyl group side gives rise to the two most probable complexes. The molecular modeling results are in agreement with the NMR observations and molecular dynamics (MD) simulations. EC forms a more stable complex with β-CD than the corresponding CA, as judged from the difference in BE. The differential interactions between each enantiomer and the chiral host give rise to the significant structural differences for the corresponding inclusion complexes. Numerous host–guest C–H⋯O interactions, resulting from induced fit of the hosts toward each of the enantiomeric guests, comprise a third significant component besides the O–H⋯O hydrogen bonds and the van der Waals contacts. [Copyright &y& Elsevier]

Abstract: The inclusion process involving β-cyclodextrin (β-CD) and quercetin has been investigated by using the PM3 quantum-mechanical semi-empirical method. In the β-CD quercetin inclusion complex, a large portion of the flavonoid skeleton is included in the β-CD cavity and the bond connected ring B with ring C is inclined to the molecular axis of β-CD. The orientation in which the B ring of the guest molecule located near the secondary hydroxyls of the β-CD cavity is preferred in energy. One intermolecular hydrogen bond is formed. The molecular modeling results are in agreement with the NMR observations and molecular dynamics (MD) simulations. The statistical thermodynamic calculations at 1atm and 298.15K by PM3 demonstrate that 1:1 quercetin/β-CD complex is favored by a negative enthalpy change. [Copyright &y& Elsevier]

Abstract: Polyparameter linear free energy relationships (LFERs) on rate constants (k OH) for gas-phase reactions of hydroxyl radicals with polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were developed. Quantum chemical descriptors and partial least squares (PLS) regression were used for model development. Acenaphthylene was found to be an outlier and was excluded in the final model development. The cumulative variance of the dependent variable explained by the PLS components and determined by cross-validation (), for the optimal model, is 0.97, indicating good robustness and predictive power of the model. The main molecular structural factor governing k OH values of PAHs and PCDD/Fs is molecular ability to donate electrons, as described by the energy of the highest occupied molecular orbital (E HOMO), the average of net atomic charges on hydrogen atoms (), and the average of net atomic charges on carbon atoms (q C). PAH and PCDD/F molecules with high E HOMO and low and q C values tend to have high log k OH values. The LFER model indicates the temperature dependence of log k OH is weak. [Copyright &y& Elsevier]

R4057 --> This project aims to investigate the molecular role of epigenetic changes from tobacco smoke exposure in the development of lung cancer, the largest cause of cancer‐related deaths. The epigenome consists of the heritable chemical groups on the genome that regulate gene expression. One well‐studied epigenetic mark is DNA methylation, which occurs at CpG dinucleotides and is usually associated with gene silencing. Environmental and lifestyle factors such as smoking can induce heritable alterations to the epigenome and can thereby influence disease risk. However, the mechanisms by which tobacco smoke exposure leads to increased lung cancer risk are not fully understood. Past studies have linked hypomethylation of cg05575921, a CpG in the aryl hydrocarbon receptor repressor (AHRR) gene, a regulator of the xenobiotic response pathway, as a strong indicator of lung cancer risk. Tobacco smoke exposure results in hypomethylation of cg05575921 in blood and lung tissue. Our previous research showed that cg05575921 flanks a tobacco smoke‐inducible enhancer linked to the induction of AHRR expression. Our guiding hypothesis is that hypomethylation of cg05575921 is a byproduct of enhancer activation by tobacco smoke, and that it is the enhancer activity that has functional consequences, not the loss of methylation at cg05575921. To evaluate the functional role of this enhancer, we used CRISPR/Cas9 gene editing technology to generate monoclonal A549 cell lines with targeted DNA deletions of either the enhancer region, the CpG site adjacent to it, or a negative control region lacking regulatory marks. Resulting clones will be treated with cigarette smoke condensate (CSC) and analyzed for AHRR expression through whole‐transcriptome mRNA sequencing (RNA‐seq). Initial findings show a high rate of successful deletions in transfected cells, bolstering the technique's potential for studying enhancers' roles in cancerous transformation. Thus far, clones in the enhancer deletion group have been screened via PCR for the desired deletion, further characterized via Sanger sequencing across deletion sites and heterozygous SNPs, exposed to CSC for 48 hours, and RNA has been subjected to RNA‐seq. Analysis of RNA‐seq data is ongoing. CpG deletion clones have been screened and sequenced and are ready to undergo CSC exposure. Negative control deletion clones have been generated and are growing in preparation for screening. Our analyses promise to shed light on the mechanism underlying the link between cg05575921 hypomethylation and lung cancer risk. [ABSTRACT FROM AUTHOR]

Sliding clamp proteins encircle duplex DNA and are involved in processive DNA replication and the DNA damage response. Clamp proteins are ring-shaped oligomers (dimers or trimers) and are loaded onto DNA by an ATP-dependent clamp loader complex that ruptures the interface between two adjacent subunits. Here we measured the solution dynamics of the human clamp protein, proliferating cell nuclear antigen, by monitoring the change in the fluorescence of a site-specifically labeled. To unravel the origins of clamp subunit interface stability, we carried out comprehensive comparative analysis of the interfaces of seven sliding clamps. We used computational modeling (molecular dynamic simulations and MM/GBSA binding energy decomposition analyses) to identify conserved networks of hydrophobic residues critical for clamp stability and ring-opening dynamics. The hydrophobic network is shared among clamp proteins and exhibits a "key in a keyhole" pattern where a bulky aromatic residue from one clamp subunit is anchored into a hydrophobic pocket of the opposing subunit. Bioinformatics and dynamic network analyses showed that this oligomeric latch is conserved across DNA sliding clamps from all domains of life and dictates the dynamics of clamp opening and closing. Unlabelled Image • A cluster of hydrophobic residues in DNA clamp proteins maintains their structural integrity. • The identified network of hydrophobic residues is conserved in clamps from all domains of life. • We provide a revised model for clamp protein oligomerization, opening and DNA loading. [ABSTRACT FROM AUTHOR]

The authors criticize the chemical vapor deposition (CVD) of graphene without metal on silicon (Si) reported by Q. Hong and colleagues. The authors say that the idea of the researchers that graphene growth temperature on Si substrate should be no more than 1000 ° Celsius (C) is their first concern regarding silicon carbide formation. They add that a vital insights on the deposition mechanism of grape he is offered by the report.

Critical for transcription initiation and bulky lesion DNA repair, TFIIH provides an exemplary system to connect molecular mechanisms to biological outcomes due to its strong genetic links to different specific human diseases. Recent advances in structural and computational biology provide a unique opportunity to re-examine biologically relevant molecular structures and develop possible mechanistic insights for the large dynamic TFIIH complex. TFIIH presents many puzzles involving how its two SF2 helicase family enzymes, XPB and XPD, function in transcription initiation and repair: how do they initiate transcription, detect and verify DNA damage, select the damaged strand for incision, coordinate repair with transcription and cell cycle through Cdk-activating-kinase (CAK) signaling, and result in very different specific human diseases associated with cancer, aging, and development from single missense mutations? By joining analyses of breakthrough cryo-electron microscopy (cryo-EM) structures and advanced computation with data from biochemistry and human genetics, we develop unified concepts and molecular level understanding for TFIIH functions with a focus on structural mechanisms. We provocatively consider that TFIIH may have first evolved from evolutionary pressure for TCR to resolve arrested transcription blocks to DNA replication and later added its key roles in transcription initiation and global DNA repair. We anticipate that this level of mechanistic information will have significant impact on thinking about TFIIH, laying a robust foundation suitable to develop new paradigms for DNA transcription initiation and repair along with insights into disease prevention, susceptibility, diagnosis and interventions. [ABSTRACT FROM AUTHOR]

Background: It has been suggested that mother-infant psychotherapy may offer an alternative approach to treating postpartum depression, but little is known about its effectiveness. This review presents a summarized effectiveness of mother-infant psychotherapy on postpartum depression.Methods: Multiple electronic databases were searched including Pubmed, Cochrane Library, EMBase, MEDLINE, et al. Hand searching of references was also performed. Randomized controlled trials reporting on mother-infant psychotherapy targeting postpartum depression were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool.Results: A total of 13 randomized controlled trials met inclusion criteria and were included in the final analysis. In the short-term effect analysis, mother-infant psychotherapy reduced standardized mean depressive scores (-0.25, 95% CI -0.40, -0.09) and risk ratio (0.71, 95% CI 0.55, 0.91). In the long-term effect analysis, mother-infant psychotherapy did not improve maternal mood, mother-infant interaction and infant attachment.Limitations: Clinical heterogeneity was observed among included studies in mother-infant psychotherapy intervention, suggesting the existence of potential moderators such as intensity, frequency, trimester of pregnancy or type of mother-infant psychotherapy.Conclusion: Mother-infant psychotherapy appears to be effective for the treatment of maternal depression in the short-term. Future studies with better design/execution and larger sample size are needed to confirm the effect of mother-infant psychotherapy on short-term and to explore its effect on long-term depression. [ABSTRACT FROM AUTHOR]

Highlights • Large area graphene is grown by chemical vapor deposition on Ta and Re catalysts at temperatures much higher than 1000 °C. • The growth parameters and material characterizations are given in detail. Graphene with reasonable quality has been achieved. • Negative effects of using refractory metals in the graphene CVD are summarized. Abstract Large area graphene is usually grown by chemical vapor deposition on Cu or Ni catalysts at ∼1000 °C. For most materials, high temperature leads to high quality. However, graphene growth at even higher temperatures is rarely reported. Therefore, here we systematically investigate the graphene deposition on refractory metals i.e. metals with extremely high melting points. The growth parameters and material characterizations are given in detail. On Ta which readily forms carbides during the carbon deposition, the growth mode is monolayer due to the chemical absorption of excess carbon in the bulk metal. On Re, there is no carbide formed (except in extreme conditions), which greatly simplifies the scenario. Because of the relatively high carbon solubility in Re, the growth temperature has to be limited in order not to drift into the dominantly multilayer graphene regime caused by the carbon segregation. Graphene with reasonable quality has been achieved, although not as good as expected. For example, on Ta, the residual bonds between the graphene and substrate deteriorate the graphene crystalline quality. Despite the difficulties in refractory metal etching, the transfer technique of the graphene is also explored. This research contributes to the fundamental understanding of the graphene growth theory and technology on refractory metals. [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]

Tyrosyl-DNA phosphodiesterase 2 (TDP2) processes protein/DNA adducts resulting from abortive DNA topoisomerase II (Top2) activity. TDP2 inhibition could provide synergism with the Top2 poison class of chemotherapeutics. By virtual screening of the NCI diversity small molecule database, we identified selective TDP2 inhibitors and experimentally verified their selective inhibitory activity. Three inhibitors exhibited low-micromolar IC 50 values. Molecular dynamics simulations revealed a common binding mode for these inhibitors, involving association to the TDP2 DNA-binding cleft. MM-PBSA per-residue energy decomposition identified important interactions of the compounds with specific TDP2 residues. These interactions could provide new avenues for synthetic optimization of these scaffolds. [ABSTRACT FROM AUTHOR]

Objective To develop and validate a scale of stigma for infertile Chinese women. Method(s) Infertile women admitted to the Xiangya Hospital, the Second Xiangya Hospital, and the Third Xiangya Hospital of Central South University for treatment were approached to participate in this study. The Infertility Stigma Scale (ISS) development involved: [1] item generation based on literature, interview (experts/patients: N = 5/N = 20) and related scale; [2] pre-test questionnaire formation with both experts' ratings (N = 9) and infertile women's feedbacks (N = 30); [3] the component structure assessed by principal components analysis with varimax rotation (N = 334); [4] convergent validity assessed with Social Support Rating scale, Self-Esteem scale, Family APGAR Index (N = 334); and [5] reliability identified by internal consistency Cronbach's α (N = 334), split-half reliability (N = 334), test–retest reliability (N = 20). Result(s) This study yielded a 27-item ISS with 4 factors (self-devaluation, social withdrawal, public stigma, and family stigma). Exploratory factor analysis indicated that these 4 factors accounted for 58.17% of total variances. The Cronbach's α, split-half coefficient and test–retest correlation coefficient for the whole scale was 0.94, 0.90, and 0.91, respectively. The associations of the ISS with other measures suggested good convergent validity. The Content Validity Index (CVI) was 0.92. Conclusion(s) The ISS appears to be a reliable and valid measure to assess levels of stigma experienced by infertile Chinese women. It may be a useful tool to help identify infertile women at greater risks of distress. [ABSTRACT FROM AUTHOR]

Summary Replication Protein A (RPA) is an essential scaffold for many DNA processing machines; its function relies on its modular architecture. Here, we report 15 N-nuclear magnetic resonance heteronuclear relaxation analysis to characterize the movements of single-stranded (ss) DNA binding and protein interaction modules in the RPA70 subunit. Our results provide direct evidence for coordination of the motion of the tandem RPA70AB ssDNA binding domains. Moreover, binding of ssDNA substrate is found to cause dramatic reorientation and full coupling of inter-domain motion. In contrast, the RPA70N protein interaction domain remains structurally and dynamically independent of RPA70AB regardless of binding of ssDNA. This autonomy of motion between the 70N and 70AB modules supports a model in which the two binding functions of RPA are mediated fully independently, but remain differentially coordinated depending on the length of their flexible tethers. A critical role for linkers between the globular domains in determining the functional dynamics of RPA is proposed. [ABSTRACT FROM AUTHOR]

Background The precise nature of how cell type specific chromatin structures at enhancer sites affect gene expression is largely unknown. Here we identified cell type specific enhancers coupled with gene expression in two different types of breast epithelial cells, HMEC (normal breast epithelial cells) and MDAMB231 (triple negative breast cancer cell line). Results Enhancers were defined by modified neighboring histones [using chromatin immunoprecipitation followed by sequencing (ChIP-seq)] and nucleosome depletion [using formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIREseq)]. Histone modifications at enhancers were related to the expression levels of nearby genes up to 750 kb away. These expression levels were correlated with enhancer status (poised or active), defined by surrounding histone marks. Furthermore, about fifty percent of poised and active enhancers contained nucleosome-depleted regions. We also identified response element motifs enriched at these enhancer sites that revealed key transcription factors (e.g. TP63) likely involved in regulating breast epithelial enhancer-mediated gene expression. By utilizing expression data, potential target genes of more than 600 active enhancers were identified. These genes were involved in proteolysis, epidermis development, cell adhesion, mitosis, cell cycle, and DNA replication. Conclusions These findings facilitate the understanding of epigenetic regulation specifically, such as the relationships between regulatory elements and gene expression and generally, how breast epithelial cellular phenotypes are determined by cell type specific enhancers. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations— we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at . 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium () with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process. [ABSTRACT FROM AUTHOR]

Breast Cancer (BCa) genome-wide association studies revealed allelic frequency differences between cases and controls at index single nucleotide polymorphisms (SNPs). To date, 71 loci have thus been identified and replicated. More than 320,000 SNPs at these loci define BCa risk due to linkage disequilibrium (LD). We propose that BCa risk resides in a subgroup of SNPs that functionally affects breast biology. Such a shortlist will aid in framing hypotheses to prioritize a manageable number of likely disease-causing SNPs. We extracted all the SNPs, residing in 1 Mb windows around breast cancer risk index SNP from the 1000 genomes project to find correlated SNPs. We used FunciSNP, an R/Bioconductor package developed in-house, to identify potentially functional SNPs at 71 risk loci by coinciding them with chromatin biofeatures. We identified 1,005 SNPs in LD with the index SNPs (r2≥0.5) in three categories; 21 in exons of 18 genes, 76 in transcription start site (TSS) regions of 25 genes, and 921 in enhancers. Thirteen SNPs were found in more than one category. We found two correlated and predicted non-benign coding variants (rs8100241 in exon 2 and rs8108174 in exon 3) of the gene, ANKLE1. Most putative functional LD SNPs, however, were found in either epigenetically defined enhancers or in gene TSS regions. Fifty-five percent of these non-coding SNPs are likely functional, since they affect response element (RE) sequences of transcription factors. Functionality of these SNPs was assessed by expression quantitative trait loci (eQTL) analysis and allele-specific enhancer assays. Unbiased analyses of SNPs at BCa risk loci revealed new and overlooked mechanisms that may affect risk of the disease, thereby providing a valuable resource for follow-up studies. [ABSTRACT FROM AUTHOR]

Constitutive activation of STAT3 can play a vital role in the development of melanoma. STAT3-targeted therapeutics are reported to show efficacy in melanomas harboring the BRAFV600E mutant and also in vemurafenib-resistant melanomas. We designed and synthesized a series of substituted nitric oxide (NO)-releasing quinolone-1,2,4-triazole/oxime hybrids, hypothesizing that the introduction of a STAT3 binding scaffold would augment their cytotoxicity. All the hybrids tested showed a comparable level of in vitro NO production. 7b and 7c exhibited direct binding to the STAT3-SH domain with IC 50 of ∼ 0.5 μM. Also, they abrogated STAT3 tyrosine phosphorylation in several cancer cell lines, including the A375 melanoma cell line that carries the BRAFV600E mutation. At the same time, they did not affect the phosphorylation of upstream kinases or other STAT isoforms. 7c inhibited STAT3 nuclear translocation in mouse embryonic fibroblast while 7b and 7c inhibited STAT3 DNA-binding activity in the A375 cell line. Their anti-proliferating activity is attributed to their ability to trigger the production of reactive oxygen species and induce G1 cell cycle arrest in the A375 cell line. Interestingly, 7b and 7c showed robust cell growth suppression and apoptosis induction in two pairs of BRAF inhibitor-naïve (-S) and resistant (-R) melanoma cell lines containing a BRAF V600E mutation. Surprisingly, MEL1617-R cells that are known to be more resistance to MEK inhibition by GSK1120212 than MEL1617-S cells exhibit a similar response to 7b and 7c. Image 1 • Design and synthesis of hybrid compounds containing dual-functional NO-releasing STAT3 inhibitors. • They inhibited STAT3 phosphorylation in several cancer cell lines without affecting other STAT isoforms. • They abrogated STAT3 nuclear translocation, DNA binding, and transcriptional activity in cancer cells. • The cytotoxicity towards cells carrying BRAF mutation was accompanied by ROS production, cell cycle arrest, and apoptosis. • They showed comparable cytotoxicity towards both SB-590885-sensitive and resistant melanoma cell lines. [ABSTRACT FROM AUTHOR]

Micro-light-emitting diodes (micro-LEDs) are the key to next-generation display technology. However, since the driving circuits are typically composed of Si devices, numerous micro-LED pixels must be transferred from their GaN substrate to bond with the Si field-effect transistors (FETs). This process is called massive transfer, which is arguably the largest obstacle preventing the commercialization of micro-LEDs. We combined GaN devices with emerging graphene transistors and for the first-time designed, fabricated, and measured a monolithic integrated device composed of a GaN micro-LED and a graphene FET connected in series. The p-electrode of the micro-LED was connected to the source of the driving transistor. The FET was used to tune the work current in the micro-LED. Meanwhile, the transparent electrode of the micro-LED was also made of graphene. The operation of the device was demonstrated in room temperature conditions. This research opens the gateway to a new field where other two-dimensional (2D) materials can be used as FET channel materials to further improve transfer properties. The 2D materials can in principle be grown directly onto GaN, which is reproducible and scalable. Also, considering the outstanding properties and versatility of 2D materials, it is possible to envision fully transparent micro-LED displays with transfer-free active matrices (AM), alongside an efficient thermal management solution. [ABSTRACT FROM AUTHOR]