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1.
Am J Clin Oncol ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31693507

RESUMO

BACKGROUND: Both regorafenib and reduced-intensity FOLFOXIRI (riFOLFOXIRI) prolong survival in patients with metastatic colorectal cancer (mCRC). However, the sequence in which they should be administrated first in late-line treatment for refractory mCRC remains unclear. PATIENTS AND METHODS: This study was a single-center retrospective cohort study that reviewed data from patients at Taipei Veterans General Hospital, Taiwan, with mCRC refractory to fluorouracil, irinotecan, oxaliplatin, cetuximab (wild-type RAS), and bevacizumab. Patients were divided into 2 groups: a regorafenib-first group and a riFOLFOXIRI-first group. The Kaplan-Meier method and log-rank test were used to analyze survival, and a Cox proportional hazards model was used for univariate, multivariate, and subgroup analyses. RESULTS: A total of 136 and 55 patients followed a regorafenib-first or riFOLFOXIRI-first treatment strategy, respectively. At baseline, patient characteristics were similar between the groups, except for younger age in the riFOLFOXIRI-first group. The regorafenib-first group had better overall survival (13.8 vs. 10.7 mo, P=0.038), whereas patients in the riFOLFOXIRI-first group had a better partial response rate (P=0.005) but a higher rate of discontinuation due to adverse effects (P=0.004) and cross-over to regorafenib (P<0.001). Thus, no significant difference was observed in progression-free survival (regorafenib-first strategy: 3.17 mo; riFOLFOXIRI-first strategy: 4.97 mo; P=0.624). Regorafenib-first strategy, sex, and pathology were identified as independent prognostic factors. Subgroup analysis indicated that younger age, better performance status, stage IV disease, and mutant RAS gene favored the regorafenib-first strategy. CONCLUSION: Treatment with regorafenib-first followed by riFOLFOXIRI resulted in better overall survival when given as late-line treatment for patients with refractory mCRC.

2.
Soft Matter ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729500

RESUMO

Poly(butylene succinate-co-propylene succinate) (PBSPS) was polymerized using succinic acid, 1,4-butanediol, 1,3-propanediol, and glycerol (GC). The PBSPS copolyester with a BS/PS ratio of 7/3 has a low melting point (Tm, 80 °C) and crystallization temperature (Tc, 20 °C) in addition to excellent thermal stability with a thermal degradation temperature (Td) above 300 °C. Isodimorphism was observed for 30-50 mol% PS, lowering Tm and Tc. The featured crystalline lattices (021) and (110) of PBS at 2θ = 21.5° and 22.5° gradually disappeared with PS content greater than 50 mol% and transformed into a PPS crystalline lattice at 2θ = 22.3°. Young's modulus decreased with increasing PS content due to crystallinity loss. Wide-angle X-ray diffraction demonstrated that the chain movement regularity was affected by the GC content, reducing the crystallinity. The PBSPS copolyesters were elastic with 0.001 mol% GC but became rigid with GC content greater than 0.01 mol%. The chain conformation was flexible for 0.001-0.01 mol% GC and exhibited an irregular steric architecture for 0.02-0.03 mol% GC due to more GC acting as nodes. Thus, the thermal and mechanical properties of the synthesized bio-based PBSPS copolyesters can be controlled by adjusting the GC content; therefore, such copolyesters are suitable for medical support, coating, and phase-change material applications.

3.
Phytochemistry ; 169: 112184, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678787

RESUMO

An extensive phytochemical investigation on the chemical constituents from the needles and twigs of the vulnerable conifer Pseudotsuga sinensis yielded 19 diterpenoids and 21 sesquiterpenoids with various carbocyclic skeletons. Among them, 13 (named pseudosinins A-M, resp.) were undescribed compounds. Their structures with absolute configurations were characterized by a combination of spectroscopic methods, calculated and experimental electronic circular dichroism (ECD) data, quantum chemical calculations of the chemical shifts, and single crystal X-ray diffraction analyses. In particular, an array of labdane-derived norditerpenoids with C19-, C18-, and C16-skeletons, and related drimane-type sesquitepenoids with C15- and C13-skeletons were found in the title plant. The possible biogenetic relationships of these degraded terpenoids were briefly discussed. Among the isolates, pseudosinin D, cis-communic acid, and 4ß,15-dihydroxy-19-norabieta-8,11,13-trien-7-one showed moderate inhibitory activities against the enzyme ATP-citrate lyase (ACL), a potential drug target for the treatment of hyperlipidemia and hypercholesterolemia.

4.
Cytometry B Clin Cytom ; 96(5): 338-350, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31566910

RESUMO

This review focuses on the roles of flow cytometric immunophenotyping has in the differential diagnosis of plasma cell neoplasms and the post-therapy monitoring of minimal (measurable) residual disease. The need to integrate flow cytometry data with clinical, laboratory, radiographic, morphological, and molecular genetic findings is emphasized. The challenges of and strategies for evaluating plasma cells in the setting of targeted therapy are also highlighted. © 2019 International Clinical Cytometry Society.

5.
Acta Crystallogr D Struct Biol ; 75(Pt 10): 918-929, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588923

RESUMO

The Y128F single mutant of p-hydroxymandelate oxidase (Hmo) is capable of oxidizing mandelate to benzoate via a four-electron oxidative decarboxylation reaction. When benzoylformate (the product of the first two-electron oxidation) and hydrogen peroxide (an oxidant) were used as substrates the reaction did not proceed, suggesting that free hydrogen peroxide is not the committed oxidant in the second two-electron oxidation. How the flavin mononucleotide (FMN)-dependent four-electron oxidation reaction takes place remains elusive. Structural and biochemical explorations have shed new light on this issue. 15 high-resolution crystal structures of Hmo and its mutants liganded with or without a substrate reveal that oxidized FMN (FMNox) possesses a previously unknown electrophilic/nucleophilic duality. In the Y128F mutant the active-site perturbation ensemble facilitates the polarization of FMNox to a nucleophilic ylide, which is in a position to act on an α-ketoacid, forming an N5-acyl-FMNred dead-end adduct. In four-electron oxidation, an intramolecular disproportionation reaction via an N5-alkanol-FMNred C'α carbanion intermediate may account for the ThDP/PLP/NADPH-independent oxidative decarboxylation reaction. A synthetic 5-deaza-FMNox cofactor in combination with an α-hydroxyamide or α-ketoamide biochemically and structurally supports the proposed mechanism.

6.
Am J Ophthalmol ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31647929

RESUMO

PURPOSE: To analyze the outcome of machine learning technique for prediction of small incision lenticule extraction (SMILE) nomogram. DESIGN: Prospective, comparative clinical study. METHODS: A comparative study was conducted on the outcomes of SMILE surgery between surgeon group (nomogram set by surgeon) and machine learning group (nomogram predicted by machine learning model). The machine learning model was trained by 865 ideal cases (spherical equivalent (SE) within ±0.5D three months postoperatively) from an experienced surgeon. The visual outcomes of both groups were compared for safety, efficacy, predictability, and SE correction. RESULTS: There was no statistically significant difference between the baseline data in both groups. The efficacy index in the machine learning group (1.48±1.08) was significantly higher than the surgeon group (1.3±0.27) (t=-2.17, P<0.05). 83% of eyes in surgeon group and 93% of eyes in machine learning group were within ± 0.50D, while 98% of eyes in surgeon group and 96% eyes in machine learning group were within ± 1.00D. The error of SE correction was -0.09±0.024 and -0.23±0.021 for machine learning and surgeon groups, respectively. CONCLUSIONS: The machine learning technique performed as well as surgeon in safety, but significantly better than surgeon in efficacy. As for predictability, machine learning technique was comparable to surgeon, although less predictable for high myopia and astigmatism.

7.
Xenotransplantation ; : e12558, 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31565822

RESUMO

BACKGROUND: Tolerance-inducing approaches to xenotransplantation would be optimal and may be necessary for long-term survival of transplanted pig organs in human patients. The ideal approach would generate donor-specific unresponsiveness to the pig organ without suppressing the patient's normal immune function. Porcine thymus transplantation has shown efficacy in promoting xenotolerance in humanized mice and large animal models. However, murine studies demonstrate that T cells selected in a swine thymus are positively selected only by swine thymic epithelial cells, and therefore, cells expressing human HLA-restricted TCRs may not be selected efficiently in a transplanted pig thymus. This may lead to suboptimal patient immune function. METHODS: To assess human thymocyte selection in a pig thymus, we used a TCR transgenic humanized mouse model to study positive selection of cells expressing the MART1 TCR, a well-characterized human HLA-A2-restricted TCR, in a grafted pig thymus. RESULTS: Positive selection of T cells expressing the MART1 TCR was inefficient in both a non-selecting human HLA-A2- or swine thymus compared with an HLA-A2+ thymus. Additionally, CD8 MART1 TCRbright T cells were detected in the spleens of mice transplanted with HLA-A2+ thymi but were significantly reduced in the spleens of mice transplanted with swine or HLA-A2- thymi. [Correction added on October 15, 2019, after first online publication: The missing superscript values +, -, and bright have been included in the Results section.] CONCLUSIONS: Positive selection of cells expressing a human-restricted TCR in a transplanted pig thymus is inefficient, suggesting that modifications to improve positive selection of cells expressing human-restricted TCRs in a pig thymus may be necessary to support development of a protective human T-cell pool in future patients.

8.
Int J Mol Sci ; 20(19)2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569432

RESUMO

Lactoferrin (LF) has demonstrated stimulation of osteogenic differentiation of mesenchymal stem cells (MSCs). Long non-coding RNAs (lncRNAs) participate in regulating the osteogenic differentiation processes. However, the impact of LF on lncRNA expression in MSC osteogenic differentiation is poorly understood. Our aim was to investigate the effects of LF on lncRNAs expression profiles, during osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), by RNA sequencing. A total number of 1331 putative lncRNAs were identified in rBMSCs during osteogenic differentiation in the study. LF influenced the expression of 120 lncRNAs (differentially expressed lncRNAs [DELs], Fold change > 1.5 or < -1.5; p < 0.05) in rBMSCs on day 14 of osteogenic differentiation, consisted of 60 upregulated and 60 down-regulated. Furthermore, the potential functions of DELs were of prediction by searching their target cis- and trans-regulated protein-coding genes. The bioinformatic analysis of DELs target gene revealed that LF led to the disfunction of transforming growth factor beta stimulus (TGF-ß) and positive regulation of I-κappa B kinase/NF-κappa B signaling pathway, which may relate to osteogenic differentiation of rBMSCs. Our work is the first profiling of lncRNA in osteogenic differentiation of rBMSCs induced by LF, and provides valuable insights into the potential mechanisms for LF promoting osteogenic activity.

9.
Sci Rep ; 9(1): 15255, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649321

RESUMO

The objective of this study was to elucidate possible relationship between middle cerebral artery (MCA) bifurcation aneurysms and bifurcation morphology. In the present study, 799 patients with three-dimensional angiography were enrolled, including 115 patients with MCA bifurcation aneurysms and 684 subjects without aneurysms. The MCA bifurcation geometry, including angles formed between two M2 segments (φ1) and between M1 and M2 segments, vessel diameters and aneurysm sizes were measured. DA ratio (larger/smaller M2 in diameter) and LA ratio (larger/smaller lateral angle) were also analyzed. The LA and DA ratios and angle φ1 were significantly (P < 0.0001) greater in patients harboring MCA bifurcation aneurysms than in the control, whereas lateral angles and bifurcation branch diameters were significantly smaller (P < 0.01) in patients with than without bifurcation aneurysms. Angle φ1 was significantly increased (P < 0.0001) while both lateral angles significantly decreased (P < 0.0001 and P = 0.0005, respectively) with increase of patients' age. The size of MCA bifurcation aneurysms was significantly (P < 0.05) positively correlated with the bifurcation vascular diameter and aneurysm neck at the MCA bifurcation. A significantly positive correlation existed between aneurysm neck and DA ratio (P = 0.0075), whereas an inverse correlation between aneurysm neck and LA ratio (P = 0.0219). MCA bifurcation aneurysms were mostly deviated toward the smaller lateral angles and smaller M2 branch. In conclusion, aneurysmal MCA bifurcations have asymmetrical bifurcation structures with widened bifurcation angles, narrowed lateral angles, decreased M1 diameter, imbalanced lateral angles and M2 segments, with the cutoff bifurcation angle of 125.0° and cutoff lateral angle ratio of 1.57 for predicting MCA bifurcation aneurysms, whereas normal MCA bifurcations show close to symmetrical structures in the lateral angles and M2 branches.

10.
Math Biosci Eng ; 16(5): 5862-5876, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31499742

RESUMO

Landing is a crucial factor in gymnastics competitions, but the underlying biomechanical and neuromuscular strategies remains unclear. This study aimed to investigate the biomechanical characteristics and neuromuscular strategies of landing for backward somersault. A 19-segment human model was developed and bilateral lower-limb joint loadings were estimated using computer stimulation. Bilateral lower-limb joint angles, vertical ground reaction force (vGRF), impulse, joint reaction force, joint torque, power, work, stiffness and electromyogram (EMG) of the rectus femoris, biceps femoris, tibialis anterior, and lateral gastrocnemius were presented during initial (touchdown to peak vGRF) and terminal impact-phases of landing (peak vGRF to vGRF equaling to body weight). The hip, knee, and ankle joints were rapidly flexed (8º, 20º, and 18º, respectively) during initial impact-phase and maintained at around 90º, 120º, and 60º, respectively terminal impact-phase. Flexor and extensor torques were demonstrated for lower-limb joints during initial and terminal impact-phases, respectively. The stiffness of lower limb joints and the EMGs amplitude of all examined muscles during terminal impact-phase were several times larger than that during initial impact-phase. The absolute symmetry indexes were less than 10% for lower limb joint angles and larger than 10% for the kinetics and muscle activation. The findings demonstrated symmetrical motion for lower limb joints with flexing rapidly at initial impact-phase and maintaining unchanged at terminal impact-phase and asymmetry in joint loading and muscle activation during landing.

11.
J Vis Exp ; (151)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31524866

RESUMO

Target Induced Local Lesions In Genomes (TILLING) is a strategy of reverse genetics for the high-throughput screening of induced mutations. However, the TILLING system has less applicability for insertion/deletion (Indel) detection and traditional TILLING needs more complex steps, like CEL I nuclease digestion and gel electrophoresis. To improve the throughput and selection efficiency, and to make the screening of both Indels and single base substitions (SBSs) possible, a new high-resolution melting (HRM)-based TILLING system is developed. Here, we present a detailed HRM-TILLING protocol and show its application in mutation screening. This method can analyze the mutations of PCR amplicons by measuring the denaturation of double-stranded DNA at high temperatures. HRM analysis is directly performed post-PCR without additional processing. Moreover, a simple, safe and fast (SSF) DNA extraction method is integrated with HRM-TILLING to identify both Indels and SBSs. Its simplicity, robustness and high throughput make it potentially useful for mutation scanning in rice and other crops.

12.
Phys Rev Lett ; 123(6): 065002, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31491159

RESUMO

We experimentally demonstrate the observation of thermally excited microscopic acoustic wave turbulence at the discrete level in quasi-two-dimensional cold dusty plasma liquids. Through multidimensional empirical mode decomposition of individual dust particle motions over a large area, the turbulence is decomposed into multiscale traveling wave modes, sharing self-similar dynamics. All modes exhibit intermittent excitation, propagation, scattering, and annihilation of coherent waves, in the form of clusters in the xyt space, with cluster sizes exhibiting self-similar power law distribution. The poor particle interlocking in the region with poor structural order is the key origin of the easier excitations of the large amplitude slow modes. The sudden phase synchronization of slow wave modes switches particle motion from cage rattling to cooperative hopping.

14.
Genetics ; 213(3): 759-770, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31537622

RESUMO

Testing for Hardy-Weinberg equilibrium (HWE) is an important component in almost all analyses of population genetic data. Genetic markers that violate HWE are often treated as special cases; for example, they may be flagged as possible genotyping errors, or they may be investigated more closely for evolutionary signatures of interest. The presence of population structure is one reason why genetic markers may fail a test of HWE. This is problematic because almost all natural populations studied in the modern setting show some degree of structure. Therefore, it is important to be able to detect deviations from HWE for reasons other than structure. To this end, we extend statistical tests of HWE to allow for population structure, which we call a test of "structural HWE." Additionally, our new test allows one to automatically choose tuning parameters and identify accurate models of structure. We demonstrate our approach on several important studies, provide theoretical justification for the test, and present empirical evidence for its utility. We anticipate the proposed test will be useful in a broad range of analyses of genome-wide population genetic data.

15.
Acta Pharmacol Sin ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383989

RESUMO

During re-read of our previously article Plumbagin attenuates cancer cell growth and osteoclast formation in the bone microenvironment of micepublished in Acta Pharmacologica Sinica, we were regretted to point out a mistake shown in Fig. 2a. The representative figure chosen to indicate the inhibitory effect of 4 mg/kg of plumbagin treatment at 1 week against MDA-MB-231SArfp cells localization within bone environment was incorrect due to the mishandling in manuscript preparation. Although this correction does not affect the results and conclusion of the paper, all the authors agree on the correction of our negligence as providing the corrected Fig. 2a presented below. We feel sorry and apologize for all the inconvenience it caused.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

16.
Acta Crystallogr D Struct Biol ; 75(Pt 8): 733-742, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373572

RESUMO

p-Hydroxymandelate oxidase (Hmo) is a flavin mononucleotide (FMN)-dependent enzyme that oxidizes mandelate to benzoylformate. How the FMN-dependent oxidation is executed by Hmo remains unclear at the molecular level. A continuum of snapshots from crystal structures of Hmo and its mutants in complex with physiological/nonphysiological substrates, products and inhibitors provides a rationale for its substrate enantioselectivity/promiscuity, its active-site geometry/reactivity and its direct hydride-transfer mechanism. A single mutant, Y128F, that extends the two-electron oxidation reaction to a four-electron oxidative decarboxylation reaction was unexpectedly observed. Biochemical and structural approaches, including biochemistry, kinetics, stable isotope labeling and X-ray crystallography, were exploited to reach these conclusions and provide additional insights.

17.
PLoS One ; 14(8): e0220699, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393937

RESUMO

BACKGROUND: Critically-ill surgical patients are at higher risk for sarcopenia, which is associated with worse survival. Sarcopenia may impair the respiratory musculature, which can subsequently influence the outcome of ventilator weaning. Although there are a variety of weaning parameters predictive of weaning outcomes, none have tried to incorporate "muscle strength" or "sarcopenia". The aim of the current study was to explore the association between sarcopenia and difficult-to-wean (DtW) in critically-ill surgical patients. The influence of sarcopenia on ICU mortality was also analyzed. METHODS: Ninety-six patients undergoing mechanical ventilation in the surgical intensive care unit (ICU) were enrolled. Demographic data and weaning parameters were recorded from the prospectively collected database, and the total psoas muscle area (TPA) was determined at the level of the 3rd lumbar vertebra by computed tomography. Sarcopenia was defined by previously established cut-off points and its influence on clinical outcomes was examined. Receiver operating characteristic (ROC) curve analysis was conducted to investigate the predictive capability of TPA and weaning parameters for predicting weaning outcomes. RESULTS: The median age of the studied patients was 73 years. Thirty patients (31.3%) were sarcopenic and 30 (31.3%) were defined as DtW. Eighteen patients (18.8%) had ICU mortality. Multivariate logistic regression analyses revealed that sarcopenia was an independent risk factor for DtW and ICU mortality. The area under the ROC curve (AUC) of TPA for predicting successful weaning was 0.727 and 0.720 in female and male patients, respectively. After combining TPA and conventional weaning parameters, the AUC for DtW increased from 0.836 to 0.911 and from 0.835 to 0.922 in female and male patients, respectively. CONCLUSION: Sarcopenia is an independent risk factor for DtW and ICU mortality. TPA has predictive value when assessing weaning outcomes and can be used as an effective adjunct predictor along with conventional weaning parameters.

18.
Org Biomol Chem ; 17(34): 7964-7972, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31407769

RESUMO

We describe the design and modular synthesis of a library of substituted hexabenzoovalene derivatives (SHBO), along with the key precursor dinaphthopyrenes (3), highlighting the influence of a wide array of substituent variation on the photophysical properties via UV-vis absorption, fluorescence spectra and electrochemical methods. The results show that the cyclized hexabenzoovalenes present a stronger spectroscopic red-shift than the corresponding dinaphthopyrenes. X-ray diffraction analysis suggests that intermediate 3hx containing two nitro groups forms a trans-configuration with twisted structures. Our systematic investigation might provide a realistic design strategy to construct large one-dimensional and two-dimensional materials via bottom-up approaches.

19.
ACS Appl Mater Interfaces ; 11(34): 30786-30792, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31362488

RESUMO

Surface defects in semiconductors have a significant role to tune the photocatalytic reactions. However, the dominant studied defect type is oxygen vacancy, and metal cation vacancies are seldom explored. Herein, bismuth vacancies are engineered into BiOBr through ultrathin structure control and employed to tune photocatalytic CO2 reduction. VBi-BiOBr ultrathin nanosheets deliver a high selective CO generation rate of 20.1 µmol g-1 h-1 in pure water, without any cocatalyst, photosensitizer, and sacrificing reagent, roughly 3.8 times higher than that of BiOBr nanosheets. The increased CO2 reduction activity is ascribed to the tuned electronic structure, optimized CO2 adsorption, activation, and CO desorption process over VBi-BiOBr ultrathin nanosheets. This work offers new opportunities for designing surface metal vacancies to optimize the CO2 photoreduction performances.

20.
PLoS One ; 14(8): e0221506, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442272

RESUMO

Expression of FosB gene in striatum is essential in addiction establishment. Activated glucocorticoid receptors (GRs) induce FosB gene expression in response to stressor. Therefore, elevation of FosB expression in striatum serves as one mechanism by which stress increases risk for addiction. In this study, adult male Sprague-Dawley rats were used to investigate whether chronic stress result in histone modifications at FosB gene promoter in striatum and how these histone modifications affect FosB expression and the establishment of addiction behavior after administration of drugs of abuse. Animals were randomly assigned to three groups: Electric foot shock (EFS) group received 7-day EFS to induce chronic stress; electric foot shock plus mifepristone (EFS + Mif) group were injected with mifepristone, a nonspecific GRs antagonist, before EFS; control group did not receive any EFS. All groups then received 2-day conditioned place preference (CPP) training with morphine (5 mg/kg body weight) to test vulnerability to drug addiction. Before and after morphine administration, FosB mRNA in striatum was quantified by real-time RT-PCR. Levels of histone H3/H4 acetylation and histone H3K4 dimethylation at FosB promoter in striatum after morphine administration were measured by using chromatin immunoprecipitation (ChIP) plus real-time PCR. EFS group had stronger place preference to morphine and had significantly higher level of FosB mRNA in striatum than the other two groups. H3K4 dimethylation was 2.6-fold higher in EFS group than control group, while no statistical difference in H3/H4 acetylation. Mifepristone administration before EFS decreased histone H3K4 dimethylation and FosB mRNA in striatum, and also diminished morphine-induced conditioned place preference. Altogether, increased level of H3K4 dimethylation at FosB promoter in striatum is partially dependent on the activation of GR and responsible for the elevated level of morphine-induced FosB mRNA in chronic stressed animals.

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