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Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTXdeficiency to drive full-blown APL in mice. Although STRN3-RARAleukemia quickly relapses after all-transretinoic acid treatment, it can be restrained by cepharanthine.

The gas phase acidity and proton affinity of nucleobases that are substrates for the DNA repair enzyme AlkB have been examined using both computational and experimental methods. These thermochemical values have not heretofore been measured and provide experimental data that help benchmark the theoretical results. We also use our gas phase results to lend insight into the AlkB mechanism, particularly in terms of the role AlkB plays in DNA repair, versus its complementary enzyme AlkA.

AbstractThe concrete-filled steel tube reinforced concrete (CFST-RC) composite shear wall is a new structure utilising the advantages of a reinforced concrete shear wall and CFST column. The finite element (FE) model for CFST-RC shear walls was validated by experimentation. Under the axial compression and cyclic loads, the mechanical properties were studied by changing the structure and material. Numerical simulation results indicate that compared with the concrete inside the tube, the concrete outside the tube can better limit the deformation of the steel tube, so it significantly affects the axial compression performance. Compared with the concrete, the steel tubes can effectively improve the seismic performance. However, when the steel content and steel tube strength increase to a certain value, the seismic performance decreases due to the synergistic effect of the concrete and the steel tube. Finally, a simple method for calculating the elastic modulus of shear walls is proposed based on the theory of composite materials. From the FE simulation results, the influencing factors of axial compression and seismic performance of CFST-RC shear walls with different parameters were also analysed, which can provide technical support for the design of shear walls and their safe application in practical engineering.

Most human immunodeficiency virus (HIV) infections occur in cisgender women in resource-limited settings. In women, self-protection with emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) constitutes a major pillar of HIV prevention. However, clinical trials in women had inconsistent outcomes, sparking uncertainty about adherence requirements and reluctance in evaluating on-demand regimens. We analyzed data from published FTC/TDF-PrEP trials to establish efficacy ranges in cisgender women. In a ‘bottom-up’ approach, we modeled hypotheses in the context of risk-group-specific, adherence–efficacy profiles and challenged those hypotheses with clinical data. We found that different clinical outcomes were related to the proportion of women taking the product, allowing coherent interpretation of the data. Our analysis showed that 90% protection was achieved when women took some product. We found that hypotheses of putative male/female differences were either not impactful or statistically inconsistent with clinical data. We propose that differing clinical outcomes could arise from pill-taking behavior rather than biological factors driving specific adherence requirements in cisgender women.

An efficient new synthesis of a peroxisome proliferator-activated receptor delta agonist fonadelpar was developed. The new process features a more practical approach to construct the ethylene linker of fonadelpar by coupling an advanced aldehyde and a ketone via Claisen–Schmidt condensation, which is followed by hydrogenation and an optimized process to obtain the isoxazole moiety. The convergent synthesis provides a robust and scalable approach to prepare the drug candidate in significantly fewer steps and with a higher yield.

A-to-I RNA editing is widespread in human cells but is uncommon in the coding regions of proteins outside the nervous system. An unusual target for recoding by the adenosine deaminase ADAR1 is the pre-mRNA of the base excision DNA repair enzyme NEIL1 that results in the conversion of a lysine (K) to arginine (R) within the lesion recognition loop and alters substrate specificity. Differences in base removal by unedited (UE, K242) vs edited (Ed, R242) NEIL1 were evaluated using a series of oxidatively modified DNA bases to provide insight into the chemical and structural features of the lesion base that impact isoform-specific repair. We find that UE NEIL1 exhibits higher activity than Ed NEIL1 toward the removal of oxidized pyrimidines, such as thymine glycol, uracil glycol, 5-hydroxyuracil, and 5-hydroxymethyluracil. Gas-phase calculations indicate that the relative rates in excision track with the more stable lactim tautomer and the proton affinity of N3 of the base lesion. These trends support the contribution of tautomerization and N3 protonation in NEIL1 excision catalysis of these pyrimidine base lesions. Structurally similar but distinct substrate lesions, 5-hydroxycytosine and guanidinohydantoin, are more efficiently removed by the Ed NEIL1 isoform, consistent with the inherent differences in tautomerization, proton affinities, and lability. We also observed biphasic kinetic profiles and lack of complete base removal with specific combinations of the lesion and NEIL1 isoform, suggestive of multiple lesion binding modes. The complexity of NEIL1 isoform activity implies multiple roles for NEIL1 in safeguarding accurate repair and as an epigenetic regulator.

The synthesis and release of LH and FSH in the pituitary of vertebrates are differentially regulated during gonadal development and maturation. However, the underlying neuroendocrine mechanisms remain to be fully elucidated. The present study examined the possible involvement of isotocin (Ist), an oxytocin-like neuropeptide, in the regulation of Lh and Fsh in a teleost, the ricefield eel Monopterus albus. The immunoreactive isotocin receptor 2 (Istr2) was shown to be localized to Lh but not Fsh cells. In contrast, immunoreactive isotocin receptor 1 (Istr1) was not observed in either Lh or Fsh cells in the pituitary. Interestingly, Lh cells in female ricefield eels expressed Istr2 and secreted Lh in response to Ist challenge stage-dependently and in correlation with ovarian vitellogenesis. Moreover, Ist decreased Lh contents in the pituitary of female fish, indicating its stimulatory roles on Lh release in vivo. The induction of Lh release by Ist in dispersed pituitary cells was blocked by a PLC or IP3R inhibitor but not by a PKA or PKC inhibitor, indicating the involvement of the IP3/Ca2+pathway. Collectively, the above results indicate that isotocin may bind to Istr2 to stimulate Lh release via the IP3/Ca2+pathway, and play important roles in the ovarian maturation in ricefield eels. Furthermore, the present study suggests a novel neuroendocrine mechanism underlying the differential regulation of Lh and Fsh in vertebrates.Summary sentence Isotocin binds to isotocin receptor 2 on Lh cells to simulate Lh release in ricefield eels, but seems to exert no effects on Fsh cells.

BACKGROUND:ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS:We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS:Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32–57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION:The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.

Background: As the complexity and diversity of the percutaneous coronary intervention (PCI) are being explored and reported, burgeoning research has progressed in this field. However, there is no comprehensive analysis available on PCI-related studies published in the literature. This study aimed to analyze and visualize the changes of scientific output regarding prognosis of coronary heart disease (CHD) after PCI over the past 20 years and to reveal the knowledge domain and development trends in this field by using CiteSpace software. Methods: Relevant articles published over the period 2004–2022 were retrieved from the Web of Science Core Collection database. After manual selection, qualified documents were included and recorded with the information of their title, abstract, keyword, author, descriptor, citation, identifier, publishing year and publishing organization. We transferred the data to CiteSpace V5.8.R2 (Version 5.8.R2) to draw knowledge maps and to conduct co-occurrence analysis, cluster analysis, timeline analysis, burst term detection and citation analysis. Results: A total of 14,699 literature records were found relating prognosis of CHD after PCI in the past 20 years (2004–2022), including 14,212 original articles and reviews, and they were published in 153 different journals. Publication production has increased annually and a total of 1182 authors, 796 institutes and 147 countries have contributed to these publications. Moreover, the most representative author was Gregg W Stone from the CardioVascular Research Foundation (CVRF) with 368 publications, whose team mainly focused on exploring the efficacy and safety of revascularization and the characteristics of susceptible population. The global productivity ranking was led by the USA with 3326 published papers, followed by Italy (n = 1355), Japan (n = 1080), China (n = 1075) and Germany (n = 937). And the keywords of these publications were “percutaneous coronary intervention” (n = 2271), “outcome” (n = 1756), “mortality” (n = 1730) and “impact” (n = 1334). Other commonly-used words were “predictor” (n = 1324), “intervention” (n = 1310), “angioplasty” (n = 1299), “risk” (n = 1144), “acute myocardial infarction” (n = 1136) and “artery disease” (n = 1098). Cluster analysis showed that 15 high connected clusters were generated with a modularity Q of 0.831 and a weighted mean silhouette of 0.9388 by applying the log-likelihood ratio algorithm, and the top 5 clusters were #0 optical coherence tomography, #1 dual antiplatelet therapy, #2 bleeding, #3 clopidogrel and #4 thrombus aspiration. Furthermore, the frontiers in the field of prognosis of CHD after PCI mainly involved “decision making”, “reperfusion”, “angioplasty”, “balloon”, “unstable angina”, “dual antiplatelet therapy”, “cardiac surgical score”, “restenosis”, “reperfusion”, “thrombolytic therapy”, etc. Conclusions: To sum up, efficacy and safety of different types of stents, the risk factors of restenosis and thrombotic events after PCI, early risk assessment, and secondary prevention and complications of patients with CHD after PCI were research hotspots and frontier topics in the area by bibliometric analysis. The results could provide a comprehensive overview of the research hotspots and frontier topics relating prognosis of CHD after PCI, promoting a better understanding of the knowledge domain and development trends in this field during the past 20 years.

Objective: To develop and validate a multivariate prediction model to estimate the risk of coronary heart disease (CHD) in middle-aged and elderly people and to provide a feasible method for early screening and diagnosis in middle-aged and elderly CHD patients. Methods: This study was a single-center, retrospective, case–control study. Admission data of 932 consecutive patients with suspected CHD were retrospectively assessed from September 1, 2020 to December 31, 2021 in the Department of Integrative Cardiology at China-Japan Friendship Hospital. A total of 839 eligible patients were included in this study, and 588 patients were assigned to the derivation set and 251 as the validation set at a 7:3 ratio. Clinical characteristics of included patients were compared between derivation set and validation set by univariate analysis. The least absolute shrinkage and selection operator (Lasso) regression analysis method was performed to avoid collinearity and identify key potential predictors. Multivariate logistic regression analysis was used to construct a clinical prediction model with identified predictors for clinical practice. Bootstrap validation was used to test performance and eventually we obtained the actual model. And the Hosmer–Lemeshow test was carried out to evaluate the goodness-fit of the constructed model. The area under curve (AUC) of receiver operating characteristic (ROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were plotted and utilized with validation set to comprehensively evaluate the predictive accuracy and clinical value of the model. Results: A total of eight indicators were identified as risk factors for the development of CHD in middle-aged and elderly people by univariate analysis. Of these candidate predictors, four key parameters were defined to be significantly related to CHD by Lasso regression analysis, including age (OR 1.034, 95% CI 1.002 ~ 1.067, P= 0.040), hemoglobin A1c (OR 1.380, 95% CI 1.078 ~ 1.768, P= 0.011), ankle-brachial index (OR 0.078, 95% CI 0.012 ~ 0.522, P = 0.009), and brachial artery flow-mediated vasodilatation (OR 0.848, 95% CI 0.726 ~ 0.990, P= 0.037). The Hosmer–Lemeshow test showed a good calibration performance of the clinical prediction model (derivation set, χ2= 7.865, P= 0.447; validation set, χ2= 11.132, P= 0.194). The ROCs of the nomogram in the derivation set and validation set were 0.722 and 0.783, respectively, suggesting excellent predictive power and suitable performance. The clinical prediction model presented a greater net benefit and clinical impact based on DCA and CIC analysis. Conclusion: Overall, the development and validation of the multivariate model combined the laboratory and clinical parameters of patients with CHD, which could be beneficial to the individualized prediction of middle-aged and elderly people, and helped to facilitate clinical assessments and decisions during treatment and management of CHD.

The gas-phase acidity and proton affinity of nucleobases that are substrates for the enzyme Plasmodium falciparumhypoxanthine-guanine-(xanthine) phosphoribosyltransferase (PfHG(X)PRT) have been examined using both computational and experimental methods. These thermochemical values have not heretofore been measured and provide experimental data to benchmark the theoretical results. PfHG(X)PRT is a target of interest in the development of antimalarials. We use our gas-phase results to lend insight into the PfHG(X)PRT mechanism, and also propose kinetic isotope studies that could potentially differentiate between possible mechanisms.

Amino-functional graphene-sponge composites decorated by graphene nanodots (G-GND/S) were synthesized. The preparation technology prevents the loss of nano-materials and reduces the amount of graphene addition. G-GND/S was used as adsorbents to remove formaldehyde, and then their performances for formaldehyde adsorption were evaluated by dynamic adsorption experiment. The adsorption properties of three different materials: sponge, graphene-sponge, and G-GND/S, the breakthrough time and adsorption capacity had been compared, the results showed G-GND/S had better formaldehyde adsorption properties with longer breakthrough time (~2137 min/g) and adsorption ability of formaldehyde (22.8 mg/g). Large amounts of amine groups were the most important factor for the strength enhancement of the adsorption efficiency.