Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

Association between alcohol consumption and sleep traits: observational and mendelian randomization studies in the UK biobank.

Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.

The density of the inner cell mass is a new indicator of the quality of a human blastocyst: a valid supplement to the Gardner scoring system.

STUDY QUESTION: Can the density of the inner cell mass (ICM) be a new indicator of the quality of the human blastocyst? SUMMARY ANSWER: The densification index (DI) developed in this study can quantify ICM density and provide positive guidance for ploidy, pregnancy, and live birth. WHAT IS KNOWN ALREADY: In evaluating the quality of ICM, reproductive care clinics still use size indicators without further evaluation. The main disadvantage of this current method is that the evaluation of blastocyst ICM is relatively rough and cannot meet the needs of clinical embryologists, especially when multiple blastocysts have the same ICM score, which makes them difficult to evaluate further. STUDY DESIGN, SIZE, DURATION: This observational study included data from 2272 blastocysts in 1991 frozen-thawed embryo transfer (FET) cycles between January 2018 to November 2021 and 1105 blastocysts in 430 preimplantation genetic testing cycles between January 2019 and February 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: FET, ICSI, blastocyst culture, trophectoderm biopsy, time-lapse (TL) monitoring, and next-generation sequencing were performed. After preliminary sample size selection, the 11 focal plane images captured by the TL system were normalized and the spatial frequency was used to construct the DI of the ICM. MAIN RESULTS AND THE ROLE OF CHANCE: This study successfully constructed a quantitative indicator DI that can reflect the degree of ICM density in terms of fusion and texture features. The higher the DI value, the better the density of the blastocyst ICM, and the higher the chances that the blastocyst was euploid (P < 0.001) and that pregnancy (P < 0.001) and live birth (P = 0.005) were reached. In blastocysts with ICM graded B and blastocysts graded 4BB, DI was also positively associated with ploidy, pregnancy, and live birth (P < 0.05). ROC analysis showed that combining the Gardner scoring system with DI can more effectively predict pregnancy and live births, when compared to using the Gardner scoring system alone. LIMITATIONS, REASONS FOR CAUTION: Accurate calculation of the DI value places high demands on image quality, requiring manual selection of the clearest focal plane and exposure control. Images with the ICM not completely within the field of view cannot be used. The association between the density of ICM and chromosomal mosaicism was not evaluated. The associations between the density of ICM and different assisted reproductive technologies and different culture conditions in embryo laboratories were also not evaluated. Prospective studies are needed to further investigate the impact of ICM density on clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: ICM density assessment is a new direction in blastocyst assessment. This study explores new ways of assessing blastocyst ICM density and develops quantitative indicators and a corresponding qualitative evaluation scheme for ICM density. The DI of the blastocyst ICM developed in this study is easy to calculate and requires only TL equipment and image processing, providing positive guidance for clinical outcomes. The qualitative evaluation scheme of ICM density can assist embryologists without TL equipment to manually evaluate ICM density. ICM density is a simple indicator that can be used in practice and is a good complement to the blastocyst scoring systems currently used in most centers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research & Development Program of China (2021YFC2700603). The authors report no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

The function and mechanism of Human nasal mucosa-derived mesenchymal stem cells in allergic rhinitis in mice.

PURPOSE: To investigate the immunomodulatory effects and potential mechanisms of human nasal mucosa-derived mesenchymal stem cells(hNMSCs) on mouse allergic rhinitis, and to compare them with human umbilical cord-derived mesenchymal stem cells (hUCMSCs). METHOD: hNMSCs and hUCMSCs were isolated and cultured for identification from human nasal mucosa and umbilical cord tissues. A co-culture system of LPS-stimulated RAW264.7 cells/mouse peritoneal macrophages and MSCs was employed.Changes in inflammatory factors in RAW264.7 cells and the culture medium as well as the expression of NF-κB signaling pathway in RAW264.7 cells were detected. Forty-eight BALB/c mice were randomly divided into control, OVA, hNMSCs, and hUCMSCs groups. An allergic rhinitis (AR) model was established through ovalbumin (OVA) stimulation and treated with hNMSCs and hUCMSCs. Subsequent assessments included related symptoms, biological changes, and the expression of the NF-κB signaling pathway in the nasal mucosa of mice. RESULTS: MSCs can be successfully isolated from human nasal mucosa. Both hNMSCs and hUCMSCs interventions significantly reverseed the inflammation induced by LPS and suppressed the upregulation of the NF-κB signaling pathway in RAW264.7 cells. Treatment with hNMSCs and hUCMSCs alleviated mouse allergic symptoms, reduced levels of total IgE, OVA-specific IgE and IgG1 in mouse serum, TH2-type cytokines and chemokines in mouse nasal mucosa, and TH2-type cytokines in mouse spleen culture medium, while also inhibiting the expression of the NF-κB signaling pathway in the nasal mucosa of mice. moreover, the hNMSCs group showed a more significant reduction in OVA-specific IgG1 in serum and IL-4 expression levels in mouse spleen culture medium compared to the hUCMSCs group. CONCLUSION: Our findings suggest that hNMSCs can ameliorate allergic rhinitis in mice, with a certain advantage in anti-inflammatory effects compared to hUCMSCs. The NF-κB pathway is likely involved in the anti-inflammatory regulation process by hNMSCs.Therefore, hNMSCs might represent a novel therapeutic approach for allergic rhinitis.

Establishment of self-reported hearing cut-off value on the Chinese version of short form of speech, spatial and qualities of hearing scale (SSQ12).

OBJECTIVE: The aim of this study was to evaluate the efficacy of the Chinese version of Speech, Spatial and Qualities of Hearing Scale (C-SSQ12) in the Chinese Mandarin-speaking population and to determine its screening cut-off value by comparing measured pure-tone average (PTA), the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S) scores and C-SSQ12 scores. DESIGN: All participants completed the C-SSQ12 questionnaire and underwent the pure-tone audiometry. Older subjects aged ≧ 60 years completed the HHIE-S questionnaire. The optimal cut-off value for the C-SSQ12 as a hearing screening tool was calculated by comparing different cut-offs and hearing thresholds. STUDY SAMPLE: A total of 300 subjects were recruited. RESULTS: There was a negative correlation between C-SSQ12 scores and HHIE-S scores (r = -0.749). C-SSQ12 scores were negatively correlated with PTA (r = -0.507; r = -0.542). The best cut-off value for the C-SSQ12 was 6.0, with a sensitivity of 78.2%, specificity of 80.3%, positive predictive value of 63.7% and negative predictive value of 97.0% (PTA > 40dBHL for bilateral ears). CONCLUSIONS: Compared to mild hearing loss, the C-SSQ12 is a reliable and validated hearing screening tool with increased sensitivity for detecting moderate-to-severe hearing loss.

Genome-Wide Characterization of the BTB Gene Family in Poplar and Expression Analysis in Response to Hormones and Biotic/Abiotic Stresses.

The BTB (Broad-complex, tramtrack, and bric-a-brac) gene family, characterized by a highly conserved BTB domain, is implicated in a spectrum of biological processes, encompassing growth and development, as well as stress responses. Characterization and functional studies of BTB genes in poplar are still limited, especially regarding their response to hormones and biotic/abiotic stresses. In this study, we conducted an HMMER search in conjunction with BLASTp and identified 95 BTB gene models in Populus trichocarpa. Through domain motif and phylogenetic relationship analyses, these proteins were classified into eight families, NPH3, TAZ, Ankyrin, only BTB, BACK, Armadillo, TPR, and MATH. Collinearity analysis of poplar BTB genes with homologs in six other species elucidated evolutionary relationships and functional conservations. RNA-seq analysis of five tissues of poplar identified BTB genes as playing a pivotal role during developmental processes. Comprehensive RT-qPCR analysis of 11 BTB genes across leaves, roots, and xylem tissues revealed their responsive expression patterns under diverse hormonal and biotic/abiotic stress conditions, with varying degrees of regulation observed in the results. This study marks the first in-depth exploration of the BTB gene family in poplar, providing insights into the potential roles of BTB genes in hormonal regulation and response to stress.

Metabolomics analysis reveals cytotoxic effects of ouabain towards psoriatic keratinocytes via impairment of glutathione metabolism.

Ouabain is a cardiac glycoside long studied for treating heart diseases, but the attempts to evaluate its anti-psoriatic activity have not been reported. We aimed to explore the effects of ouabain on proliferation and metabolism towards psoriatic keratinocytes. In human HaCaT keratinocytes, ouabain potently decreased viability, promoted apoptosis and caused G2/M cycle arrest. Metabolomics analysis indicated that ouabain markedly impaired glutathione metabolism. The solute carrier family 7 member 11 (SLC7A11) is an amino acid transporter highly specific to cysteine, which is critical for glutathione synthesis. Ouabain downregulated SLC7A11, reduced cysteine uptake and subsequently inhibited glutathione synthesis, probably through inhibiting Akt/mTOR/beclin axis that regulate protein activity of SLC7A11. The impaired glutathione synthesis and oxidative stress caused by ouabain may contribute to its cytotoxicity towards psoriatic keratinocytes. Our results provide experimental evidence supporting further study of ouabain as a potential anti-psoriatic agent.

Dual-mode tunable absorber based on quasi-bound states in the continuum.

In this Letter, we propose a novel, to the best of our knowledge, dual-mode tunable absorber that utilizes quasi-bound states in the continuum (q-BIC) based on the periodically arranged silicon cylinders tetramer. By introducing asymmetry perturbation through manipulating the diameters of diagonal cylinders in the all-dielectric structure, the symmetry-protected BIC (SP-BIC) transforms into q-BIC, leading to the emergence of one transmission and one reflection Fano-like resonant mode. The relationship between the quality factor of each mode and the asymmetry parameter α is analyzed, revealing an exponential dependence with an exponent of -1.75, i.e., Q ∝ α-1.75. To explain the underlying physics, multipole decomposition analysis and Aleksandra's theory are applied. Subsequently, a monolayer graphene is introduced to the all-dielectric structure to demonstrate the application of the dual-mode tunable absorber. When the critical coupling condition is satisfied, each mode can achieve the theoretical maximum absorption, demonstrating the distinctive capability of our proposed absorber for tuning and efficient light absorption. This research provides valuable insights into light-matter interactions and opens up possibilities for optical modulation and the development of graphene-based devices.

Effects of peripheral blood leukocyte count and tumor necrosis factor-alpha on early death in acute promyelocytic leukemia.

BACKGROUND: Early death remains a major factor in survival in APL. We aimed to analyze the risk factors for differentiation syndrome and early death in acute promyelocytic leukemia (APL). METHODS: The clinical data of APL patients who were newly diagnosed at Mianyang Central Hospital from January 2013 to January 2022 were retrospectively analyzed. RESULTS: Eighty-six newly diagnosed APL patients (37 males and 49 females) were included in this study. The median age was 46 (17-75) years. Sixty-one patients (70.9%) had low/intermediate-risk APL, and 25 patients (29.1%) had high-risk APL. The incidence of differentiation syndrome (DS) was 62.4%. The multivariate analysis showed that a peak white blood cell (WBC) count ≥16 × 10^9/L was an independent risk factor (OR = 11.000, 95% CI: 2.830-42.756, P = 0.001) for DS in all APL patients, while a WBC count ≥10 × 10^9/L on Day 5 was an independent risk factor for DS in low-intermediate risk APL patients (OR = 9.114, 95% CI: 2.384-34.849, P = 0.001). There were 31 patients (36.5%) with mild DS and 22 patients (25.9%) with severe DS. The multivariate analysis showed that WBC count ≥23 × 10^9/L at chemotherapy was an independent risk factor for severe DS (OR = 10.500, 95% CI: 2.344-47.034, P = 0.002). The rate of early death (ED) was 24.4% (21/86). The multivariate analysis showed that male gender (OR = 7.578,95% CI:1.136-50.551, P = 0.036), HGB < 65 g/L (OR = 16.271,95% CI:2.012-131.594, P = 0.009) and WBC count ≥7 × 10^9/L on Day 3(OR = 23.359,95% CI:1.825-298.959, P = 0.015) were independent risk factors for ED. The WBC count at diagnosis, WBC count on Day 3 and WBC count on Day 5 had moderate positive correlations with tumor necrosis factor-α (TNF-α) at diagnosis, and the correlation coefficients were 0.648 (P = 0.012), 0.615 (P = 0.033), and 0.609 (P = 0.035), respectively. The WBC count had no correlation with IL-6. CONCLUSION: During induction treatment, cytotoxic chemotherapy may need to be initiated to reduce the risk of DS for APL patients with a low-intermediate risk WBC count ≥10 × 10^9/L on Day 5 or for all patients with a peak WBC count ≥16 × 10^9/L. Patients with WBC > 7 × 10^9/L on Day 3 have a higher risk of ED. Leukocyte proliferation is associated with TNF-α rather than IL-6, and TNF-α may be a potential biomarker for predicting ED.

A novel PEGylated form of granulocyte colony-stimulating factor, mecapegfilgrastim, for peripheral blood stem cell mobilization in patients with hematologic malignancies.

BACKGROUND: The Pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) has longer half-life and is given once only, which is more comfortable for patients. We aimed to evaluate the efficacy of mecapegfilgrastim for hematopoietic stem cell (HSC) mobilization in patients with hematologic malignancies and to explore the potential factors related to HSC mobilization. METHODS: A retrospective analysis was performed on patients who underwent HSC mobilization in the hematology department of Mianyang Central Hospital from April 2016 to November 2022. The number of CD34 + cells collected was compared between the patients receiving mecapegfilgrastim (PEG group) and those receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF group), and the possible factors for mobilization failure were analyzed. RESULTS: The success rates of collecting CD34 + cells in the PEG group and rhG-CSF group were 80.6% and 67.7%, respectively (χ = 1.444, P = 0.229). The median CD34 + cell counts were 3.62 × 10^6/kg and 2.92 × 10^6/kg (P = 0.178), respectively. After combination with plerixafor for mobilization, the median number of CD34 + cells collected in the PEG group and rhG-CSF group were 3.64 × 10^6/kg and 3.92 × 10^6/kg, respectively, with no significant difference (P = 0.754). There was no significant difference in hematopoietic cell recovery or infection between the groups (P > 0.05). Multivariate analysis showed that more than 5 cycles of chemotherapy (OR = 15.897, 95% CI: 1.766-143.127, P = 0.014), a precollection WBC count < 32 × 10^9/L (OR = 14.441, 95% CI: 2.180-95.657, P = 0.006) and a precollection to premobilization lymphocyte ratio < 1.7 (OR = 11.388, 95% CI: 2.129-60.915, P = 0.004) were independent risk factors for HSC mobilization failure. CONCLUSIONS: The HSC mobilization efficacy of mecapegfilgrastim in patients with hematologic malignancies was comparable to that of rhG-CSF, and combination with plerixafor for mobilization was feasible and effective. Patients with more than 5 cycles of chemotherapy before HSC mobilization, a precollection WBC count lower than 32 × 10^9/L, and a precollection lymphocyte count less than 1.7 times the premobilization lymphocyte count have a high probability of HSC mobilization failure.