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As a composer who remained true to traditional style and compositional rigour during the Romantic period, Bruckner's work is permeated with both religious ethics and Romantic catharsis. It adds a unique dimension to the religious music of the Romantic period.

In recent years, China’s industrialization and urbanization have deepened, and the economy has grown considerably. But at the same time, they have also brought about many environmental problems. As a pillar of the national economy, the iron and steel (IS) industry is one of the most emitting and energy-consuming sub-sectors of the industrial sector. It is also one of the industries with the most severe overcapacity problem in China. In this paper, we explore the impact of capacity utilization on carbon dioxide emission based on panel data of China’s iron and steel industry from 2005 to 2014. We also tested the heterogeneity in different regions and different sub-samples. Results show that capacity utilization and carbon dioxide emission are positively correlated. However, the impact of capacity utilization on carbon dioxide emission differs when considering regional heterogeneity. Results in all three regions show a positive relationship between capacity utilization and carbon dioxide emission, but the impact intensity is strongest in the western region, followed by the eastern and central regions. Moreover, capacity utilization impacts carbon dioxide emission by influencing firm numbers in the iron and steel industry and energy consumption. Further analysis shows that there exists a threshold effect in different stages of energy consumption and energy structure. Finally, some findings and practical policy recommendations are provided.

Patients suffering diabetic bone defects still need some new and effective strategies to achieve enhanced prognostic effects. Although medical implants are the common treatment of bone defects, the excessive oxidative stress and high risk of bacterial infection in diabetes mellitus lead to a higher risk of implant failure. To improve the healing ability of diabetic bone defects, herein, polyetheretherketone (PEEK) was modified through a developed layer-by-layer (LBL) construction strategy to obtain multifunctional PEEK (SP@(TA-GS/PF)*3) by the assembly of tannic acid (TA), gentamicin sulfate (GS) and Pluronic F127 (PF127) on the basis of prepared porous PEEK through sulfonation (SPEEK). The prepared SP@(TA-GS/PF)*3 exhibited sustained antimicrobial activity and enhanced the differentiation of osteoblast (MC3T3-E1) for needed osteogenesis. Moreover, SP@(TA-GS/PF)*3 scavenged excessive oxidative stress to promote the growth of H

Previous studies have reached different conclusions regarding the effect of vitamin D supplementation and the incidence of fractures in the elderly. As more and more high-quality studies are published, an updated Meta-analysis is needed. We searched the PubMed, Cochrane Library, Embase, and Web of Science databases (from creation date to September 10, 2022) using the keywords vitamin D and fracture. We also searched at https://clinicaltrials.gov/ to search for unpublished clinical studies. Randomized clinical trials comparing vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling adults older than 50 years was included. Hip fracture was defined as the primary outcome. Secondary outcomes were total fracture, vertebral fracture, and nonvertebral fracture. The protocol is available in PROSPERO (ID: CRD42022360619). A total of 15 randomized trials involving 53291 participants fulfilled the inclusion criteria. Supplementing with vitamin D had no significant effect on reducing the incidence of hip fracture (RR = 1.18, [95% CI, 0.99 − 0.41]), total fracture (RR = 1.01, [95% CI, 0.92–1.11]), vertebral fracture (RR = 0.97, [95% CI, 0.54–1.77]), or non-vertebral fracture (RR = 1.04, [95% CI, 0.97–1.12]). On the contrary, taking high doses of vitamin D once a year may increase the incidence of hip fractures (OR = 1.44, [95% CI, 1.03–2.02]). Besides, being in a low-light environment increased the incidence of hip fractures (OR = 1.25, [95% CI, 1.01–1.55]). There were no significant findings from subgroup analyses based on sex, fracture history, calcium consumption, baseline 25-hydroxyvitamin levels, or trial durations. Vitamin D use in community-dwelling older adults does not reduce the risk of fracture. High doses of vitamin D at one-year intervals may even increase the risk of fracture. In addition, older adults in low sunlight exposure areas had a higher risk of fracture regardless of vitamin D use.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, which makes the prognostic prediction challenging. Cuproptosis, a recently discovered mode of regulated cell death (RCD), may be associated with the development of multiple diseases. However, the prognostic value of cuproptosis-related genes in NSCLC remains uncertain. In this study, we obtained the mRNA expression profiles and corresponding clinical data of NSCLC patients online and made some analysis. Our results showed that 16 cuproptosis-related genes were differentially expressed between NSCLC and normal tissues. GO and KEGG enrichment analysis revealed that these genes were mainly enriched in cellular energy metabolism-related pathways. According to the survival analysis of these 16 genes, the up-regulation of 13 genes predicted a poor overall survival (OS) rate in patients with NSCLC. Then, A 13-genes signature model was built to distinguish the patients into two risk groups. Patients in the high-risk group showed significantly a poor OS rate compared with patients in the low-risk group (P P 2+ levels before and after gene knockdown, we found that four genes may affect the progression of NSCLC by regulating cuproptosis. In conclusion, a novel cuproptosis-related gene signature can predict the prognostic of NSCLC. Targeting cuproptosis may be a therapeutic approach for NSCLC.

The content of deferasirox (DEF) in plasma is significant in β-thalassemia patient that needs long-term transfusion therapy, while the effective and simple strategy for DEF monitoring is still limited. The carbon dots (CDs) prepared from citric acid monohydrate and glutathione exhibit weakly modulated fluorescence intensity to several common metal ions containing Cu

Leading by cytotoxicity against HepG2 cells, bioactivity-guided fractionation of the EtOAc fraction from Artemisia atrovirens led to the isolation of 18 new guaianolide dimers, artematrolides A–R and lavandiolides A, B, C, H, and J. Eight compounds (1, 4, 10, 12, 13, and 19–21) were unambiguously confirmed by the single-crystal X-ray diffraction analyses, and the others were elucidated based on IR, UV, HRESIMS, 1D and 2D NMR experiments, and comparison of the experimental and calculated ECD data. Structurally, all of them were [4 + 2] Diels–Alder adducts of two monomeric guaianolides. The isolates were evaluated for their cytotoxicity against three human hepatoma cell lines, and 19 compounds demonstrated cytotoxicity against HepG2, SMMC-7721, and Huh7 cell lines. Especially, compounds 1, 12, 14, and 15 exhibited cytotoxicity with IC50 values of 4.4, 3.8, 7.6, and 6.7 μmol/L (HepG2), 9.6, 4.6, 6.6, and 6.0 μmol/L (SMMC-7721), and 7.6, 4.5, 6.9, and 5.6 μmol/L (Huh7), respectively. Notably, compound 12 showed the most promising activity against three human hepatoma cell lines and dose-dependently inhibited cell migration and invasion, induced G2/M cell cycle arrest and cell apoptosis in HepG2 cells, down-regulated the expression of BCL-2 and PARP-1, and activated PARP-1 to up-regulate the expression of cleaved-PARP-1., Graphical abstract Twenty-three guaianolide dimers were isolated from Artemisia atrovirens. Nineteen compounds demonstrated cytotoxicity against HepG2, SMMC-7721, and Huh7 cell lines. The mechanism of the most active compound 12 was investigated.Image 1

PURPOSE: To compare chromosomal aberrations and aneuploidy features in (i) blastocysts following intracytoplasmic sperm injection (ICSI) and trophectoderm (TE) biopsy using preimplantation genetic screening (PGS) and (ii) early spontaneous abortion chorionic villus biopsies (SA-CVB) using single-nucleotide polymorphism (SNP) array detection. METHODS: We retrospectively reviewed the data for 1014 TEs from 220 PGS cycles and 1724 SA-CVBs originating from naturally pregnant couples and patients undergoing assisted reproductive technology (ART) during 2017 to 2018. SNP array was applied in both PGS and SA-CVBs detection. Aberrations were defined, and the frequency and ratio of each chromosome aberration were compared between the two groups. RESULTS: There were more abnormalities in TEs in the form of complex chromosome aneuploidies and monosomies, while SA-CVBs had more trisomies, sex chromosome abnormalities, and polyploidies. In both groups, chromosomal aneuploidies (including monosomies and trisomies) were confined to chromosomes 14, 15, 16, 18, 21, and 22, but showed varying distributions across the groups. Aneuploidy of chromosome 22 was most frequent in TEs, whereas that of chromosome 16 predominated in SA-CVBs. Among the sex chromosome abnormalities, X monosomies were significantly more prevalent in SA-CVBs. CONCLUSIONS: Chromosomal aberrations and aneuploidy manifested specific characteristics that differed between TEs and SA-CVBs, which indicates that distinct chromosomal abnormalities can affect certain developmental stages of embryos. Further analysis is needed to explore the chromosomal mechanisms affecting embryo development and implantation. Such information will help clinical assessments in prenatal diagnosis and reduce the incidence of genetically abnormal fetuses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-019-01682-9) contains supplementary material, which is available to authorized users.

In this study, calcium alginate/agar (CA/Ag) 3D structures were printed as strip assembles with high resolution and tailorable mechanical properties by a thermal-assisted 3D printing method. Specifically, alginate and agar were combined to minimize the Barus effect, and further improved the printing resolution. The introduction of agar altered the rheological properties of the ink, such as increasing its viscosity to obtain a 3D printing structure with higher precision. The alginate chains were crosslinked by calcium ions, which connected different layers together and had good interface adhesion among layers in 3D printing constructs. In addition, after printing, the crosslinking of calcium alginate affected the swelling behavior and mechanical properties of printing gels. The width of extrusion gel stripes was close to the diameter of needle, demonstrating that the printing resolution is well controlled by minimizing the Barus effect of concentrated solution. Furthermore, the printed gel structures showed low cytotoxicity, indicating that these biocompatible 3D printed structures are promising substitutes for tissue engineering. Most importantly, soft polyacrylamide (PAAm) network was introduced into 3D printed CA/Ag hydrogels to toughen interfacial surfaces between adjacent stripes by combination of rigid calcium alginate network and soft PAAm network. These 3D printed hydrogels with excellent mechanical properties, high compatibility and high shape fidelity can be regarded as a potential candidate in bio-medical field.

Estrogen receptor (ER)-negative breast cancers are aggressive and unresponsive to antiestrogens, and current therapeutic modalities for ER-negative breast cancer patients are usually associated with strong toxicity and side effects. Less toxic and more effective targeted therapies are urgently needed to treat this type of breast cancer. Here, we report that Broussoflavonol B, a chemical purified from the bark of the Paper Mulberry tree (Broussonetia papyrifera) exhibited potent growth inhibitory activity in ER-negative breast cancer MDA-MB-231 cells at sub-micromolar concentrations. Broussoflavonol B induced cell cycle arrest at both the G₀/G₁ and G₂/M phases accompanied by a downregulation of c-Myc protein, a upregulation of the cell cycle inhibitory proteins p16(INK4a), p19(INK4D) and p21(WAF1/CIP1) and a down-regulation of the expression levels of the G₂/M regulatory proteins such as cyclin B1, cdc2 and cdc25C. Broussoflavonol B also induced apoptotic cell death characterized by accumulation of the annexin V- and propidium iodide-positive cells, and cleavage of caspases 8, 9 and 3. In addition, Broussoflavonol B treatment also decreased the steady state levels of the epidermal growth factor receptor (EGFR) and ER-α36, a variant of estrogen receptor-α, and restricted growth of the stem-like cells in ER-negative breast cancer MDA-MB-231 cells. Our results thus indicate that Broussoflavonol B is a potent growth inhibitor for ER-negative breast cancer cells and provide a rational for preclinical and clinical evaluation of Broussoflavonol B for ER-negative breast cancer therapy.

Two new prenylflavones 5,7,3′,4′-tetrahydroxy-3-methoxy-8-geranylflavone (1) and 5,7,3′,4′-tetrahydroxy-3-methoxy-8,5′-diprenylflavone (2), as well as four known ones, uralenol (3), papyriflavonol A (4), broussoflavonol B (5) and broussochalcone A (6) were isolated and purified from an ethyl acetate-soluble extract of the barks of Broussonetia papyrifera. Their structures were determined with the spectroscopic methods including HR-EI-MS, 1D and 2D NMR. We found that compounds 2–6 showed potent anti-proliferation effects on ER-positive breast cancer MCF-7 cells in vitro. The IC50 values of compounds 2 and 5 were 4.41 and 4.19 μM respectively after the treatment of 72 h. We also found that compounds 2 and 5 strongly down-regulated expression concentrations of estrogen receptor-α (ER-α) and were able to inhibit tumor growth in a xenograft model of the human breast cancer line BCAP-37 in vivo. Our results demonstrated that prenylflavones from B. Papyrifera exhibit potent anti-tumor activity.

Evidence suggests that estrogen signaling is involved in sex differences in the prevalence rates and control of asthma, but the expression patterns of estrogen receptor variants and estrogen function in the lung are not well established. We investigated the expression of major estrogen receptor variants occurring naturally and after the development of allergen-induced airway hyperreactivity in a murine model of allergic asthma, along with the role of estrogen signaling in small-airway ciliary motion and smooth muscle contraction. Female BALB/c mice were sensitized with ovalbumin, and estrogen receptor expression patterns were examined by immunofluorescence and Western blot analysis. Time-lapse video and photodiode-based displacement measurement systems were used to assess the effects of estrogen signaling on airway ciliary beat frequency and smooth muscle contraction. We found that a novel variant of estrogen receptor (ER)–α, ER-α36, is expressed in airway epithelial and smooth muscle cells. ER-α36 was predominately localized on the plasma membranes of airway cells. After sensitization to allergen, the expression levels of ER-α36 increased significantly (P < 0.01), whereas the expression of ER-β and ER-α66 did not significantly change. Estrogen treatment in vitro resulted in a rapid increase in airway cilia motion in a dose-dependent fashion, but did not exert any effect on airway smooth muscle contraction. We speculate that the up-regulation of estrogen receptor expression associated with allergen-induced airway hyperresponsiveness may constitute a protective mechanism to facilitate the clearance of mucus. The identification and localization of specific estrogen receptor subtypes in the lung could lead to newer therapeutic avenues aimed at addressing sex differences of asthma susceptibility.

Icaritin, a prenylflavonoid derivative from Epimedium Genus, regulates many cellular processes. However, the function and the underlying mechanisms of icaritin in breast cancer cell growth have not been well established. Here, we report that icaritin strongly inhibited the growth of breast cancer MDA-MB-453 and MCF7 cells. At concentrations of 2-3 μM, icaritin induced cell cycle arrest at the G(2)/M phase accompanied by a down-regulation of the expression levels of the G(2)/M regulatory proteins such as cyclinB, cdc2 and cdc25C. Icaritin at concentrations of 4-5 μM, however, induced apoptotic cell death characterized by the accumulation of the annexin V- and propidium iodide-positive cells, cleavage of poly ADP-ribose polymerase (PARP) and down-regulation of the Bcl-2 expression. In addition, icaritin also induced a sustained phosphorylation of extracellular signal-regulated kinase (ERK) in these breast cancer cells. U0126, a specific ERK activation inhibitor, abrogated icaritin-induced G2/M cell cycle arrest and cell apoptosis. Icaritin more potently inhibited growth of the breast cancer stem/progenitor cells compared to anti-estrogen tamoxifen. Our results indicate that icaritin is a potent growth inhibitor for breast cancer cells and provide a rationale for preclinical and clinical evaluations of icaritin for breast cancer therapy.

The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-alpha66), its 46-kDa splice variant hER-alpha46, and the closely related hER-beta have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, and expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-alpha66, termed hER-alpha36. hER-alpha36 differs from hER-alpha66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-alpha66. It also contains three myristoylation sites postulated to direct ER-alpha36 to the plasma membrane. It is concluded that ER-alpha36 is a unique variant of ER-alpha66; ER-alpha36 is predicted to function as a dominant-negative effector of hER-alpha66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling.

The Pro12Ala and C161T polymorphisms in peroxisome proliferator-activated receptor γ (PPARγ) have been shown to be associated with carotid artery atherosclerosis. It remains unclear whether these two polymorphisms are associated with risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Therefore, the PPARγ genotypes in 99 HD patients and 149 controls were determined, and clinical characteristics among the different genotypes were compared. We found that the frequency of the Pro12Ala and C161T polymorphisms in HD patients was similar to that in healthy controls, but C161T polymorphism and T allele frequencies in HD patients with CVD were lower than that in HD patients without CVD. Carotid artery plaque (CAP) and carotid intima-media thickness (CIMT) in HD patients with CT + TT or Pro12Ala genotypes were also less than that in patients with CCor Pro12Pro genotypes, respectively. HD patients with CT + TT genotype had lower serum C reactive protein (CRP) levels, as well as higher triceps skin fold (TSF) thickness, mid arm circumference (MAC) and mean mid arm circumference (MMAC) than HD patients with CC genotype (P

Changes in serum magnesium (Mg) may affect some clinical features of patients on maintenance hemodialysis (HD). The aims of our study were to evaluate the correlation between serum Mg concentration and clinical characteristics in Chinese HD patients, and to determine whether it has any relevance for cardiovascular outcomes.98 chronic HD patients were recruited, and clinical features related to cardiovascular disease (CVD) were measured: the correlation between Mg and these characteristics was analyzed.In patients who were hypomagnesemic, serum Mg, creatinine (Scr), albumin (Alb), pre-albumin (pre-Alb) levels, protein catabolic rate per normalized body weight (nPCR), dietary protein intake (DPI), triceps skin fold (TSF) thickness, mid-arm circumference (MAC), mean mid-arm circumference (MAMC), subjective global assessment (SGA) scores and Kt/V were lower than in hypermagnesemic patients. On the other hand, the incidence of intradialytic hypotension (IDH), levels of serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), C reactive protein (CRP), high-density lipoprotein cholesterol (HDL-c) levels, carotid artery plaque (CAP), and carotid intima-media thickness (CIMT) (all p0.05, respectively) were higher in patients with low serum magnesium. Correlation analysis showed Mg to be not only positively associated with the nutritional status index, but also negatively correlated with other characteristics, such as IDH incidence, Kt/V, Ca, P, iPTH, CRP, HDL-c, CAP, CIMT (p0.05, respectively). There was no significant correlation between Mg and low-density lipoprotein cholesterol (LDL-c), lipoprotein-a (LP-a), cholesterol (TC), serum triglycerides (TG), or subjective global assessment (SGA) scores (p0.05, respectively). Multiple linear regression analysis showed that Mg was negatively associated with CIMT, a direct predictor of CVD (β coefficient=-0.260, p=0.009).It is suggested that lower serum Mg reflects poorer nutritional status and that it is also associated with other risk factors for cardiovascular disease in hemodialysis patients, such as greater incidence of IDH, poorer HD adequacy, deteriorating calcium-phosphate metabolism, inflammation and CIMT.

Accumulating experimental and clinical evidence has indicated that tumor-initiating or cancer stem-like cells are a sub-population of tumor cells capable of initiating and driving tumor growth, and cancer stem-like cells are resistant to most current cancer therapies, including chemo- and radiation therapy. More effective targeted-therapeutic approaches are urgently needed to eliminate cancer stem-like cells. Here, we report that broussoflavonol B, a chemical purified from the bark of the Paper Mulberry tree (broussonetia papyrifera), exhibited potent growth inhibitory activity towards estrogen receptor (ER)-negative breast cancer SK-BR-3 cells at sub-micromolar concentrations. Broussoflavonol B more potently inhibited growth and induced differentiation of stem-like SK-BR-3 cells-compared to the anti-estrogen tamoxifen. In addition, broussoflavonol B treatment also reduced the steady, state levels of the Human epidermal growth factor receptor-2 (HER2) and ER-α36, a variant of ER-α. Our results, thus, indicate that broussoflavonol B is a potent growth inhibitor of ER-negative breast cancer stem-like cells and provide a rationale for pre-clinical and clinical evaluation of broussoflavonol B for breast cancer therapy.

In human breast cancer, a growth status switched from estrogen-dependent to growth factor-dependent is a critical step during development of acquired tamoxifen resistance. However, the molecular mechanisms underlying this switch remain poorly understood. The Wilms' tumor suppressor gene, WT1, encodes a zinc-finger protein WT1 that functions as a transcription regulator. High levels of the WT1 expression have been associated with de novo tamoxifen resistance. The goal of this study was to investigate the function of WT1 in acquired tamoxifen resistance.A stable tamoxifen-resistance cell line MCF7(TAM) was established by selecting ER-positive breast cancer MCF7 cells in a medium containing tamoxifen. Western blot, cell growth assay and shRNA method were used to examine the role of WT1 in acquired tamoxifen resistance.MCF7(TAM) cells expressed EGFR, HER2 and WT1 at higher levels compared to tamoxifen-sensitive parental MCF7 cells. MCF7(TAM) cells responded weakly to estrogen stimulation, grew rapidly in the absence of estrogen and were insensitive to tamoxifen. We also established stable cell lines from MCF7(TAM) cells to express shRNA specific for WT1, and found expression levels of the epidermal growth factor receptor (EGFR), HER2 and estrogen receptor (ER)-α to be down-regulated in MCF7(TAM) cells with knocked-down levels of WT1 expression. MCF7(TAM) cells with WT1 expression knocked-down by shRNA still retained tamoxifen insensitivity.Our results indicated that WT1 is involved in expressional regulation of the EGFR family members and ER-α during development of acquired tamoxifen resistance.

Constitutive activation of estrogen receptor alpha (ER-alpha) expression is an early event in breast cancer tumorigenesis. However, the mechanism whereby ER-alpha is constitutively activated during transformation of normal mammary cells has not been well established. Previously, we reported that haploinsufficiency of caveolin-1, a major structural protein that forms caveolae, resulted in anchorage-independent growth of a normal mammary epithelial cell line, MCF10A. Here, we further demonstrated that ER-alpha but not ER-beta expression was constitutively activated in these caveolin-1 haploinsufficient cells. Transient treatment of MCF10A cells with beta-methyl-cyclodextrin, a chemical that can displace caveolin-1 from the plasma membrane, also stimulated ER-alpha expression. We further found that the 17beta-estradiol (E2) accelerated anchorage-independent growth of these cells in vitro and promoted their tumorigenesis in nude mice. These results suggest that dysregulation of caveolin-1 is one of the mechanisms by which ER-alpha expression is activated during initiation of breast tumorigenesis.