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The AA5052 aluminum alloy is widely used in automobile and aerospace manufacturing, and with the development of light-weight alloys, it is required that these materials exhibit better mechanical properties. Previous studies have demonstrated that the addition of Sc to aluminum alloys can improve both the microstructure and properties of the alloys. In this study, the effect of Sc on the Fe-rich phase and properties of the AA5052 aluminum alloy was studied by adding 0%, 0.05%, 0.2%, and 0.3% Sc. The results show that with the increase of Sc, the coarse needle-like Fe-rich phase gradually transforms into Chinese-script and then nearly spherical particles, reduce the size of Fe-rich phase, and refine the grain with increase of high angle grain boundaries (HAGBs). These microstructure changes enhance the strength of the AA5052 alloy through Sc addition. The ductility of the alloy is obviously improved because the addition of a lower amount of Sc changes the morphology of Fe-rich phase from needle-like into a Chinese-script, and it is subsequently reduced as a result of significant increase in HAGBs with increasing Sc content. [ABSTRACT FROM AUTHOR]

Purpose: To measure the changes of macular microcirculation in cases with unilateral acute primary angle closure (APAC) who were managed by phacoemulsification. Methods: Patients with unilateral APAC and managed by phacoemulsification were enrolled. The contralateral unaffected eyes were served as fellow group, and normal individuals were recruited as control group. Optical coherence tomography angiography (OCT-A) was performed to analyze the macular whole image vessel density (wiVD) and parafoveal vessel density (pfVD). The retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses were assessed using spectral-domain optical coherence tomography. Results: A total of 36 APAC patients and 35 eyes from 35 normal individuals were recruited. In the APAC eyes, the mean wiVD (42.1% ± 3.7%) and pfVD (45.2% ± 3.8%) in the superficial layers (wiVD-SL and pfVD-SL) were both significantly reduced, compared to fellow eyes (45.7% ± 3.1%, 48.7% ± 3.1%) and control eyes (44.4% ± 4.7%, 47.4% ± 5.1%) (P < 0.05). They were all statistically correlated with RNFL, GCC, visual field pattern standard deviation (PSD), and mean deviation (MD). Conclusion: The macular OCT-A parameters including wiVD-SL and pfVD-SL were significantly reduced in the eyes with APAC compared to the fellow unaffected eyes and normal control eyes. They were correlated well with RNFL, GCC, PSD and MD. The macular vessel density parameters may help monitor the progression of APAC. [ABSTRACT FROM AUTHOR]

Purpose: Obtaining tumour-free margins is critical for avoiding re-excision and reducing local recurrence following breast-conserving surgery; however, it remains challenging. Imaging-guided surgery provides precise detection of residual lesions and assists surgical resection. Herein, we described water-soluble melanin nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast cancer photoacoustic imaging (PAI) and surgical navigation. Methods: The cRGD-MNPs were synthesised and characterized for morphology, photoacoustic characteristics and stability. Tumour targeting and toxicity of cRGD-MNPs were determined by using either breast cancer cells, MDA-MB-231 tumour-bearing mice or the FVB/N-Tg (MMTV-PyVT) 634Mul/J mice model. PAI was used to locate the tumour and guide surgical resection in MDA-MB-231 tumour-bearing mice. Results: The cRGD-MNPs exhibited excellent in vitro and in vivo tumour targeting with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site to that in the surrounding normal tissue was 3.2 ± 0.1, which was higher than that using MNPs (1.7 ± 0.3). Similarly, the PA signal in the spontaneous breast cancer increased ~ 2.5-fold at 2 h post-injection of cRGD-MNPs in MMTV-PyVT transgenic mice. Preoperative PAI assessed tumour volume and offered three-dimensional (3D) reconstruction images for accurate surgical planning. Surgical resection following real-time PAI showed high consistency with histopathological analysis. Conclusion: These results highlight that cRGD-MNP-mediated PAI provide a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs with fine PA properties have great potential for clinical translation. [ABSTRACT FROM AUTHOR]

Many functional activities of endometrium epithelium are energy consuming which are very important for maintaining intrauterine environment needed by early embryonic development and establishment of implantation window. Glucose is a main energy supplier and one of the main components of intrauterine fluid. Obviously, glucose transports in endometrium epithelium involve in for these activities but their functions have not been elucidated. In this research, we observed a spatiotemporal pattern of sodium glucose transporter 1 (SGLT1) expression in the mouse endometrium. We also determined that progesterone can promote the expression of SGLT1 in the mouse endometrial epithelium in response to the action of oestrogen. Treatment with the SGLT1 inhibitor phlorizin or small interfering RNA specific for SGLT1 (SGLT1-siRNA) altered glucose uptake in primary cultured endometrial epithelial cells, which exhibited reduced ATP levels and AMPK activation. The injection of phlorizin or SGLT1-siRNA into one uterine horn of each mouse on day 2 of pregnancy led to an increased glucose concentration in the uterine fluid and decreased number of harvested normal blastocysts and decreased expression of integrin αVβ3 in endometrial epithelium and increased expression of mucin 1 and lactoferrin in endometrial epithelium and the uterine homogenates exhibited activated AMPK, a decreased ATP level on day 4, and a decreased number of implantation sites on day 5. In embryo transfer experiments, pre-treatment of the uterine horn with phlorizin or SGLT1-siRNA during the implantation window led to a decreased embryo implantation rate on day 5 of pregnancy, even when embryos from normal donor mice were used. In conclusion, SGLT1, which participates in glucose transport in the mouse endometrial epithelium, inhibition and/or reduced expression of SGLT1 affects early embryo development by altering the glucose concentration in the uterine fluid. Inhibition and/or reduced expression of SGLT1 also affects embryo implantation by influencing energy metabolism in epithelial cells, which consequently influences implantation-related functional activities. [ABSTRACT FROM AUTHOR]

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors. Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer. [ABSTRACT FROM AUTHOR]

Two novel metal–organic compounds have been prepared via altering metal ions under the hydrothermal conditions, i.e. [Zn(HL)(4,4′-bipy)(H2O)2]n (1) and [Cd(HL)(4,4′-bipy)]n (2) (4,4′-bipy = 4,4′-bipyridine and H3L = 5-(4-carboxyphenoxy)-isophthalic acid). Moreover, the luminescent performances and stabilities of the two compounds were also investigated. For the prevention and treatment evaluation of compounds 1 and 2 in this present research, serious of biological experiments were performed in this study. Firstly, the non-invasive blood pressure monitoring was used for blood pressure determination. In addition to this, the real time RT-PCR assay was conducted in this study for the assessment of the α receptor expression on the vascular endothelial cells. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the changes and evaluate the diagnosis value of circumpapillary vessel density (VD) in cases of acute primary angle closure (APAC). Design: Case–control study. Methods: APAC patients with a history of unilateral acute attack were enrolled. The eyes with acute episode constituted the case group while the contralateral eyes without attack consisted of the control group. Ophthalmic examinations including slit-lamp examination, best-corrected visual acuity, intraocular pressure and visual field were carried out. Retinal nerve fiber layer (RNFL), macular ganglion cell complex (GCC) were measured by spectral-domain optical coherence tomography, while VD was assessed by optical coherence tomography angiography. Results: The whole en face image vessel density (wiVD), circumpapillary vessel density (cpVD) and inside disk VD for both all vessels and capillary were all significantly lower in the APAC eyes compared to the fellow eyes (P < 0.01 for all). In APAC eyes, the wiVD, inside disk VD and cpVD both for all vessels and capillary were all positively correlated with RNFL and GCC thicknesses but negatively correlated with the mean deviation (MD), pattern standard deviation (PSD) and the duration of acute attack (all P < 0.01). From the ROC curve, the cpVDcap, wiVDcap, cpVDall and wiVDall all showed comparable diagnostic ability with RNFL, GCC and MD to differentiate eyes with APAC from the fellow eyes (all P > 0.05). The inside disk VDcap and VDall demonstrated significant lower diagnostic ability than the cpVDcap, wiVDcap, cpVDall and wiVDall (all P < 0.001). Conclusions: In APAC eyes, circumpapillary VD decreased significantly compared with the fellow unaffected eyes. They were significantly correlated with thicknesses of RNFL and GCC, and visual field MD and PSD in the APAC eyes. The patients with longer duration of acute attack were more likely to have lower cpVD. For APAC, the diagnostic ability of wiVD and cpVD was similar with RNFL, GCC and MD and was higher than inside disk VD. [ABSTRACT FROM AUTHOR]

We explore the interaction between estrogen and PCSK9 and their collective impact on lipid metabolism, especially concerning the regulation of low-density lipoprotein receptor levels. Utilizing both animal and cellular models, including ovariectomized mice and HepG2 cell lines, we demonstrate that estrogen deficiency leads to a disruption in lipid metabolism, characterized by elevated levels of total cholesterol and LDL-C. The study commences with mice undergoing ovariectomy, followed by a diet regimen comprising either high-fat diet or normal feed for a four-week duration. Key assessments include analyzing lipid metabolism, measuring PCSK9 levels in the bloodstream, and evaluating hepatic low-density lipoprotein receptor expression. We will also conduct correlation analyses to understand the relationship between PCSK9 and various lipid profiles. Further, a subset of ovariectomized mice on high-fat diet will undergo treatment with either estrogen or PCSK9 inhibitor for two weeks, with a subsequent re-evaluation of the earlier mentioned parameters. Our findings reveal that estrogen inhibits PCSK9-mediated degradation of low-density lipoprotein receptor, a process crucial for maintaining lipid homeostasis. Through a series of experiments, including immunohistochemistry and western blot analysis, we establish that PCSK9 is involved in lipid metabolism disorders caused by estrogen deficiency and that estrogen regulates PCSK9 and low-density lipoprotein receptor at post-transcriptional level. The study provides a mechanism for the involvement of PCSK9 in elucidating the disorders of lipid metabolism caused by estrogen deficiency due to perimenopause and ovarian decline. [ABSTRACT FROM AUTHOR]

In this paper, a ratiometric fluorescence biosensor was introduced for alkaline phosphatase (ALP) detection based on 2-aminopurine (2-Amp) and thioflavin T (ThT)-G-quadruplex system. We designed a special DNA (5'-AGGGTTAGGGTTAGGGTTAGGGAAA/i2-Amp/AAAA-PO4-3', AP) modified with a phosphate moiety at the 3’-end, G-quadruplex at the 5’-end, and a fluorophore (2-Amp) in the middle. In the absence of ALP, the G-rich AP strand could be prone to fold into G-quadruplex structures in the presence of K+. Then, ThT combined with G-quandruplex, resulting in the enhancement of fluorescence emission peak at 485 nm. However, ALP-mediated hydrolysis of the 3’-phosphoryl end promoted the cleavage of AP by the exonuclease I (Exo I), releasing 2-Amp which displayed a strong fluorescence emission peak at 365 nm. Moreover, the quantitative fluorescence model (QFM) was derived for the analysis of the fluorescence measurements obtained by the proposed ratiometric fluorescent biosensor. With the aid of the advanced model, the proposed ratiometric fluorescent biosensor possessed satisfactory results for the detection of ALP in the human serum samples, with accuracy comparable to that of the reference method—the commercial ALP assay kit. Under the optimized experimental conditions, this method exhibited good selectivity and higher sensitivity, and the detection limit was found to be as low as 0.017 U/L. Therefore, it is reasonable to expect that the method had a great potential to detect ALP quantitatively in clinical diagnosis. [ABSTRACT FROM AUTHOR]