Glycol Monomethyl Ether-Substituted Carbazolyl Hole-Transporting Material for Stable Inverted Perovskite Solar Cells with Efficiency of 25.52 .

Organic self-assembled molecules (OSAMs) based hole-transporting materials play a pivotal role in achieving highly efficient and stable inverted perovskite solar cells (IPSCs). However, the reported carbazol-based OSAMs have serious drawbacks, such as poor wettability for perovskite solution spreading due to the nonpolar surface, worse matched energy arrangement with perovskite, and limited molecular species, which greatly limit the device performance. To address above problems, a novel OSAM [4-(3,6-glycol monomethyl ether-9H-carbazol-9-yl) butyl]phosphonic acid (GM-4PACz) was synthesized as hole-transporting material by introducing glycol monomethyl ether (GM) side chains at carbazolyl unit. GM groups enhance the surface energy of Indium Tin Oxide (ITO)/SAM substrate to facilitate the nucleation and growth of up perovskite film, suppress cation defects, release the residual stress at SAM/perovskite interface, and evaluate energy level for matching with perovskite. Consequently, the GM-4PACz based IPSC achieves a champion PCE of 25.52 %, a respectable open-circuit voltage (VOC) of 1.21 V, a high stability, possessing 93.29 % and 91.75 % of their initial efficiency after aging in air for 2000 h or tracking at maximum power point for 1000 h, respectively.

GDF9His209GlnfsTer6/S428T and GDF9Q321X/S428T bi-allelic variants caused female subfertility with defective follicle enlargement.

BACKGROUND: Antral follicles consist of an oocyte cumulus complex surrounding by somatic cells, including mural granulosa cells as the inner layer and theca cells as the outsider layer. The communications between oocytes and granulosa cells have been extensively explored in in vitro studies, however, the role of oocyte-derived factor GDF9 on in vivo antral follicle development remains elusive due to lack of an appropriate animal model. Clinically, the phenotype of GDF9 variants needs to be determined. METHODS: Whole-exome sequencing (WES) was performed on two unrelated infertile women characterized by an early rise of estradiol level and defect in follicle enlargement. Besides, WES data on 1,039 women undergoing ART treatment were collected. A Gdf9Q308X/S415T mouse model was generated based on the variant found in one of the patients. RESULTS: Two probands with bi-allelic GDF9 variants (GDF9His209GlnfsTer6/S428T, GDF9Q321X/S428T) and eight GDF9S428T heterozygotes with normal ovarian response were identified. In vitro experiments confirmed that these variants caused reduction of GDF9 secretion, and/or alleviation in BMP15 binding. Gdf9Q308X/S415T mouse model was constructed, which recapitulated the phenotypes in probands with abnormal estrogen secretion and defected follicle enlargement. Further experiments in mouse model showed an earlier expression of STAR in small antral follicles and decreased proliferative capacity in large antral follicles. In addition, RNA sequencing of granulosa cells revealed the transcriptomic profiles related to defective follicle enlargement in the Gdf9Q308X/S415T group. One of the downregulated genes, P4HA2 (a collagen related gene), was found to be stimulated by GDF9 protein, which partly explained the phenotype of defective follicle enlargement. CONCLUSIONS: GDF9 bi-allelic variants contributed to the defect in antral follicle development. Oocyte itself participated in the regulation of follicle development through GDF9 paracrine effect, highlighting the essential role of oocyte-derived factors on ovarian response.

Crossbreeding Effect of Chalcogenation and Iodination on Benzene Additives Enables Optimized Morphology and 19.68% Efficiency of Organic Solar Cells.

Volatile solid additives have attracted increasing attention in optimizing the morphology and improving the performance of currently dominated non-fullerene acceptor-based organic solar cells (OSCs). However, the underlying principles governing the rational design of volatile solid additives remain elusive. Herein, a series of efficient volatile solid additives are successfully developed by the crossbreeding effect of chalcogenation and iodination for optimizing the morphology and improving the photovoltaic performances of OSCs. Five benzene derivatives of 1,4-dimethoxybenzene (DOB), 1-iodo-4-methoxybenzene (OIB), 1-iodo-4-methylthiobenzene (SIB), 1,4-dimethylthiobenzene (DSB) and 1,4-diiodobenzene (DIB) are systematically studied, where the widely used DIB is used as the reference. The effect of chalcogenation and iodination on the overall property is comprehensively investigated, which indicates that the versatile functional groups provided various types of noncovalent interactions with the host materials for modulating the morphology. Among them, SIB with the combination of sulphuration and iodination enabled more appropriate interactions with the host blend, giving rise to a highly ordered molecular packing and more favorable morphology. As a result, the binary OSCs based on PM6:L8-BO and PBTz-F:L8-BO as well as the ternary OSCs based on PBTz-F:PM6:L8-BO achieved impressive high PCEs of 18.87%, 18.81% and 19.68%, respectively, which are among the highest values for OSCs.

Unusual Post-Translational Modifications in the Biosynthesis of Lasso Peptides.

Lasso peptides are a subclass of ribosomally synthesized and post-translationally modified peptides (RiPPs) and feature the threaded, lariat knot-like topology. The basic post-translational modifications (PTMs) of lasso peptide contain two steps, including the leader peptide removal of the ribosome-derived linear precursor peptide by an ATP-dependent cysteine protease, and the macrolactam cyclization by an ATP-dependent macrolactam synthetase. Recently, advanced bioinformatic tools combined with genome mining have paved the way to uncover a rapidly growing number of lasso peptides as well as a series of PTMs other than the general class-defining processes. Despite abundant reviews focusing on lasso peptide discoveries, structures, properties, and physiological functionalities, few summaries concerned their unique PTMs. In this review, we summarized all the unique PTMs of lasso peptides uncovered to date, shedding light on the related investigations in the future.

A Novel Nomogram for Individualized Gonadotropin Starting Dose in GnRH Antagonist Protocol.

Controlled ovarian stimulation (COS) is one of the most vital parts of in vitro fertilization-embryo transfer (IVF-ET). At present, no matter what kinds of COS protocols are used, clinicians have to face the challenge of selection of gonadotropin starting dose. Although several nomograms have been developed to calculate the appropriate gonadotropin starting dose in gonadotropin releasing hormone (GnRH) agonist protocol, no nomogram was suitable for GnRH antagonist protocol. This study aimed to develop a predictive nomogram for individualized gonadotropin starting dose in GnRH antagonist protocol. Single-center prospective cohort study was conducted, with 198 women aged 20-45 years underwent IVF/intracytoplasmic sperm injection (ICSI)-ET cycles. Blood samples were collected on the second day of the menstrual cycle. All women received ovarian stimulation using GnRH antagonist protocol. Univariate and multivariate analysis were performed to identify predictive factors of ovarian sensitivity (OS). A nomogram for gonadotropin starting dose was developed based on the multivariate regression model. Validation was performed using concordance statistics and bootstrap resampling. A multivariate regression model based on serum anti-Müllerian hormone (AMH) level, antral follicle count (AFC), and body mass index (BMI) was developed and accounted for 59% of the variability of OS. An easy-to-use predictive nomogram for gonadotropin starting dose was established with excellent accuracy. The concordance index (C-index) of the nomogram was 0.833 (95% CI, 0.829-0.837). Internal validation using bootstrap resampling further showed the good performance of the nomogram. In conclusion, gonadotropin starting dose in antagonist protocol can be predicted precisely by a novel nomogram.

Core clock gene Bmal1 deprivation impairs steroidogenesis in mice luteinized follicle cells.

Luteinization is the event of corpus luteum formation, a way of follicle cells transformation and a process of steroidogenesis alteration. As the core clock gene, Bmal1 was involved in the regulation of ovulation process and luteal function afterwards. Till now, the underlying roles of luteinization played by Bmal1 remain unknown. To explore the unique role of Bmal1 in luteal steroidogenesis and its underlying pathway, we investigated the luteal hormone synthesis profile in Bmal1 knockout female mice. We found that luteal hormone synthesis was notably impaired, and phosphorylation of PI3K/NfκB pathway was significantly activated. Then, the results were verified in in vitro cultured cells, including isolated Bmal1 interference granulosa cells (GCs) and theca cells (TCs), respectively. Hormones levels of supernatant culture media and mRNA expressions of steroidogenesis-associated genes (star, Hsd3ß2, cyp19a1 in GCs, Lhcgr, star, Hsd3ß2, cyp17a1 in TCs) were mutually decreased, while the phosphorylation of PI3K/NfκB was promoted during in vitro luteinization. After PI3K specific-inhibitor LY294002 intervention, mRNA expressions of Lhcgr and Hsd3ß2 were partially rescued in Bmal1 interference TCs, together with significantly increased androstenedione and T synthesis. Further exploration in TCs demonstrated BMAL1 interacted directly but negatively with NfκB p65 (RelA), a subunit which was supposed as a mediator in Bmal1-governed PI3K signaling regulation. Taken together, we verified the novel role of Bmal1 in luteal steroidogenesis, achieving by negative interplay with RelA-mediated PI3K/NfκB pathway.

The role of serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome.

OBJECTIVE: To study the role of selected serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome (PCOS). METHODS: Selected serum inflammatory cytokines were analyzed in the particle cells, which were interfered by berberine, from 78 infertile women who were to be treated with In Vitro Fertilization (IVF) /Intracytoplasmic Sperm Injection-Embryo Transfer (icsi-et). Among them, 49 patients had PCOS infertility, and 29 were non-PCOS patients whose infertility resulted from fallopian tube and male factors. The elisa method was used to detect the changes in the expression levels of inflammatory factors in the cells. The correlations between the serum inflammatory cytokine expression levels and the corresponding clinical hormones were analyzed. The changes in the expression (mRNA and protein) levels of the serum inflammatory cytokines were studied by real-time quantitative PCR and protein printing. Fluorescence microscope and flow cytometry were used to detect the glucose uptake capacity of ovarian granulosa cells in PCOS patients under the action of insulin after berberine. RESULTS: In the PCOS group, IL-17a (P = 0.001), IL-1Ra (P<0.0001), and IL-6 (P = 0.035) were significantly higher than those in the non-PCOS group. In the non-PCOS group, AMH level was negatively correlated with inflammatory cytokines IL-17a (r = -0.819;P = 0.004), IL-1a (r = -0.716;P = 0.0.02), IL-1b (r = -0.678;P = 0.031), IL-2 (r = -0.765;P = 0.01), and IL-8 (r = -0.705;P = 0.023). However, in the PCOS group, AMH levels were not significantly correlated with the levels of the examined inflammatory cytokines. Berberine significantly reduced the expression level of mTOR mRNA (P = 0.001), and increased the expression level of IRS-1 mRNA (P = 0.009) in the PCOS granule cells. CONCLUSION: In this study, we find that the elevated levels of serum inflammatory factors IL-17a, IL-1Ra, and IL-6 cause women to be in a subclinical inflammatory state for a long time. Abnormal changes in inflammatory factors alter their original negative correlations with AMH levels, thereby weakening the metabolism of glycolipids, promoting insulin resistance, destroying the normal ovulation and fertilization system of women, leading to polycystic ovary syndrome characterized by menstrual thinning and abnormal ovulation. Berberine can improve the sensitivity of insulin by regulating the signal pathway of insulin receptor substrate-1 (IRS-1) and mammalian target of rapamycin (mTOR) in PCOS patients and achieve a therapeutic effect of treating PCOS.

Evaluation in vitro and in vivo of curcumin-loaded mPEG-PLA/TPGS mixed micelles for oral administration.

The aim of this work is to prepare and characterize curcumin-loaded methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA)/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) mixed micelles (CUR-MPP-TPGS-MMs), analyze the influence of formulation on enhancing the solubility of curcumin in water, and evaluate the improvement of intestinal absorption after oral administration. CUR-MPP-TPGS-MMs were prepared using the thin film diffusion method and optimized with the uniform design. The optimal CUR-MPP-TPGS-MMs were provided with high drug-loading (16.1%), small size (46.0 nm) and spherical shape. Low critical micelle concentration (CMC) and superior dilution stability showed that CUR-MPP-TPGS-MMs could keep integrity during the dilution of gastrointestinal fluid. In vitro drug release study indicated a sustained release of curcumin from CUR-MPP-TPGS-MMs in simulated gastrointestinal solution. The absorption mechanism of passive diffusion was obtained by measuring in situ intestinal absorption of CUR-MPP-TPGS-MMs in rats, and the best absorption segment was found to be the duodenum. The pharmacokinetics was evaluated in rats at the dose of 75 mg/kg by intragastric administration. The Cmax and mean retention time (MRT0-24) for CUR-MPP-TPGS-MMs were both increased, and the relative bioavailability of micelle formulation to curcumin suspension was 927.3%. These results suggested that mPEG-PLA/TPGS mixed micelle system (MPP-TPGS-MMs) showed great potential in improving oral bioavailability of curcumin.

Novel in situ gel systems based on P123/TPGS mixed micelles and gellan gum for ophthalmic delivery of curcumin.

Curcumin, a natural polyphenol compound, has been widely reported for diverse pharmacological effects and already been investigated for eye diseases. However, the water-insolubility of curcumin and the inherent penetration barriers in cornea make it difficult for curcumin to enter eye. This work aimed to develop ion-sensitive curcumin-loaded Pluronic P123 (P123)/D-a-tocopheryl polyethylene glycolsuccinate (TPGS) mixed micelle in situ gels (CUR-MM-ISGs) to prolong ocular retention time and improve cornea permeability. Central composite design-response surface methodology was applied for the optimization of curcumin-loaded P123/TPGS mixed micelles (CUR-MMs). Characterization tests showed that CUR-MMs were in spherical shape with small size and low critical micelle concentration. After dispersing the micelles in gellan gum solution (0.2%, w/w) at the ratio of 3:1 and 1:1 (v/v), respectively, CUR-MM-ISGs were formed and presented transparent appearance. Sustained release profile was obtained in vitro for both CUR-MM-ISGs (3:1 or 1:1, v/v). The irritation test proved that CUR-MM-ISGs as ophthalmic formulations were gentle and biocompatible towards ocular tissues. In addition, the ex vivo corneal penetration study indicated that the cumulative drug permeation amount of CUR-MM-ISGs (3:1, v/v) was respectively 1.16-fold and 1.32-fold higher than CUR-MM-ISGs (1:1, v/v) and curcumin solution. It can be concluded from these results that the developed ion-sensitive mixed micelle in situ gel system is a potential ophthalmic delivery carrier for curcumin as a poorly soluble drug.

Curcumin-loaded mixed micelles: preparation, optimization, physicochemical properties and cytotoxicity in vitro.

Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5 nm, the zeta potential was about -26.96 mV and critical micelle concentration was 0.0087 g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14 mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC50 values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10 µg/ml and 6.93 µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.

A hybrid coumarin-thiazole fluorescent sensor for selective detection of bisulfite anions in vivo and in real samples.

A hybrid coumarin-thiazole compound was developed as a novel ratiometric and colorimetric sensor for bisulfite anions. Structure identification of the compound was confirmed by (1)H NMR, (13)C NMR, (1)H,(1)H COSY, heteronuclear single quantum coherence (HSQC), IR, and HRMS spectroscopy. The detection of bisulfite anions was performed through the Michael addition of the bisulfite anion toward the hybrid coumarin-thiazole sensor. The reaction between the sensor and bisulfite anion caused the fluorescence intensity to decrease at 600 nm and to increase at 450 nm and simultaneously yielded a visible color change from purplish red to colorless because the π conjugation between thiazole and coumarin was blocked. The sensor possessed high selectivity and sensitivity for bisulfite with respect to other common anions in aqueous solution. Moreover, the practical value of this sensor was confirmed by its application in the detection of bisulfite anion in human breast adenocarcinoma cells and granulated sugar.

Curcumin loaded mixed micelles composed of Pluronic P123 and F68: preparation, optimization and in vitro characterization.

In this study, curcumin (Cur) loaded mixed micelles (Cur-PF), composed of Pluronic P123 (P123) and Pluronic F68 (F68), was prepared using the thin-film hydration method and evaluated in vitro. The preparation process was optimized with a central composite design (CCD). The average size of the mixed micelles was 68.2 nm, and the encapsulating efficiency for Cur was 86.93%, and 6.996% for drug-loading. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-PF presented the sustained-release property. The in vitro cytotoxicity assay showed that the IC(50) values on MCF-7 cells for Cur-PF and free Cur in DMSO solution were 5.04 µg/mL and 8.35 µg/mL, while 2.52 µg/mL and 8.27 µg/mL on MCF-7/ADR cells. It could be concluded from the results that P123/F68 mixed micelles might serve as a potential nanocarrier to improve the solubility and biological activity of Cur.