| 1. |
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| 2. |
- Zhang, Lixiu, et al.
(author)
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Advances in the Application of Perovskite Materials
- 2023
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In: NANO-MICRO LETTERS. - : SHANGHAI JIAO TONG UNIV PRESS. - 2311-6706. ; 15:1
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Research review (peer-reviewed)abstract
- Nowadays, the soar of photovoltaic performance of perovskite solar cells has set off a fever in the study of metal halide perovskite materials. The excellent optoelectronic properties and defect tolerance feature allow metal halide perovskite to be employed in a wide variety of applications. This article provides a holistic review over the current progress and future prospects of metal halide perovskite materials in representative promising applications, including traditional optoelectronic devices (solar cells, light-emitting diodes, photodetectors, lasers), and cutting-edge technologies in terms of neuromorphic devices (artificial synapses and memristors) and pressure-induced emission. This review highlights the fundamentals, the current progress and the remaining challenges for each application, aiming to provide a comprehensive overview of the development status and a navigation of future research for metal halide perovskite materials and devices.
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| 3. |
- Benrick, Anna, 1979, et al.
(author)
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Enhanced insulin sensitivity and acute regulation of metabolic genes and signaling pathways after a single electrical or manual acupuncture session in female insulin-resistant rats.
- 2014
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In: Acta Diabetologica. - 0940-5429 .- 1432-5233. ; 51:6, s. 963-972
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Journal article (peer-reviewed)abstract
- AIM: To compare the effect of a single session of acupuncture with either low-frequency electrical or manual stimulation on insulin sensitivity and molecular pathways in the insulin-resistant dihydrotestosterone-induced rat polycystic ovary syndrome (PCOS) model. Both stimulations cause activation of afferent nerve fibers. In addition, electrical stimulation causes muscle contractions, enabling us to differentiate changes induced by activation of sensory afferents from contraction-induced changes. MATERIALS AND METHODS: Control and PCOS rats were divided into no-stimulation, manual-, and electrical stimulation groups and insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. Manually stimulated needles were rotated 180° ten times every 5 min, or low-frequency electrical stimulation was applied to evoke muscle twitches for 45 min. Gene and protein expression were analyzed by real-time PCR and Western blot. RESULTS: The glucose infusion rate (GIR) was lower in PCOS rats than in controls. Electrical stimulation was superior to manual stimulation during treatment but both methods increased GIR to the same extent in the post-stimulation period. Electrical stimulation decreased mRNA expression of Adipor2, Adrb1, Fndc5, Erk2, and Tfam in soleus muscle and increased ovarian Adrb2 and Pdf. Manual stimulation decreased ovarian mRNA expression of Erk2 and Sdnd. Electrical stimulation increased phosphorylated ERK levels in soleus muscle. CONCLUSIONS: One acupuncture session with electrical stimulation improves insulin sensitivity and modulates skeletal muscle gene and protein expression more than manual stimulation. Although electrical stimulation is superior to manual in enhancing insulin sensitivity during stimulation, they are equally effective after stimulation indicating that it is activation of sensory afferents rather than muscle contraction per se leading to the observed changes.
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| 4. |
- Hu, Min, et al.
(author)
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Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production.
- 2019
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 316:5
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Journal article (peer-reviewed)abstract
- Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesised that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress, inflammation and perturbed gene expression. Here we tested this hypothesis by studying the metabolic, endocrine and uterine abnormalities in pregnant rats after exposure to daily injection of 5α-dihydrotestosterone (DHT, 1.66 mg/kg body weight/day) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that while DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT+insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared to controls, hyperandrogenism and insulin resistance in the dam was associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization, placentation, angiogenesis and insulin signaling. Moreover, we observed changes in uterine mitochondrial function and homeostasis and suppression of both oxidative and antioxidative defenses in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.
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| 5. |
- Hu, Min, et al.
(author)
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Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring.
- 2015
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 112:46, s. 14348-53
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Journal article (peer-reviewed)abstract
- During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers.
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| 6. |
- Hu, Min, et al.
(author)
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Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance.
- 2019
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In: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 232
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Journal article (peer-reviewed)abstract
- This study aimed to determine whether glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in rats with hyperandrogenism and insulin resistance compared to controls.Female Sprague Dawley rats were exposed to daily injections of human chorionic gonadotropin and/or insulin.In both the ovary and the uterus, decreased expression of the two GR isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in hCG+insulin-treated rats. However, these rats exhibited contrasting regulation of Hsd11b1 and Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related proteins decreased in the ovary and uterus following hCG and insulin stimulation, in contrast to increased expression of many genes involved in mitochondrial function and homeostasis. Additionally, hCG+insulin-treated rats showed increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. The mRNA expression of Il1b, Il6, and Mmp2 was decreased in both tissues, while the mRNA expression of Tnfa, Ccl2, Ccl5, and Mmp3 was increased in the uterus. Ovaries and uteri from animals co-treated with hCG and insulin showed increased collagen deposition compared to controls.Our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance activate NFκB signaling resulting in aberrant regulation of inflammation-related gene expression.
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| 7. |
- Hu, Min, et al.
(author)
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Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome. : Ferroptosis and N-acetylcysteine
- 2021
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In: Molecular human reproduction. - : Oxford University Press (OUP). - 1460-2407 .- 1360-9947. ; 27:12
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Journal article (peer-reviewed)abstract
- The mechanisms that link hyperandrogenism and insulin resistance to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin. Molecular and histological analyses showed that NAC attenuated DHT and insulin-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and insulin, such as increased glutathione peroxidase 4 protein level. Further, increased apoptosis inducing factor mitochondria associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT+insulin-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, and homeobox A11 mRNA expression and placental estrogen related receptor beta and trophoblast specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of hyperandrogenism and insulin resistance-induced uterine and placental dysfunction.
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| 8. |
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| 9. |
- Raja-Khan, Nazia, et al.
(author)
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The physiological basis of complementary and alternative medicines for polycystic ovary syndrome.
- 2011
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 301:1
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Research review (peer-reviewed)abstract
- Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.
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| 10. |
- Stener-Victorin, Elisabet, 1964, et al.
(author)
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Effects and mechanisms of acupuncture in the reproductive system.
- 2010
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In: Autonomic neuroscience : basic & clinical. - : Elsevier BV. - 1872-7484. ; 157:1-2, s. 46-51
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Journal article (peer-reviewed)abstract
- The use of acupuncture to treat reproductive dysfunction has not been well investigated. Only a few clinical studies have been reported, most of which are flawed by poor design and a lack of valid outcome measures and diagnostic criteria, making the results difficult to interpret. Experimental studies, however, show that acupuncture has substantial effects on reproductive function. Here we review the possible mechanisms of action of acupuncture on the reproductive system and its effects on reproductive dysfunction, focusing in particular on polycystic ovary syndrome, the most common endocrine and metabolic disorder in women. Clinical and experimental evidence demonstrates that acupuncture is a suitable alternative or complement to pharmacological induction of ovulation, without adverse side effects. Clearly, acupuncture modulates endogenous regulatory systems, including the sympathetic nervous system, the endocrine system, and the neuroendocrine system. Randomized clinical trials are warranted to further evaluate the clinical effects of acupuncture in reproductive disorders.
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| 11. |
- Sun, Miao, et al.
(author)
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Maternal androgen excess reduce placental and fetal weights, increase placental steroidogenesis and leads to long-term health effects in their female offspring.
- 2012
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 303:11
-
Journal article (peer-reviewed)abstract
- Here we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg free testosterone from gestational day 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptors α and ß, androgen receptor, and 17 beta-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of non-alcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction, however at 6 weeks of age there was no difference in body weight between the offspring of testosterone-, and control-treated rats. At 10-11 weeks of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams and they developed non-alcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.
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| 12. |
- Wang, Kang, et al.
(author)
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Luminescent metal-halide perovskites: fundamentals, synthesis, and light-emitting devices
- 2024
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In: Science in China Series B. - : SCIENCE PRESS. - 1674-7291 .- 1869-1870. ; 67:6, s. 1776-1838
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Research review (peer-reviewed)abstract
- Metal-halide perovskites have garnered considerable research attention as highly efficient light emitters in recent years due to their outstanding optoelectronic properties with remarkable tunability and excellent solution processabilities. Substantial advancements have been achieved in the development of novel halide perovskites, and the exploitations of these materials in light-emitting devices. This review comprehensively outlines recent breakthroughs in metal-halide perovskites, encompassing the rational design of perovskite materials with tunable light emission properties, the controllable growth of single crystal for a deeper understanding of their structure-property relationships, as well as the fundamental insights into the photophysics and carrier dynamics in perovskite systems. Additionally, it provides an overview of recent applications of perovskite materials in high-performance light-emitting diodes (LEDs) and lasers.
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| 13. |
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| 14. |
- Yang, Xinming, et al.
(author)
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Cryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of signaling mechanisms and androgen synthesis.
- 2011
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In: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 1522-1490 .- 0363-6119. ; 300:4
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Journal article (peer-reviewed)abstract
- This trial explores (i) prenatally androgenized (PNA) rats as a model of polycystic ovary syndrome (PCOS) and (ii) reproductive and metabolic effects of cryptotanshinone in PNA ovaries. On days 16-18 of pregnancy, 10 rats were injected with testosterone propionate (PNA mothers) and 10 with sesame oil (control mothers). At age 3 mo, 12 female offspring from each group were randomly assigned to receive saline and 12 cryptotanshinone treatment during 2 weeks. Before treatment, compared with the 24 controls, the 24 PNA rats had (i) disrupted estrus cycles, (ii) higher 17-hydroxyprogesterone, (P = 0.030), androstenedione (P = 0.016), testosterone and insulin (Ps = 0.000), and glucose (P = 0.047) levels, and (iii) higher areas under the curve (AUC) for glucose (AUC-Glu, P = 0.025) and homeostatic model assessment for insulin resistance (HOMA-IR, P = 0.008). After treatment, compared with vehicle-treated PNA rats, cryptotanshinone-treated PNA rats had (i) improved estrus cycles (P = 0.045), (ii) reduced 17-hydroxyprogesterone (P = 0.041), androstenedione (P = 0.038), testosterone (P = 0.003), glucose (P = 0.036), and insulin (P = 0.041) levels, and (iii) lower AUC-Glu (P = 0.045) and HOMA-IR (P = 0.024). Western blot showed that cryptotanshinone reversed the altered protein expressions of insulin receptor substrate-1 and -2, phosphatidylinositol 3-kinase p85α, glucose transporter-4, ERK-1, and 17α-hydroxylase within PNA ovaries. We conclude that PNA model rats exhibit reproductive and metabolic phenotypes of human PCOS and that regulation of key molecules in insulin signaling and androgen synthesis within PNA ovaries may explain cryptotanshinone's therapeutic effects.
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| 15. |
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| 16. |
- Zhang, Jiangbin, et al.
(author)
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Efficient non-fullerene organic solar cells employing sequentially deposited donor-acceptor layers
- 2018
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In: Journal of Materials Chemistry A. - : ROYAL SOC CHEMISTRY. - 2050-7488 .- 2050-7496. ; 6:37, s. 18225-18233
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Journal article (peer-reviewed)abstract
- Non-fullerene acceptors (NFAs) have recently outperformed their fullerene counterparts in binary bulk-heterojunction (BHJ) organic solar cells (OSCs). Further development of NFA OSCs may benefit other novel OSC device structures that alter or extend the standard BHJ concept. Here, we report such a new processing route that forms a BHJ-like morphology between sequentially processed polymer donor and NFA with high power conversion efficiencies in excess of 10%. Both devices show similar charge generation and recombination behaviours, supporting formation of similar BHJ active layers. We correlate the approximate to 30 meV smaller open-circuit voltage in sq-BHJ devices to more substantial non-radiative recombination by voltage loss analysis. We also determine the exciton diffusion length of benchmark polymer PBDB-T to be 10 +/- 3 nm. Our results demonstrate high-efficiency OSC devices using sequential deposition method and provide new opportunities to further improve performance of state-of-the-art OSCs.
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| 17. |
- Zhang, Liangdong, et al.
(author)
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Bright Free Exciton Electroluminescence from Mn-Doped Two-Dimensional Layered Perovskites
- 2019
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In: The Journal of Physical Chemistry Letters. - : AMER CHEMICAL SOC. - 1948-7185. ; 10:11, s. 3171-3175
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Journal article (peer-reviewed)abstract
- Two-dimensional (2D) perovskites incorporating hydrophobic organic spacer cations show improved film stability and morphology compared to their three-dimensional (3D) counterparts. However, 2D perovskites usually exhibit low photoluminescence quantum efficiency (PLQE) owing to strong exciton-phonon interaction at room temperature, which limits their efficiency in light-emitting diodes (LEDs). Here, we demonstrate that the device performance of 2D perovskite LEDs can be significantly enhanced by doping Mn(2+)in (benzimidazolium)(2)PbI4 2D perovskite films to suppress the exciton-phonon interaction. The distorted [PbI6](4-) octahedra by Mn-doping and the rigid benzimidazolium (BIZ) ring without branched chains in the 2D perovskite structure lead to improved crystallinity and rigidity of the perovskites, resulting in suppressed phonon-exciton interaction and enhanced PLQE. On the basis of this strategy, for the first time, we report yellow electroluminescence from free excitons in 2D (n = 1) perovskites with a maximum brightness of 225 cd m(-2) and a peak EQE of 0.045%.
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| 18. |
- Zhang, Yuehui, et al.
(author)
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Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats. : Uterine and placental ferroptosis in pregnant PCOS-like rats
- 2020
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In: The Journal of endocrinology. - 1479-6805. ; 246:3, s. 247-63
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Journal article (peer-reviewed)abstract
- Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces hyperandrogenism and insulin resistance (HAIR) and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, and increased Dpp4 mRNA expression. In contrast, in placentas co-exposed to DHT and INS we found decreased Dpp4 mRNA expression and increased Cisd1 mRNA expression. Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.
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| 19. |
- Zhang, Yuehui, et al.
(author)
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Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats.
- 2020
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In: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 246:3, s. 247-263
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Journal article (peer-reviewed)abstract
- Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces hyperandrogenism and insulin resistance (HAIR) and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, and increased Dpp4 mRNA expression. In contrast, in placentas co-exposed to DHT and INS we found decreased Dpp4 mRNA expression and increased Cisd1 mRNA expression. Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.
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| 20. |
- Zhang, Yuehui, et al.
(author)
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Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance. : Deciphering the role of uterine AR in PCOS during early pregnancy
- 2021
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In: Journal of molecular medicine (Berlin, Germany). - : Springer Science and Business Media LLC. - 1432-1440 .- 0946-2716. ; 99, s. 1427-1446
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Journal article (peer-reviewed)abstract
- In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility. KEY MESSAGES: The proper regulation of uterine androgen receptor (AR) contributes to a normal pregnancy process, whereas the aberrant regulation of uterine AR might be linked to polycystic ovary syndrome (PCOS)-induced pregnancy-related complications. In the current study, we found that during normal rat pregnancy there is a stage-dependent decrease in AR abundance in the gravid uterus and that this is correlated with the differential expression of the endometrial receptivity and decidualization genes Spp1, Prl, Igfbp1, and Hbegf. Pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin (INS) or to DHT alone show elevated uterine AR protein abundance and implantation failure related to the aberrant expression of genes involved in endometrial receptivity and decidualization in early to mid-gestation. Treatment with the anti-androgen flutamide, starting from pre-implantation, effectively prevents DHT + INS-induced defects in endometrial receptivity and decidualization gene expression, restores uterine mitochondrial homeostasis, and increases the pregnancy rate and the numbers of viable fetuses. This study adds to our understanding of the mechanisms underlying poor pregnancy outcomes in PCOS patients and the possible therapeutic use of anti-androgens, including flutamide, after spontaneous conception.
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