36 research outputs found

    Competing endogenous RNA network analysis of Turner syndrome patient-specific iPSC-derived cardiomyocytes reveals dysregulation of autosomal heart development genes by altered dosages of X-inactivation escaping non-coding RNAs

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    Abstract Background A 45,X monosomy (Turner syndrome, TS) is the only chromosome haploinsufficiency compatible with life. Nevertheless, the surviving TS patients still suffer from increased morbidity and mortality, with around one-third of them subjecting to heart abnormalities. How loss of one X chromosome drive these conditions remains largely unknown. Methods Here, we have generated cardiomyocytes (CMs) from wild-type and TS patient-specific induced pluripotent stem cells and profiled the mRNA, lncRNA and circRNA expression in these cells. Results We observed lower beating frequencies and higher mitochondrial DNA copies per nucleus in TS-CMs. Moreover, we have identified a global transcriptome dysregulation of both coding and non-coding RNAs in TS-CMs. The differentially expressed mRNAs were enriched of heart development genes. Further competing endogenous RNA network analysis revealed putative regulatory circuit of autosomal genes relevant with mitochondrial respiratory chain and heart development, such as COQ10A, RARB and WNT2, mediated by X-inactivation escaping lnc/circRNAs, such as lnc-KDM5C-4:1, hsa_circ_0090421 and hsa_circ_0090392. The aberrant expressions of these genes in TS-CMs were verified by qPCR. Further knockdown of lnc-KDM5C-4:1 in wild-type CMs exhibited significantly reduced beating frequencies. Conclusions Our study has revealed a genomewide ripple effect of X chromosome halpoinsufficiency at post-transcriptional level and provided insights into the molecular mechanisms underlying heart abnormalities in TS patients

    Electric Field Facilitating Hole Transfer in Non-Fullerene Organic Solar Cells with a Negative HOMO Offset

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    The record high photoinduced current and power conversion efficiencies of organic solar cells (OSCs) should be attributed to the significant contribution of non-fullerene electron acceptors via hole transfer to electron donors and/or a pronounced decrease in energy losses for exciton dissociation by aligned highest occupied molecular orbitals (HOMOs) or lowest unoccupied molecular orbitals (LUMOs). However, the hole transfer mechanism in those highly efficient non-fullerene OSCs with small HOMO offsets has not been extensively studied and fully understood, yet. Herein, we comparatively study the hole transfer kinetics in two OSCs with a positive (0.05 eV) and a negative (-0.07 eV) HOMO offset (Delta HOMO) based on polymer donor PTQ10 paired with non-fullerene acceptors ZITI-C or ZITI-N. Short-circuit current densities (J(sc)) of 20.42 and 12.81 mA cm(-2) are achieved in the OSCs based on PTQ10:ZITI-C (Delta HOMO = 0.05 eV) and PTQ10:ZITI-N (Delta HOMO = -0.07 eV) with an optimized donor (D):acceptor (A) ratio of 1:1, respectively, despite the small and even negative Delta HOMO. Results from time-resolved transient absorption spectroscopy show slower hole transfer (14.3 ps) in PTQ10:ZITI-N than that (3.7 ps) in PTQ10:ZITI-C. To understand the decent J(sc) value in the OSCs of PTQ10:ZITI-N, the temperature and electric field dependences of hole transfer are investigated in low-donor-content OSCs (D:A ratio of 1:9) in which photocurrent is dominated by the contribution via hole transfer from ZITI-N to PTQ10. Devices based on PTQ10:ZITI-C and PTQ10:ZITI-N show similar free charge generation behavior as a function of temperature, whereas the external quantum efficiencies of the PTQ10:ZITI-N device exhibit a much stronger bias dependence than that of PTQ10:ZITI-C, which suggests that the electric field facilitates exciton dissociation in PTQ10:ZITI-N where the energetic driving force alone cannot efficiently dissociate excitons.Funding Agencies|Swedish Government Strategic Research Area in Material Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU ) [200900971]; Swedish Research CouncilSwedish Research Council [2017-04123]; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation [2016.0059]; China Scholarship Council (CSC)China Scholarship Council; National Key R&amp;D Program of China [2019YFA0705900, 2017YFA0204701]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [21572234, 21661132006, 91833304]</p

    Attenuation of TGFBR2 expression and tumour progression in prostate cancer involve diverse hypoxia-regulated pathways

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    Abstract Background Dysregulation of transforming growth factor β (TGF-β) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-β signaling, may contribute to carcinogenesis and progression of prostate cancer (PCa). However, the biological function and regulatory mechanism of TGFBR2 in PCa remain poorly understood. In this study, we propose to investigate the crosstalk of hypoxia and TGF-β signaling and provide insight into the molecular mechanism underlying the regulatory pathways in PCa. Methods Prostate cancer cell lines were cultured in hypoxia or normoxia to evaluate the effect of hypoxia on TGFBR2 expression. Methylation specific polymerase chain reaction (MSP) and demethylation agents was used to evaluate the methylation regulation of TGFBR2 promoter. Besides, silencing of EZH2 via specific siRNAs or chemical inhibitor was used to validate the regulatory effect of EZH2 on TGFBR2. Moreover, we conducted PCR, western blot, and luciferase assays which studied the relationship of miR-93 and TGFBR2 in PCa cell lines and specimens. We also detected the impacts of hypoxia on EZH2 and miR-93, and further examined the tumorigenic functions of miR-93 on proliferation and epithelial-mesenchymal transition via a series of experiments. Results TGFBR2 expression was attenuated under hypoxia. Hypoxia-induced EZH2 promoted H3K27me3 which caused TGFBR2 promoter hypermethylation and contributed to its epigenetic silencing in PCa. Besides, miR-93 was significantly upregulated in PCa tissues and cell lines, and negatively correlated with the expression of TGFBR2. Ectopic expression of miR-93 promoted cell proliferation, migration and invasion in PCa, and its expression could also be induced by hypoxia. In addition, TGFBR2 was identified as a bona fide target of miR-93. Conclusions Our findings elucidate diverse hypoxia-regulated pathways including EZH2-mediated hypermethylation and miR-93-induced silencing contribute to attenuation of TGFBR2 expression and promote cancer progression in prostate cancer

    Subtle Molecular Tailoring Induces Significant Morphology Optimization Enabling over 16% Efficiency Organic Solar Cells with Efficient Charge Generation

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    Manipulating charge generation in a broad spectral region has proved to be crucial for nonfullerene-electron-acceptor-based organic solar cells (OSCs). 16.64% high efficiency binary OSCs are achieved through the use of a novel electron acceptor AQx-2 with quinoxaline-containing fused core and PBDB-TF as donor. The significant increase in photovoltaic performance of AQx-2 based devices is obtained merely by a subtle tailoring in molecular structure of its analogue AQx-1. Combining the detailed morphology and transient absorption spectroscopy analyses, a good structure-morphology-property relationship is established. The stronger pi-pi interaction results in efficient electron hopping and balanced electron and hole mobilities attributed to good charge transport. Moreover, the reduced phase separation morphology of AQx-2-based bulk heterojunction blend boosts hole transfer and suppresses geminate recombination. Such success in molecule design and precise morphology optimization may lead to next-generation high-performance OSCs

    Revealing the Critical Role of the HOMO Alignment on Maximizing Current Extraction and Suppressing Energy Loss in Organic Solar Cells

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    For state-of-the-art organic solar cells (OSCs) consisting of a large-bandgap polymer donor and a near-infrared (NIR) molecular acceptor, the control of the HOMO offset is the key to simultaneously achieve small energy loss (Eloss) and high photocurrent. However, the relationship between HOMO offsets and the efficiency for hole separation is quite elusive so far, which requires a comprehensive understanding on how small the driving force can effectively perform the charge separation while obtaining a high photovoltage to ensure high OSC performance. By designing a new family of ZITI-X NIR acceptors (X = S, C, N) with a high structural similarity and matching them with polymer donor J71 forming reduced HOMO offsets, we systematically investigated and established the relationship among the photovoltaic performance, energy loss, and hole-transfer kinetics. We achieved the highest PCEavgs of 14.05 ± 0.21% in a ternary system (J71:ZITI-C:ZITI-N) that best optimize the balance between driving force and energy loss

    Gut Microbiota Profile in Adult Patients with Idiopathic Nephrotic Syndrome

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    Background. Increasing evidences have reported gut microbiota dysbiosis in many diseases, including chronic kidney disease and pediatric idiopathic nephrotic syndrome (INS). There is lack evidence of intestinal microbiota dysbiosis in adults with INS, however. Here, we to address the association between the gut microbiome and INS. Methods. Stool samples of 35 adult INS patients and 35 healthy volunteers were collected. Total bacterial DNA was extracted, and the V4 regions of the bacterial 16S ribosomal RNA gene were sequenced. The fecal microbiome was analyzed using bioinformatics. The correlation analysis between altered taxa and clinical parameters was also included. Results. We found that microbial diversity in the gut was reduced in adult patients with INS. Acidobacteria, Negativicutes, Selenomonadales, Veillonellaceae, Clostridiaceae, Dialister, Rombousia, Ruminiclostridium, Lachnospira, Alloprevotella, Clostridium sensu stricto, Megamonas, and Phascolarctobacterium were significantly reduced, while Pasteurellales, Parabacteroides, Bilophila, Enterococcus, Eubacterium ventriosum, and Lachnoclostridium were markedly increased in patients with INS. In addition, Burkholderiales, Alcaligenaceae, and Barnesiella were negatively correlated with serum creatinine. Blood urea nitrogen levels were positively correlated with Christensenellaceae, Bacteroidales_S24.7, Ruminococcaceae, Ruminococcus, and Lachnospiraceae_NK4A136, but were negatively correlated with Flavonifractor_plautii and Erysipelatoclostridium_ramosum. Enterobacteriales, Enterobacteriaceae, Porphyromonadaceae, Escherichia/Shigella, Parabacteroides, and Escherichia_coli were positively correlated with albumin. Proteinuria was positively correlated with Verrucomicrobia, Coriobacteriia, Thermoleophilia, Ignavibacteria, Coriobacteriales, Nitrosomonadales, Coriobacteriaceae, and Blautia, but was negatively correlated with Betaproteobacteria, Burkholderiales, and Alcaligenaceae. Conclusion. Our findings show compositional alterations of intestinal microbiota in adult patients with INS and correlations between significantly altered taxa and clinical parameters, which points out the direction for the development of new diagnostics and therapeutic approaches targeted intestinal microbiota

    Near infrared electron acceptors with a photoresponse beyond 1000 nm for highly efficient organic solar cells

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    Developing near infrared (NIR) organic semiconductors is indispensable for promoting the performance of organic solar cells (OSCs), but addressing the trade-off between voltage and current density thus achieving high efficiency with low energy loss is still an urgent challenge. Herein, NIR acceptors (H1, H2 and H3) with a photoresponse beyond 1000 nm were developed by conjugating dithienopyrrolobenzothiadiazole to 2-(5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrileviavaried alkyl thiophene bridges. It was found that the linear outward chains in thiophene bridges could mitigate both the conformation disorder of H3 and the electronic disorder of the PBDB-T:H3 blends, which could help to form a favorable blend morphology, facilitating highly efficient photoelectric conversion in the resultant OSCs. As a result, devices based on PBDB-T:H3 achieve a high efficiency of 13.75% with a low energy loss of 0.55 eV, which is one of the highest efficiencies and the lowest energy loss among OSCs with an optoelectronic response near 1000 nm. This work provides a new design strategy towards NIR acceptors for efficient OSCs and future exploration of functional optoelectronics.Funding Agencies|National Key Research and Development program of China [2019YFA0705900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [21734008, 51803178, 61721005, 21722404, 21674093]; Zhejiang Natural Science Fund for Distinguished Young Scholars [LR17E030001]; NSFC/RGC Joint Research SchemeNational Natural Science Foundation of China (NSFC) [N_CUHK418/17]; Knut and Alice Wallenberg FoundationKnut &amp; Alice Wallenberg Foundation [2016.00590]; Government Strategic Research Area in Material Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [200900971]; China Scholarship Council (CSC)China Scholarship Council</p

    Asymmetric Electron Acceptors for High‐Efficiency and Low‐Energy‐Loss Organic Photovoltaics

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    Low energy loss and efficient charge separation under small driving forces are the prerequisites for realizing high power conversion efficiency (PCE) in organic photovoltaics (OPVs). Here, a new molecular design of nonfullerene acceptors (NFAs) is proposed to address above two issues simultaneously by introducing asymmetric terminals. Two NFAs, BTP-S1 and BTP-S2, are constructed by introducing halogenated indandione (A(1)) and 3-dicyanomethylene-1-indanone (A(2)) as two different conjugated terminals on the central fused core (D), wherein they share the same backbone as well-known NFA Y6, but at different terminals. Such asymmetric NFAs with A(1)-D-A(2) structure exhibit superior photovoltaic properties when blended with polymer donor PM6. Energy loss analysis reveals that asymmetric molecule BTP-S2 with six chlorine atoms attached at the terminals enables the corresponding devices to give an outstanding electroluminescence quantum efficiency of 2.3 x 10(-2)%, one order of magnitude higher than devices based on symmetric Y6 (4.4 x 10(-3)%), thus significantly lowering the nonradiative loss and energy loss of the corresponding devices. Besides, asymmetric BTP-S1 and BTP-S2 with multiple halogen atoms at the terminals exhibit fast hole transfer to the donor PM6. As a result, OPVs based on the PM6:BTP-S2 blend realize a PCE of 16.37%, higher than that (15.79%) of PM6:Y6-based OPVs. A further optimization of the ternary blend (PM6:Y6:BTP-S2) results in a best PCE of 17.43%, which is among the highest efficiencies for single-junction OPVs. This work provides an effective approach to simultaneously lower the energy loss and promote the charge separation of OPVs by molecular design strategy.Funding Agencies|National Key Research and Development Program of China [2019YFA0705900]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [21734008, 21875216, 51803178, 61721005]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2017M621907, 2019T120501]; S&amp;T Innovation 2025 Major Special Programme of Ningbo [2018B10055]; Research Grant Council of Hong KongHong Kong Research Grants Council [N_CUHK418/17, 14303519, 4053304]; Swedish Government Strategic Research Area in Material Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [200900971]; Swedish Research CouncilSwedish Research Council [2017-04123]; China Scholarship Council (CSC)China Scholarship Council</p
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