Liquid-crystalline circularly polarised fluorescent emitters with a high luminescence dissymmetry factor.

Chiral liquid-crystalline emitters based on 9,9-dimethyl-10-(4-(phenylsulfonyl)phenyl)-9,10-dihydroacridine and a functionalised binaphthol show smectic liquid crystal phases and circularly polarised blue fluorescence with a high luminescence dissymmetry factor |glum| of 0.13. Solution-processable organic light-emitting diodes (OLEDs) based on the enantiomers were explored.

Liquid-crystalline circularly polarised TADF emitters for high-efficiency, solution-processable organic light-emitting diodes.

Achieving a high emission efficiency and a large luminescence asymmetry factor (glum) in a single molecule exhibiting circularly polarised thermally activated delayed fluorescence (CP-TADF) remains a formidable challenge. In this work, a proof-of-concept, liquid-crystalline CP-TADF molecule is proposed to realise high glum by taking advantage of the order inherent in liquid crystals. Employing a chiral dinaphthol-based CP-TADF molecule as the emissive unit, a pair of liquid-crystalline CP-TADF molecules (R/S-4) is synthesised via the introduction of six mesogenic moieties. The enantiomers show intense emission at about 520 nm which has clear TADF and liquid-crystalline characteristics. Both enantiomers display symmetrical electronic circular dichroism (CD) and circular polarisation luminescence (CPL) signals as thin films. Impressively, relatively large glum values of 0.11 are realised for the films. Solution-processed devices were fabricated using R/S-4 as the dopants, with the TADF molecule CzAcSF as the sensitiser. The OLEDs so prepared show a very high maximum external quantum efficiency of 21.2%, revealing a novel strategy for realising large glum values in CP-TADF.

Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

Binaphthol-based chiral host molecules for efficient solution-processed circularly polarized OLEDs.

Two kinds of chiral hosts, named (R/S)-BN-mCP and (R/S)-BN-2mCP, are prepared. Solution processable circularly polarized organic light-emitting diodes (CP-OLEDs) based on the chiral hosts and achiral emitter Ir(mypp)3 present the maximum external quantum efficiency (EQEmax) and dissymmetry factor values (gEL) of 12.7%/-1.7 × 10-3 and 17.1%/-1.3 × 10-3, respectively. Using (R)-BN-2mCP as the chiral host and Ir(mypp)3 and Ir(piq)2(acac) as the achiral emitters, the solution-processed OLED exhibits a broad emission spectrum with the EQEmax of 12.1% and gEL of -1.1 × 10-3.

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2.

Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function.

Proteomics and phosphoproteomics of chordoma biopsies reveal alterations in multiple pathways and aberrant kinases activities.

Background: Chordoma is a slow-growing but malignant subtype of bone sarcoma with relatively high recurrence rates and high resistance to chemotherapy. It is urgent to understand the underlying regulatory networks to determine more effective potential targets. Phosphorylative regulation is currently regarded as playing a significant role in tumorigenesis, and the use of tyrosine kinase inhibitors in clinical practice has yielded new promise for the treatment of a variety of sarcoma types. Materials and methods: We performed comprehensive proteomic and phosphoproteomic analyses of chordoma using four-dimensional label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. The potential aberrantly expressed kinases and their functions were validated using western blotting and CCK-8 assays. Results: Compared with paired normal muscle tissues, 1,139 differentially expressed proteins (DEPs) and 776 differentially phosphorylated proteins (DPPs) were identified in chordoma tumor tissues. The developmentally significant Wnt-signaling pathway and oxidative phosphorylation were aberrant in chordoma. Moreover, we predicted three kinases (AURA, CDK9, and MOK) with elevated activity by kinase-pathway network analysis (KiPNA) and verified their increased expression levels. The knockdown of these kinases markedly suppressed chordoma cell growth, and this was also the case for cells treated with the CDK9 inhibitor AZD4573. We additionally examined 208 proteins whose expression and phosphorylation levels were synergetically altered. Conclusions: We herein depicted the collective protein profiles of chordomas, providing insight into chordomagenesis and the potential development of new therapeutic targets.

Eight-lncRNA signature of cervical cancer were identified by integrating DNA methylation, copy number variation and transcriptome data.

BACKGROUND: Copy number variation (CNV) suggests genetic changes in malignant tumors. Abnormal expressions of long non-coding RNAs (lncRNAs) resulted from genomic and epigenetic abnormalities play a driving role in tumorigenesis of cervical cancer. However, the role of lncRNAs-related CNV in cervical cancer remained largely unclear. METHODS: The data of messenger RNAs (mRNAs), DNA methylation, and DNA copy number were collected from 292 cervical cancer specimens. The prognosis-related subtypes of cervical cancer were determined by multi-omics integration analysis, and protein-coding genes (PCGs) and lncRNAs with subtype-specific expressions were identified. The CNV pattern of the subtype-specific lncRNAs was analyzed to identify the subtype-specific lncRNAs. A prognostic risk model based on lncRNAs was established by least absolute shrinkage and selection operator (LASSO). RESULTS: Multi-omics integration analysis identified three molecular subtypes incorporating 617 differentially expressed lncRNAs and 1395 differentially expressed PCGs. The 617 lncRNAs were found to intersect with disease-related lncRNAs. Functional enrichment showed that 617 lncRNAs were mainly involved in tumor metabolism, immunity and other pathways, such as p53 and cAMP signaling pathways, which are closely related to the development of cervical cancer. Finally, according to CNV pattern consistent with differential expression analysis, we established a lncRNAs-based signature consisted of 8 lncRNAs, namely, RUSC1-AS1, LINC01990, LINC01411, LINC02099, H19, LINC00452, ADPGK-AS1, C1QTNF1-AS1. The interaction of the 8 lncRNAs showed a significantly poor prognosis of cervical cancer patients, which has also been verified in an independent dataset. CONCLUSION: Our study expanded the network of CNVs and improved the understanding on the regulatory network of lncRNAs in cervical cancer, providing novel biomarkers for the prognosis management of cervical cancer patients.

Low KLOTHO level related to aging is associated with diminished ovarian reserve.

OBJECTIVE: To explore the relationship between KLOTHO expression and diminished ovarian reserve (DOR). DESIGN: A case-control study. SETTING: Reproductive medicine center. PATIENT(S): A total of 157 patients with DOR and 159 control women were recruited from the Centre of Reproductive Medicine, Peking University Third Hospital. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The granulosa cells were isolated from follicular fluid after oocyte retrieval, and the KLOTHO level of granulosa cell was measured using a modified quantitative polymerase chain reaction technique. The serum KLOTHO level was measured by solid-phase sandwich enzyme-linked immunosorbent assay. RESULT(S): In both granulosa cells and serum derived from women with DOR, KLOTHO expressions were significantly lower compared with normal ovarian reserve controls. Moreover, KLOTHO expression diminished with advancing age. CONCLUSION(S): Diminished KLOTHO expression was associated with DOR. Further longitudinal studies in a similar population accompanying disease progression and mechanism exploration are needed to substantiate the rules of KLOTHO in reproductive aging.

Integrative analysis of genomic and epigenetic regulation of endometrial cancer.

Endometrial carcinomas (EC) are characterized by high DNA copy numbers and DNA methylation aberrations. In this study, we sought to comprehensively explore the effect of these two factors on development and progression of EC by analyzing integrated genomic and epigenetic analysis to. We found high DNA copy number and DNA methylation abnormalities in EC, with 6308 copy-number variation genes (CNV-G) and 4376 methylation genes (MET-G). We used these CNV-G and MET-G to subcategorize the samples for prognostic analysis, and identified three molecular subtypes (iC1, iC2, iC3). Moreover, the subtypes exhibited different tumor immune microenvironment characteristics. A further analysis of their molecular characteristics revealed three potential prognostic markers (KIAA1324, nonexpresser of pathogenesis-related genes1 (NPR1) and idiopathic hypogonadotropic hypogonadism (IHH)). Notably, all three markers showed distinct CNV, DNA methylation, and gene expression profiles. Analysis of mutations among the three subtypes revealed that iC2 had fewer mutations than the other subtypes. Conversely, iC2 showed significantly higher CNV levels than other subtypes. This comprehensive analysis of genomic and epigenetic profiles identified three prognostic markers, therefore, provides new insights into the multi-layered pathology of EC. These can be utilized for accurate treatment of EC patients.

Identification of a point mutation PMLS214L-RARα that alters PML body organization, dynamics and SUMOylation.

Genetic mutations on PML-RARα in acute promyelocytic leukemia (APL) are reported to associate with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) resistance. Here we performed a retrospective analysis of APL patients and identified that the patient with S214L mutation on the PML moiety of PML-RARα showed resistance to both ATO and ATRA. Super-resolution microcopy was used to examine the structural response of PML bodies in wild-type or the S214L mutant cells upon drug treatment. Different protein density and fluidity were identified with the S214L mutant PML bodies by single particle quantification and FRAP analysis. We discovered that altered SUMOylation and ubiquitination might contribute to the drug resistance. Taken together, we have revealed that the S214L mutation on PML-RARα disrupted the organization of PML body and dynamics changes, perturbing structural responses to ATRA and subsequent oncoprotein degradation. Our findings shed new light on the structural alterations of PML bodies and mechanisms of APL drug resistance.