Nitrogen-doped mesoporous carbons (NMCs) with controllable nitrogen doping and similar mesoporous structures are prepared by a facile colloidal silica nanocasting method using melamine, phenol, and ...formaldehyde as precursors. Various physicochemical properties, such as the oxidation stability, the conductivity and the electrochemical capacitive performance, the CO2 adsorption, the basicity, and the metal-free catalytic activity of the NMCs, are studied extensively in relation to the incorporation amount of nitrogen in the carbon backbone. The dependence of the oxidation stability and the conductivity of the NMCs on the nitrogen content are similar; both of the biggest improvements are achieved at a low nitrogen content of ca. 4.2 wt %. While used as the supercapacitor electrodes, the NMCs with a mediate nitrogen content of ca. 8 wt % can take full advantage of the nitrogen-induced pseudocapacitance and the nitrogen-enhanced conductivity, delivering an excellent high-rate capacitive performance. The nitrogen content does not play an important role in the CO2 physical adsorption, where the effect of microporosity prevails over the nitrogen-doped carbon surface. However, the nitrogen content determines the basicity of the NMCs, which governs their CO2 chemical adsorption ability and the metal-free catalytic activity for direct oxidation of H2S. The higher the nitrogen content, the higher the basicity and the catalytic activity. Our studies give a reliable relationship between nitrogen doping and the physicochemical properties of mesoporous carbons, which should provide a useful guide to their practical applications.
Alternative cleavage and polyadenylation (APA) generates diverse mRNA isoforms. We developed 3' region extraction and deep sequencing (3'READS) to address mispriming issues that commonly plague ...poly(A) site (pA) identification, and we used the method to comprehensively map pAs in the mouse genome. Thorough annotation of gene 3' ends revealed over 5,000 previously overlooked pAs (∼8% of total) flanked by A-rich sequences, underscoring the necessity of using an accurate tool for pA mapping. About 79% of mRNA genes and 66% of long noncoding RNA genes undergo APA, but these two gene types have distinct usage patterns for pAs in introns and upstream exons. Quantitative analysis of APA isoforms by 3'READS indicated that promoter-distal pAs, regardless of intron or exon locations, become more abundant during embryonic development and cell differentiation and that upregulated isoforms have stronger pAs, suggesting global modulation of the 3' end-processing activity in development and differentiation.
Squamous metaplasia of the breast is a rare and unusual finding. A number of benign and malignant differential entities exist when squamous cells are present in a breast lesion. Our patient was found ...to have pronounced squamous metaplasia and keratin cysts arising in a complex fibroadenoma. The rare nature of squamous metaplasia arising in such a lesion poses some diagnostic challenges, as squamous epithelium and squamous metaplasia in the breast may raise suspicion for malignancy. Herein we present a unique case and discussion of benign and malignant differential entities. We also retrospectively reviewed a series of complex fibroadenomas in our institution, including the demographic and histologic features, and more importantly the associated breast cancer risk.
Immune checkpoint blockade of the inhibitory immune receptors PD-L1, PD-1 and CTLA-4 has emerged as a successful treatment strategy for several advanced cancers. Here we demonstrate that miR-424(322) ...regulates the PD-L1/PD-1 and CD80/CTLA-4 pathways in chemoresistant ovarian cancer. miR-424(322) is inversely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression. High levels of miR-424(322) in the tumours are positively correlated with the progression-free survival of ovarian cancer patients. Mechanistic investigations demonstrated that miR-424(322) inhibited PD-L1 and CD80 expression through direct binding to the 3'-untranslated region. Restoration of miR-424(322) expression reverses chemoresistance, which is accompanied by blockage of the PD-L1 immune checkpoint. The synergistic effect of chemotherapy and immunotherapy is associated with the proliferation of functional cytotoxic CD8+ T cells and the inhibition of myeloid-derived suppressive cells and regulatory T cells. Collectively, our data suggest a biological and functional interaction between PD-L1 and chemoresistance through the microRNA regulatory cascade.
Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3' untranslated regions (3'UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors ...regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3'UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5' end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS), a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors.
Vibration energy harvesting, which converts the mechanical vibrations that are commonly available in the surrounding environment to electrical energy, can realize self-power sensing, control and ...actuation, with the advantages of convenience, energy saving, eco friendliness and sustainability. However, it has some weakness, such as low output power, low efficiency, poor environmental adaptability and low reliability, which restrict its practical applications. It is necessary to optimize the harvester's structure, bias conditions and so on to adapt to the characteristics of ambient vibration, and then enhance the mechanical energy harvesting capability. This paper focuses on improving capability of the cantilever magnetostrictive harvester which is a new technology and still in the stage of proof-of working mechanism and concept prototype design. It systematically clarified the qualitative laws of the major factors affecting harvesting performance, including geometry, bias conditions, etc. Moreover, considering the low frequency characteristics of ambient vibration, it proposed an elastic magnifier with additional mass which can simultaneously enhance vibration harvesting, reduce resonance frequency and broaden effective frequency range. It was experimentally verified that the optimized magnetostrictive harvester can convert the mechanical vibration of 1 g acceleration into the voltage of 1210 mV. It was able to output 11 mW power to a load and the normalized power density reached to 18.3 mW/cm3/g. The magnetostrictive harvesting prototype successfully powered for multiple light emitting diode lamps, multiple digital display tubes and a low power electronic meter.
Alternative polyadenylation (APA) produces mRNA isoforms with different 3′ UTR lengths. Previous studies indicated that 3′ end processing and mRNA export are intertwined in gene regulation. Here, we ...show that mRNA export factors generally facilitate usage of distal cleavage and polyadenylation sites (PASs), leading to long 3′ UTR isoform expression. By focusing on the export receptor NXF1, which exhibits the most potent effect on APA in this study, we reveal several gene features that impact NXF1-dependent APA, including 3′ UTR size, gene size, and AT content. Surprisingly, NXF1 downregulation results in RNA polymerase II (Pol II) accumulation at the 3′ end of genes, correlating with its role in APA regulation. Moreover, NXF1 cooperates with CFI-68 to facilitate nuclear export of long 3′ UTR isoform with UGUA motifs. Together, our work reveals important roles of NXF1 in coordinating transcriptional dynamics, 3′ end processing, and nuclear export of long 3′ UTR transcripts, implicating NXF1 as a nexus of gene regulation.
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•mRNA export factors generally promote expression of long 3′ UTR isoforms•Gene size and AT content impact alternative polyadenylation of 3′ UTRs•NXF1 regulates RNA polymerase II distribution along the gene•NXF1 together with CFI-68 facilitates nuclear export of long 3′ UTR transcripts
3′ end processing and mRNA export are intertwined in gene regulation. Chen et al. show that the mRNA export receptor NXF1 globally impacts Pol II dynamics, enhances expression of long 3′ UTR isoforms, and facilitates their nuclear export, implicating NXF1 as a nexus for gene expression.
Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD ...factor is the ATP-dependent RNA helicase upframeshift 1 (UPF1). Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for premature termination codon (PTC)-containing reporter mRNAs when compared with their PTC-free counterparts. Here, we map phosphorylated UPF1 (p-UPF1)-binding sites using transcriptome-wide footprinting or DNA oligonucleotide-directed mRNA cleavage to report that p-UPF1 provides the first reliable cellular NMD target marker. p-UPF1 is enriched on NMD target 3' untranslated regions (UTRs) along with suppressor with morphogenic effect on genitalia 5 (SMG5) and SMG7 but not SMG1 or SMG6. Immunoprecipitations of UPF1 variants deficient in various aspects of the NMD process in parallel with Förster resonance energy transfer (FRET) experiments reveal that ATPase/helicase-deficient UPF1 manifests high levels of RNA binding and disregulated hyperphosphorylation, whereas wild-type UPF1 releases from nonspecific RNA interactions in an ATP hydrolysis-dependent mechanism until an NMD target is identified. 3' UTR-associated UPF1 undergoes regulated phosphorylation on NMD targets, providing a binding platform for mRNA degradative activities. p-UPF1 binding to NMD target 3' UTRs is stabilized by SMG5 and SMG7. Our results help to explain why steady-state UPF1 binding is not a marker for cellular NMD substrates and how this binding is transformed to induce mRNA decay.
For a number of human genes that encode transcripts containing inverted repeat Alu elements (IRAlus) within their 3' untranslated region (UTR), product mRNA is efficiently exported to the cytoplasm ...when the IRAlus, which mediate nuclear retention, are removed by alternative polyadenylation. Here we report a new mechanism that promotes gene expression by targeting mRNAs that maintain their 3' UTR IRAlus: Binding of the dsRNA-binding protein Staufen1 (STAU1) to 3' UTR IRAlus inhibits nuclear retention so as to augment the nuclear export of 3' UTR IRAlus-containing mRNAs (IRAlus mRNAs). Moreover, we found that 3' UTR IRAlus-bound STAU1 enhances 3' UTR IRAlus mRNA translation by precluding protein kinase R (PKR) binding, which obviates PKR activation, eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and repression of global cell translation. Thus, STAU1 binding to 3' UTR IRAlus functions along with 3' UTR IRAlus-mediated nuclear retention to suppress the shutdown of cellular translation triggered by PKR binding to endogenous cytoplasmic dsRNAs. We also show that a changing STAU1/PKR ratio contributes to myogenesis via effects on the 3' UTR IRAlus of mRNA encoding the microRNA-binding protein LIN28.
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