Understanding information processing in the brain requires monitoring neuronal activity at high spatiotemporal resolution. Using an ultrafast two-photon fluorescence microscope empowered by ...all-optical laser scanning, we imaged neuronal activity in vivo at up to 3,000 frames per second and submicrometer spatial resolution. This imaging method enabled monitoring of both supra- and subthreshold electrical activity down to 345 μm below the brain surface in head-fixed awake mice.
Plant recognition and defence against pathogens employs a two‐tiered perception system. Surface‐localized pattern recognition receptors (PRRs) act to recognize microbial features, whereas ...intracellular nucleotide‐binding leucine‐rich repeat receptors (NLRs) directly or indirectly recognize pathogen effectors inside host cells. Employing the tomato PRR LeEIX2/EIX model system, we explored the molecular mechanism of signalling pathways. We identified an NLR that can associate with LeEIX2, termed SlNRC4a (NB‐LRR required for hypersensitive response‐associated cell death‐4). Co‐immunoprecipitation demonstrates that SlNRC4a is able to associate with different PRRs. Physiological assays with specific elicitors revealed that SlNRC4a generally alters PRR‐mediated responses. SlNRC4a overexpression enhances defence responses, whereas silencing SlNRC4 reduces plant immunity. Moreover, the coiled‐coil domain of SlNRC4a is able to associate with LeEIX2 and is sufficient to enhance responses upon EIX perception. On the basis of these findings, we propose that SlNRC4a acts as a noncanonical positive regulator of immunity mediated by diverse PRRs. Thus, SlNRC4a could link both intracellular and extracellular immune perceptions.
Plant–microbe interactions involve a large number of regulatory systems essential for plant defence responses against biotic attack. Employing the tomato pattern recognition receptor (PRR) LeEIX2/EIX model system, we have identified a nucleotide‐binding leucine‐rich repeat (NB‐LRR) able to associate with LeEIX2, termed SlNRC4a. Our data suggest that SlNRC4a acts as a noncanonical NB‐LRR, positively regulating immunity mediated by diverse PRRs.
ABSTRACT
MicroRNAs (miRNAs) play a crucial role in the growth, development, morphogenesis, signal transduction, and stress response in plants. The ICE (Inducer of CBF expression)‐CBF (C‐repeat ...binding factor)‐COR (Cold‐regulated gene) regulatory cascade is an important signalling pathway in plant response to low temperature stress, and it remains unknown whether this pathway is regulated by miRNAs.
In this study, high‐throughput sequencing was employed for predicting and identifying the miRNAs that were likely to target the ICE‐CBF‐COR pathway in Eucalyptus camaldulensis. A novel ICE1‐targeting miRNA, eca‐novel‐miR‐259‐5p (nov‐miR259), was further analysed.
A total of 392 conserved miRNAs and 97 novel miRNAs were predicted, including 80 differentially expressed miRNAs. Of these, 30 miRNAs were predicted to be associated with the ICE‐CBF‐COR pathway. The full‐length of mature nov‐miR259 was 22 bp and its precursor gene was 60 bp in length, with a typical hairpin structure. The RNA ligase‐mediated 5′ amplification of cDNA ends (5′‐RLM‐RACE) and Agrobacterium‐mediated tobacco transient expression assays demonstrated that nov‐miR259 could cleave EcaICE1 in vivo. Moreover, qRT‐PCR and Pearson's correlation analysis further revealed that the expression levels of nov‐miR259 were almost significantly negatively correlated with those of its target gene, EcaICE1, and the other genes in the ICE‐CBF‐COR pathway.
We first identified the nov‐miR259 as a novel ICE1‐targeting miRNA, and the nov‐miR259‐ICE1 module may be involved in regulating the cold stress response in E. camaldulensis.
We identified a novel miRNA nov‐miR259 in Eucalyptus sp. that could cleave ICE1 and respond to cold stress via the CBF signalling pathway.
PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP ...inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor-resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC.
The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links ...to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl‐2 family, cytochrome c, Apaf‐1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross‐talk between several caspases and autophagy‐related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD‐modulating agents that may target caspases‐3, ‐8 and ‐9, and their substrates PARP‐1 and Beclin‐1, which may help us harness caspase‐modulated PCD pathways for future drug discovery.
Chemotherapy has been reported to induce epithelial-mesenchymal transition (EMT) in tumor cells, which is a critical step in the process of metastasis leading to cancer spreading and treatment ...failure. However, the underlying mechanisms of chemotherapy-induced EMT remain unclear, and the involvement of microRNAs (miRNA) in this process is poorly understood. To address these questions, we established stable chemotherapy-resistant tongue squamous cell carcinoma (TSCC) cell lines CAL27-res and SCC25-res by exposing the parental CAL27 and SCC25 lines to escalating concentrations of cisplatin for 6 months. CAL27-res and SCC25-res cells displayed mesenchymal features with enhanced invasiveness and motility. MiRNA microarray illustrated that miR-200b and miR-15b were the most significantly downregulated microRNAs in CAL27-res cells. Ectopic expression of miR-200b and miR-15b with miRNA mimics effectively reversed the phenotype of EMT in CAL27-res and SCC25-res cells, and sensitized them to chemotherapy, but inhibition of miR-200b and miR-15b in the sensitive lines with anti-sense oligonucleotides induced EMT and conferred chemoresistance. Retrieving the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a target for miR-200b and miR-15b, in the presence of the miRNA mimics by transfecting CAL27-res cells with pcDNA3.1-BMI1-carrying mutated seed sequences of miR-200b or miR-15b at its 3'-UTR recapitulated chemotherapy-induced EMT. In vivo, enforced miR-200b or miR-15b expression suppressed metastasis of TSCC xenografts established by CAL27-res cells. Clinically, reduced miR-200b or miR-15b expression was associated with chemotherapeutic resistance in TSCCs and poor patient survival. Our data suggest that reduced expression of miR-200b and miR-15b underscores the mechanisms of chemotherapy-induced EMT in TSCC, and may serve as therapeutic targets to reverse chemotherapy resistance in tongue cancers.
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Supercapacitors, also known as electrochemical capacitors, have witnessed a fast evolution in the recent years, but challenges remain. This review covers the fundamentals and ...state-of-the-art developments of supercapacitors. Conventional and novel electrode materials, including high surface area porous carbons for electrical double layer capacitors (EDLCs) and transition metal oxides, carbides, nitrides and their various nanocomposites for pseudocapacitors – are described. Latest characterization techniques help to better understand the charge storage mechanisms in such supercapacitors and recognize their current limitations, while recently proposed synthesis approaches enable various breakthroughs in this field.
We present a consistent and complete description of the coupling to matter in the Teleparallel Equivalent to General Relativity (TEGR) theory built from a Cartan connection, as we proposed in ...previous works. A first theorem allows us to obtain parallel transport from the Cartan connection into a proper Ehresmann connection, while a second ensures to link the TEGR-Cartan connection to the Ehresmann one-form that contains the Levi-Civita connection. This yields a coupling to matter in agreement with observations and the Equivalence Principle. As the fundamental fields proceed from the Cartan connection, if one insists on interpreting TEGR as a gauge theory of translations, such translation gauge field can be extracted from the consistent theory presented. However, this would entail a fundamental change in the structures known for gauge theory and a split between gauge field and connection is imperative. The willingness to take such a step is left to the reader.
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