The first phosphoric acid catalyzed direct arylation of 2‐naphthylamines with iminoquinones for the atroposelective synthesis of axially chiral biaryl amino alcohols has been developed. This reaction ...constitutes a highly functional‐group‐tolerant route for the rapid construction of enantioenriched axially chiral biaryl amino alcohols, and is a rare example of 2‐naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation. Furthermore, the products, which feature various halogen atoms, provide access to structurally diverse axially chiral amino alcohols through further transformations.
The phosphoric acid catalyzed direct arylation of 2‐naphthylamines with iminoquinones enables the atroposelective synthesis of axially chiral biaryl amino alcohols. Many functional groups are tolerated in this reaction, and it is a rare example of 2‐naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation.
MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides, which negatively regulate the gene expression at the post-transcriptional level. This study describes an update of the ...miRTarBase (http://miRTarBase.mbc.nctu.edu.tw/) that provides information about experimentally validated miRNA-target interactions (MTIs). The latest update of the miRTarBase expanded it to identify systematically Argonaute-miRNA-RNA interactions from 138 crosslinking and immunoprecipitation sequencing (CLIP-seq) data sets that were generated by 21 independent studies. The database contains 4966 articles, 7439 strongly validated MTIs (using reporter assays or western blots) and 348 007 MTIs from CLIP-seq. The number of MTIs in the miRTarBase has increased around 7-fold since the 2014 miRTarBase update. The miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) are integrated to provide an effective overview of this exponential growth in the miRNA experimental data. These improvements make the miRTarBase one of the more comprehensively annotated, experimentally validated miRNA-target interactions databases and motivate additional miRNA research efforts.
Peptide drugs that target protein-protein interactions have attracted mounting research efforts towards clinical developments over the past decades. Increasing reports have indicated that expression ...of Musashi 1 (MSI1) is tightly correlated to high grade of cancers as well as enrichment of cancer stem cells. Treatment failure in malignant tumors glioblastoma multiform (GBM) had also been correlated to CSC-regulating properties of MSI1. It is thus imperative to develop new therapeutics that could effectively improve current regimens used in clinics. MSI1 and AGO2 are two emerging oncogenic molecules that both contribute to GBM tumorigenesis through mRNA regulation of targets involved in apoptosis and cell cycle. In this study, we designed peptide arrays covering the C-terminus of MSI1 and identified two peptides (Pep#11 and Pep#26) that could specifically interfere with the binding with AGO2. Our Biacore analyses ascertained binding between the identified peptides and AGO2. Recombinant reporter system Gaussian luciferase and fluorescent bioconjugate techniques were employed to determine biological functions and pharmacokinetic characteristics of these two peptides. Our data suggested that Pep#11 and Pep#26 could function as decoy peptides by mimicking the interaction function of MSI1 with its binding partner AGO2 in vitro and in vivo. Further experiments using GMB animal models corroborated the ability of Pep#11 and Pep#26 in disrupting MSI1/AGO2 interaction and consequently anti-tumorigenicity and prolonged survival rates. These striking therapeutic efficacies orchestrated by the synthetic peptides were attributed to the decoy function to C-terminal MSI1, especially in malignant brain tumors and glioblastoma.
Notch receptors (Notch1-4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the ...importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.
Cancer metastasis, a leading cause of death in patients, is associated with aberrant expression of epigenetic modifiers, yet it remains poorly defined how epigenetic readers drive metastatic growth ...and whether epigenetic readers are targetable to control metastasis. Here, we report that bromodomain-containing protein 4 (BRD4), a histone acetylation reader and emerging anticancer therapeutic target, promotes progression and metastasis of gastric cancer. The abundance of BRD4 in human gastric cancer tissues correlated with shortened metastasis-free gastric cancer patient survival. Consistently, BRD4 maintained invasiveness of cancer cells
and their dissemination at distal organs
. Surprisingly, BRD4 function in this context was independent of its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at posttranslational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to prevent Snail recognition by its E3 ubiquitin ligases FBXL14 and β-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analyses identified that BRD4 and Snail regulate a partially shared metastatic gene signature in gastric cancer cells. These findings reveal a noncanonical posttranscriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implications for treating gastric metastatic malignancies with clinically available bromodomain inhibitors. SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4869/F1.large.jpg.
Organic electrochemical transistors (OECTs) rely on both efficient ionic doping/de‐doping process and carrier transport in the mixed ionic‐electronic channel under the modulation of gate bias. ...Moreover, channels that hold photopatterning capability are highly desired to minimize parasitic capacitance and simplify the fabrication process/cost. However, yielding photo‐patternable channels with both precise/robust patterning capability and controllable ionic‐electronic coupling is still challenging. Herein, double‐end trifluoromethyl diazirines (DtFDA) with different chain lengths are introduced in the OECT channel to act as both photo‐crosslinker and medium to regulate ionic‐electronic transport. Specifically, high‐resolution patterns with a minimum line width/gap of 2 μm are realized in p(g2T‐T) or Homo‐gDPP based channels by introducing DtFDA. Maximum transconductances of 68.6 mS and 81.6 mS, current on/off ratio of 106 and 107 (under a drain voltage of only ±0.1 V), are achieved in p‐ and n‐type vertical OECTs (vOECTs), respectively, along with current densities exceeding 1 kA cm−2 and good cycling stability of more than 100,000 cycles (2000 seconds). This work provides a new and facile strategy for the fabrication of vOECT channels with high resolution and high performance via the introduction of a simple and efficient crosslinker.
Organic electrochemical transistors (OECTs) have attracted interest in the field of neuromorphic devices and implantable electronics due to their excellent characteristics. Here, we use small molecule photo‐crosslinkers double‐end trifluoromethyl diazirine (DtFDA) to precisely pattern the channel layer and modulate ion transport in OECTs to fabricate high‐performance vertical electrochemical transistors.
Objective:
In this study, we intended to evaluate whether swallow treatment with neuromuscular electrical stimulation is superior to that without neuromuscular electrical stimulation, and whether ...neuromuscular electrical stimulation alone is superior to swallow therapy.
Methods:
We searched the PubMed and Scopus databases from their earliest record to 31 December 2014 for randomized and quasi-randomized controlled trials that used neuromuscular electrical stimulation to treat post-stroke dysphagia. The Jadad scale was used to assess the quality of the included studies. We extracted the mean differences and standard deviation (SD) between baseline and posttreatment or posttreatment mean and SD for selected outcomes measured in the experimental and control groups for subsequent meta-analyses.
Results:
Eight studies were identified. For the comparison “swallow treatment with neuromuscular electrical stimulation vs. swallow treatment without neuromuscular electrical stimulation,” we found a significant standardized mean difference (SMD) of 1.27 (95% confidence interval (CI) = 0.51–2.02, P = 0.001) with significant heterogeneity (I2 = 85%). The meta-analysis for the comparison of neuromuscular electrical stimulation alone and swallow therapy demonstrated a non-significant SMD of 0.25 (95% CI = –0.16–0.65, P = 0.23) without significant heterogeneity (I2 = 16%).
Conclusion:
Swallow treatment with neuromuscular electrical stimulation seems to be more effective than that without neuromuscular electrical stimulation for post-stroke dysphagia in the short term considering the limited number of studies available. Evidence was insufficient to indicate that neuromuscular electrical stimulation alone was superior to swallow therapy.
Abiotic stresses, such as drought and salt, are major environmental stresses, affecting plant growth and crop productivity. Plant bZIP transcription factors (bZIPs) confer stress resistances in harsh ...environments and play important roles in each phase of plant growth processes. In this research, 15 soybean bZIP family members were identified from drought-induced de novo transcriptomic sequences of soybean, which were unevenly distributed across 12 soybean chromosomes. Promoter analysis showed that these 15 genes were rich in ABRE, MYB and MYC
-acting elements which were reported to be involved in abiotic stress responses. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that 15
genes could be induced by drought and salt stress.
was significantly upregulated under stress conditions and thus was selected for further study. Subcellular localization analysis revealed that the GmbZIP2 protein was located in the cell nucleus. qRT-PCR results show that
can be induced by multiple stresses. The overexpression of
in
and soybean hairy roots could improve plant resistance to drought and salt stresses. The result of differential expression gene analysis shows that the overexpression of
in soybean hairy roots could enhance the expression of the stress responsive genes
,
,
,
and
. These results indicate that soybean
s played pivotal roles in plant resistance to abiotic stresses.
The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to ...uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC). We identify a member of the microrchidia (MORC) protein family, MORC2, as an inhibitor of the Hippo pathway by controlling upstream Hippo regulators, neurofibromatosis 2 (NF2) and kidney and brain protein (KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters of NF2 and KIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result, NF2 and KIBRA are crucial targets of MORC2 to regulate confluence-induced activation of Hippo signaling and contact inhibition of cell growth under both physiological and pathological conditions. The MORC2-NF2/KIBRA axis is critical for maintaining self-renewal, sorafenib resistance, and oncogenicity of HCC cells in vitro and in nude mice. Furthermore, MORC2 expression is elevated in HCC tissues, associated with stem-like properties of cancer cells, and disease progression in patients. Collectively, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling and could be a potential molecular target for cancer therapeutics.
PDF
