Abstract
Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, ...which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.
The follicle is the functional unit of the ovary, whereby ovarian development is largely dependent on the development of the follicles themselves. The activation, growth, and progression of follicles ...are modulated by a diverse range of factors, including reproductive endocrine system and multiple signaling pathways. The Hippo pathway exhibits a high degree of evolutionary conservation between both
and mammalian systems, and is recognized for its pivotal role in regulating cellular proliferation, control of organ size, and embryonic development. During the process of follicle development, the components of the Hippo pathway show temporal and spatial variations. Recent clinical studies have shown that ovarian fragmentation can activate follicles. The mechanism is that the mechanical signal of cutting triggers actin polymerization. This process leads to the disruption of the Hippo pathway and subsequently induces the upregulation of downstream CCN and apoptosis inhibitors, thereby promoting follicle development. Thus, the Hippo pathway plays a crucial role in both the activation and development of follicles. In this article, we focused on the development and atresia of follicles and the function of Hippo pathway in these processes. Additionally, the physiological effects of Hippo pathway in follicle activation are also explored.
CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2- breast cancer patients. Nevertheless, the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance ...are of great interest. Here, we show that the palbociclib-resistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis. Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib. Furthermore, PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells, leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation. Targeting PI3K/mTOR pathway with a specific PI3Kα inhibitor (BYL719) or an mTOR inhibitor (everolimus) reduced the protein levels of Cyclin D1 and CDK4, and restored the sensitivity to palbociclib. The tumor samples expressed significantly higher levels of Cyclin D1, CDK4, p-AKT and p-4E-BP1 after progression on palbociclib treatment. In conclusion, our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors, which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The ...etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.
Global identification of protein C-termini is highly challenging due to their low abundance in conventional shotgun proteomics. Several enrichment strategies have been developed to facilitate the ...detection of C-terminal peptides. One major issue of previous approaches is the limited C-terminome coverage. Herein, we integrated LysargiNase digestion, chemical acetylation on neo-N-terminus, and a-ion-aided peptide matching into poly(allylamine)-based C-terminomics (termed as LAACTer). In this strategy, we leveraged LysargiNase, a protease with cleavage specificity N-terminal to Lys and Arg residues, to cover previously unidentifiable C-terminome and employed chemical acetylation and a-ion-aided peptide matching to efficiently boost peptide identifications. Triplicates of LAACTer identified a total of 834 C-termini from proteome of 293T cell, which expanded the coverage by 164% (643 more unique C-termini) compared with the parallel experiments using the original workflow. Compared with the largest human C-terminome data sets (containing 800–900 C-termini), LAACTer not only achieved comparable profiling depth but also yielded 465 previously unidentified C-termini. In a SILAC (stable isotope labeling with amino acids in cell culture)-based quantitative study for identification of GluC-cleaved products, LAACTer quantified 300% more C-terminal peptides than the original workflow. Using LAACTer and the original workflow, we performed global analysis for the C-terminal sequences of 293T cell. The original and processed C-termini displayed distinct sequence patterns, implying the “C-end rules” that regulates protein stability could be more complex than just amino acid motifs. In conclusion, we reason LAACTer could be a powerful proteomic tool for in-depth C-terminomics and would benefit better functional understanding of protein C-termini.
Background Chronic rhinosinusitis with polyps (CRSwNP) is a global health concern. Nasal nitric oxide (nNO), a clinical biomarker, have been studied to assess the presence of airway mucosal ...inflammation. This study aimed to clarify the roles of nNO in diagnosis and endotypes of CRSwNP. Methods Eighty-two CRSwNP patients and thirty healthy volunteers were recruited for this study. The patients were classified into eosinophilic CRSwNP (Eos CRSwNP) and nonâeosinophilic CRSwNP (Non-Eos CRSwNP) endotypes by tissue eosinophil percentage. nNO levels were measured with an electrochemical sensor-based device. nNO levels and clinical factors were compared among the groups. Receiver-operating characteristic (ROC) curve and logistic regression analyses were performed to evaluate the predictive ability of the nNO for diagnosis and endotypes of CRSwNP. Results Eos CRSwNP patients(143.9 + or - 106.2, ppb) had lower nNO levels than Non-Eos CRSwNP(228.3 + or - 109.2, ppb, p = 0.013) and healthy subjects(366.5 + or - 88, ppb, p < 0.0001). Patients with atopy exhibited significantly higher levers of nNO compared with patients without atopy (p < 0.05). For Eos CRSwNP diagnosis, nNO had high predictive value for Eos CRSwNP (AUC: 0.939; sensitivity: 76.74%; specificity: 96.67%; cut-off value: 231 ppb, p < 0.001). Furthermore, nNO levels were associated with CRSwNP endotypes (odds ratio: 1.010; 95% confidence interval: 1.003, 1.016%; p = 0.002). When the nNO concentration was 158 ppb, we could discriminate Eos CRSwNP from Non-Eos CRSwNP (AUC = 0.710, sensitivity: 76.92%; specificity, 60.47%, P = 0.001). After it was combinated by nNO, peripheral blood eosinophil count (PEAC) and VAS score, the AUC was increased to 0.894 (95%CI = 0.807 to 0.951, p < 0.0001, sensitivity:76.74%, specificity: 89.74%). Conclusions nNO may have potential for non-invasive diagnosis and endotype of CRSwNP. nNO combined with PEAC and VAS score may be a good diagnostic tool for endotyps of Eos CRSwNP. However, the atopic status of the patients influenced the levels of nNO. Keywords: Chronic rhinosinusitis, Nasal polyps, Nasal nitric oxide, Eosinophil
Convolutional neural network (CNN)-based object detectors perform excellently but lack global feature extraction and cannot establish global dependencies between object pixels. Although the ...Transformer is able to compensate for this, it does not incorporate the advantages of convolution, which results in insufficient information being obtained about the details of local features, as well as slow speed and large computational parameters. In addition, Feature Pyramid Network (FPN) lacks information interaction across layers, which can reduce the acquisition of feature context information. To solve the above problems, this paper proposes a CNN-based anchor-free object detector that combines transformer global and local feature extraction (GLFT) to enhance the extraction of semantic information from images. First, the segmented channel extraction feature attention (SCEFA) module was designed to improve the extraction of local multiscale channel features from the model and enhance the discrimination of pixels in the object region. Second, the aggregated feature hybrid transformer (AFHTrans) module combined with convolution is designed to enhance the extraction of global and local feature information from the model and to establish the dependency of the pixels of distant objects. This approach compensates for the shortcomings of the FPN by means of multilayer information aggregation transmission. Compared with a transformer, these methods have obvious advantages. Finally, the feature extraction head (FE-Head) was designed to extract full-text information based on the features of different tasks. An accuracy of 47.0% and 82.76% was achieved on the COCO2017 and PASCAL VOC2007 + 2012 datasets, respectively, and the experimental results validate the effectiveness of our method.
Abstract
Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most ...mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.
The FKBP (FK506-binding protein) gene family is an important member of the PPlase protease family and plays a vital role during the processes of plant growth and development. However, no studies of ...the FKBP gene family have been reported in cucumber. In this study, 19 FKBP genes were identified in cucumber, which were located on chromosomes 1, 3, 4, 6, and 7. Phylogenetic analysis divided the cucumber FKBP genes into three subgroups. The FKBP genes in the same subgroup exhibited similar structures and conserved motifs. The cis-acting elements analysis revealed that the promoters of cucumber FKBP genes contained hormone-, stress-, and development-related cis-acting elements. Synteny analysis of the FKBP genes among cucumber, Arabidopsis, and rice showed that 12 kinds of syntenic relationships were detected between cucumber and Arabidopsis FKBP genes, and 3 kinds of syntenic relationships were observed between cucumber and rice FKBP genes. The tissue-specific expression analysis showed that some FKBP genes were expressed in all tissues, while others were only highly expressed in part of the 10 types of tissues. The expression profile analysis of cucumber FKBP genes under 13 types of stresses showed that the CsaV3_1G007080 gene was differentially expressed under abiotic stresses (high temperature, NaCl, silicon, and photoperiod) and biotic stresses (downy mildew, green mottle mosaic virus, Fusarium wilt, phytophthora capsica, angular leaf spot, and root-knot nematode), which indicated that the CsaV3_1G007080 gene plays an important role in the growth and development of cucumber. The interaction protein analysis showed that most of the proteins in the FKBP gene family interacted with each other. The results of this study will lay the foundation for further research on the molecular biological functions of the cucumber FKBP gene family.
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