10 research outputs found
Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
No full textThe tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.</p
Evaluation of osteoinductive and endothelial differentiation potential of Platelet-Rich Plasma incorporated Gelatin-Nanohydroxyapatite Fibrous Matrix
No full textIn this study, platelet-rich plasma (PRP) was incorporated into gelatin-nanohydroxyapatite fibrous scaffold in two forms (PRP gel as coating on the scaffold [PCSC] and PRP powder within the scaffold [PCSL] and investigated for (a) growth factor release; (b) stability of scaffold at different temperature; (c) stability of scaffold before and after ETO sterilization; and (d) osteogenic and endothelial differentiation potential using mesenchymal stem cells (MSCs). PCSC demonstrated a high and burst growth factor release initially followed by a gradual reduction in its concentration, while PCSL showed a steady state release pattern for 30 days. The stability of growth factors released from PCSL was not altered either through ETO sterilization or through its storage at different temperature. PRP-loaded scaffolds induced the differentiation of MSCs into osteogenic and endothelial lineage without providing any induction factors in the cell culture medium and the differentiation rate was significantly higher when compared to the scaffolds devoid of PRP. PCSC performed better than PCSL. In general, PRP in combination with composite fibrous scaffold could be a promising candidate for bone tissue engineering applications. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 771-781, 2016
E3 Ubiquitin Ligase TRIP12 Controls Exit from Mitosis via Positive Regulation of MCL-1 in Response to Taxol
No full textChemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (FBW7) mutations leads to the accumulation of its substrate MCL-1 which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase TRIP12 is a negative regulator of FBW7 protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of MCL-1 protein. Genetic inhibition of TRIP12 accelerates MCL-1 protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of FBW7 to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, TRIP12 deletion leads to enhanced mitotic arrest and cell death in an FBW7 and MCL-1 dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the TRIP12/FBW7/MCL-1 axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer
CNN vs. SIFT for Image Retrieval: Alternative or Complementary?
No full textIn the past decade, SIFT is widely used in most vision tasks such as image retrieval. While in recent several years, deep convolutional neural networks (CNN) features achieve the state-of-the-art performance in several tasks such as image classification and object detection. Thus a natural question arises: for the image retrieval task, can CNN features substitute for SIFT? In this paper, we experimentally demonstrate that the two kinds of features are highly complementary. Following this fact, we propose an image representation model, complementary CNN and SIFT (CCS), to fuse CNN and SIFT in a multi-level and complementary way. In particular, it can be used to simultaneously describe scene level, object-level and point-level contents in images. Extensive experiments are conducted on four image retrieval benchmarks, and the experimental results show that our CCS achieves state-of-the-art retrieval results.CPCI-S(ISTP)[email protected]; [email protected]; [email protected]; [email protected]; [email protected]
Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12
No full textInternational audienceTransforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFβ signalling in multiple models. Interestingly, TRIP12 control of TGFβ signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFβ signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFβ signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFβ mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFβ induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFβ signalling in health and disease. © 2023. The Author(s)
Development of a Wireless Communication System for Concrete Pavement Health Monitoring
No full textIn recent years, structural health monitoring and management (SHM) has become a popular approach and is considered essential for achieving well-performing, long-lasting, sustainable transportation infrastructure systems. Key requirements in ideal SHM of road infrastructure include long-term, continuous, and real-time monitoring of pavement behavior under various pavement geometry-materials-loading configurations and environmental conditions. With advancements in wireless technologies, integration of wireless communications into sensing device is considered an alternate and superior solution to existing time- and labor-intensive wired sensor systems to meet these requirements. This study explored the development and deployment of a wireless communications sub-system into a commercial off-the-shelf concrete pavement monitoring sensor system. The overall goal was to investigate the feasibility of developing wireless based Micro-Electromechanical Sensors and Systems (MEMS) by integrating a wireless network system with off-the-shelf MEMS sensors. A success rate test was performed after the wireless transmission system was buried in the concrete slab, and the test results indicated that the system was able to provide reliable communications at a distance of more than 46 m (150 ft.). This will be a useful feature for highway engineers performing routine pavement scans from the pavement shoulder without the need for traffic control or road closure.This conference proceeding is published as Yang, S., Shen, K., Ceylan, H., Kim, S., Qiao, D., and Gopalakrishnan, K. (2014). “Development of a Wireless Communication System for Concrete Pavement Health Monitoring,” The 8th International DUT-Workshop on Research and Innovations for Design of Sustainable and Durable Concrete Pavements, Prague, Czech Republic, Sep. 20-21, 2014. Copyright 2014 The Author(s). Posted with permission
LLMCL-GEC: Advancing Grammatical Error Correction with LLM-Driven Curriculum Learning
No full textWhile large-scale language models (LLMs) have demonstrated remarkable capabilities in specific natural language processing (NLP) tasks, they may still lack proficiency compared to specialized models in certain domains, such as grammatical error correction (GEC). Drawing inspiration from the concept of curriculum learning, we have delved into refining LLMs into proficient GEC experts by devising effective curriculum learning (CL) strategies. In this paper, we introduce a novel approach, termed LLM-based curriculum learning, which capitalizes on the robust semantic comprehension and discriminative prowess inherent in LLMs to gauge the complexity of GEC training data. Unlike traditional curriculum learning techniques, our method closely mirrors human expert-designed curriculums. Leveraging the proposed LLM-based CL method, we sequentially select varying levels of curriculums ranging from easy to hard, and iteratively train and refine using the pretrianed T5 and LLaMA series models. Through rigorous testing and analysis across diverse benchmark assessments in English GEC, including the CoNLL14 test, BEA19 test, and BEA19 development sets, our approach showcases a significant performance boost over baseline models and conventional curriculum learning methodologies.Derek F. Wong is the corresponding author. The preprint version consists of 15 Pages, 5 Figures, 5 Tables, and 3 Appendice
Degradation assessment of Mg-Incorporated 3D printed PLA scaffolds for biomedical applications
No full textPolylactic acid (PLA)/Magnesium (Mg)-based composites exhibit great potential for applications in bone regeneration and tissue engineering. PLA is a biodegradable and biocompatible polymer, that has the ability to be easily shaped into diverse structures like scaffolds, films, and fibers. However, its inherent low biodegradability limits its applicability for tissue engineering. On the other hand, magnesium, a biocompatible metal known for its good biodegradability and osteoconductivity, is well-suited for bone tissue engineering. In this study, we fabricated and characterized a composite material of Mg/PLA with 5, 10, and 15 wt%Mg alloy (AZ61), which was subsequently 3D printed. The incorporation of Mg particles into PLA matrix offers a solution to overcome the low biodegradation limitations typically associated with the PLA. Moreover, it helps counteract the negative consequences related to the rapid degradation of Mg, such as alkalinization and excessive release of H2. Additionally, the change in pH values and changes in mass during in vitro degradation indicated that the addition of Mg effectively counteracted the acidic byproducts generated by PLA. Furthermore, X-Ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FT-IR) spectroscopy were utilized to investigate the degradation of the scaffolds, while thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to compare and contrast the thermal properties of the composites. Our findings demonstrate that the addition of Mg significantly influences the thermal properties of PLA and notably accelerates its degradation, in addition to its noticeable influence on cell adhesion.Other InformationPublished in: BioprintingLicense: http://creativecommons.org/licenses/by/4.0/See article on publisher's website: https://dx.doi.org/10.1016/j.bprint.2023.e00302Additional institutions affiliated with: Cole Labs - QEERI</p
Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
No full textThe tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability
Transcriptional mediators of treatment resistance in lethal prostate cancer
No full text© 2021, The Author(s). Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition
