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1.
Org Biomol Chem ; 22(22): 4445-4449, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38752342

ABSTRACT

A palladium-catalyzed ring-opening cyclization of (E) & (Z)-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis- & trans-bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

2.
Front Cardiovasc Med ; 11: 1338156, 2024.
Article in English | MEDLINE | ID: mdl-38742174

ABSTRACT

Objective: While hypertension is a well-recognized risk factor for non-alcoholic fatty liver disease (NAFLD), the specific roles of various common blood pressure measurements [diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), mean arterial pressure (MAP)] in detecting NAFLD and evaluating the associated risk in adults remain unclear. Methods: A retrospective analysis was conducted on 14,251 adult participants undergoing health screenings in the NAfld in the Gifu Area, Longitudinal Analysis project (NAGALA). Following the Z-transformation of the independent variables, we evaluated the relationships between the four blood pressure indices and NAFLD through multivariable logistic regression models. This analysis documented the odds ratio (OR) and 95% confidence interval (CI) for each standard deviation (SD) increase. Additionally, the effectiveness of these indices in identifying NAFLD was comparatively analyzed using receiver operating characteristic (ROC) curves. Results: After adequately adjusting for confounders, all blood pressure indices except PP showed a positive correlation with NAFLD. For each SD increment, MAP had the strongest association with NAFLD compared to SBP and DBP. This finding was confirmed in populations without exercise habits, under 60 years of age, with normal blood pressure, and in non-obese groups. Furthermore, based on ROC analysis, MAP was found to have the highest accuracy in identifying NAFLD compared to the other three blood pressure indices. Conclusion: Among the four blood pressure indices evaluated, MAP demonstrates the greatest efficacy in identifying NAFLD and assessing its associated risk. These findings underscore the potential of MAP as the most promising blood pressure index for screening NAFLD.

3.
Sci Rep ; 14(1): 10148, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698130

ABSTRACT

We demonstrate enhanced acoustic sensing arising from the synergy between resonator-based acoustic sensor and deep learning. We numerically verify that both vibration amplitude and phase are enhanced and preserved at and off the resonance in our compact acoustic sensor housing three cavities. In addition, we experimentally measure the response of our sensor to single-frequency and siren signals, based on which we train convolutional neural networks (CNNs). We observe that the CNN trained by using both amplitude and phase features achieve the best accuracy on predicting the incident direction of both types of signals. This is even though the signals are broadband and affected by noise thought to be difficult for resonators. We attribute the improvement to a complementary effect between the two features enabled by the combination of resonant effect and deep learning. This observation is further supported by comparing to the CNNs trained by the features extracted from signals measured on reference sensor without resonators, whose performances fall far behind. Our results suggest the advantage of this synergetic approach to enhance the sensing performance of compact acoustic sensors on both narrow- and broad-band signals, which paves the way for the development of advanced sensing technology that has potential applications in autonomous driving systems to detect emergency vehicles.

4.
Article in English | MEDLINE | ID: mdl-38624155

ABSTRACT

The novel 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) groups immobilized on functional polymers or nanoparticles emerged as potential Pickering interfacial catalysts (PICs) for effective catalysis in biphasic systems. In this study, a snowman-shaped Janus-structured polymer with TEMPO-anchored nanohybrid particles (SM-JPP-TEMPO) was prepared and employed as a potential PIC in the Anelli-Montanari system for the selective oxidation of alcohol. The amphiphilic character of SM-JPP-TEMPO particles plays a dual role as an emulsifier and catalyst in the Pickering emulsion. As a result, it enables smaller droplets (102 µm) at the water-in-oil (W/O) interface and reduces the interfacial tension from 26.58 to 17.38 mN/m, which improves the stability of the Pickering emulsion system. This constructed Pickering emulsion microreactor offers a larger interface contact area and shortens the mass transfer distance of the substrate of cinnamyl alcohol, which significantly enhances the catalytic conversion at the Anelli-Montanari oxidation system, thus achieving remarkable conversion efficiency of (92.3%) with excellent selectivity (99%) in static (stirring-free) condition. It was found that the Janus nanohybrid catalyst (SM-JPP-TEMPO) enhanced 1.29-fold catalytic efficiency compared to the TEMPO grafted spherical polystyrene nanoparticle (PS-NPs-TEMPO) catalyst (72%). Moreover, after seven consecutive cycles, the Janus nanocatalyst (SM-JPP-TEMPO) maintained the conversion significantly. Hence, these results collectively highlight that the amphiphilic SM-JPP-TEMPO catalyst provides an efficient and eco-friendly strategy for the intensification of liquid-liquid biphasic reaction systems for potential applications in industries.

5.
Heliyon ; 10(8): e29837, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38681536

ABSTRACT

Unmanned aerial vehicle (UAV) granular fertilizer spreading technology has been gradually applied in agricultural production. However, in the process of spreading operation, the actual influence effect of each factor in field operation is still unclear. Based on the self-developed UAV fertilizer spreading system, this paper explores the effects of three factors, the baffle retraction (B), spreading disc speed (D), and UAV flight altitude (H), on the granular fertilizer spreading effect in the actual field scenarios through the orthogonal test and taking the coefficient of variation (Cv) and relative error of fertilizer application rate (λ) as the evaluation indexes. The results showed that the optimal factor level combination of Cv was 11.23 % for BbDbHa (the baffle retraction is 6 %, spreading disc speed is 600r/min, and UAV flight height is 1.5 m) at UAV flight speed of 2 m/s. The best factor level combination for λ was BbDbHb of 7.99 % (the baffle retraction is 6 %, spreading disc speed is 600r/min, and UAV flight height is 2 m). In addition, by analysing the influence of the weather and the vortex of the rice canopy on the actual spreading effect, it was found that the weather has less influence on the spreading effect of this system, while the vortex caused by the airflow of the UAV rotor has a certain influence on the spreading effect, which is also relatively easy to ignore in fertilizer spreading operations. The results of the study can be used to explore the operational effects of actual fertilizer application by UAVs in rice field, which will help promote the development of UAV spreading technology and provide a reference for precision fertilizer application through agricultural aviation.

6.
Cancer Res ; 84(10): 1630-1642, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38588407

ABSTRACT

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvß3 via upregulation of the ß3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvß3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. SIGNIFICANCE: Upregulation of integrin αvß3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Integrin alphaVbeta3 , Lung Neoplasms , Up-Regulation , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/genetics , Animals , Integrin alphaVbeta3/metabolism , Mice , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , AMP-Activated Protein Kinases/metabolism , Stress, Physiological , Nutrients/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic
7.
Am J Physiol Endocrinol Metab ; 326(6): E767-E775, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38506752

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.


Subject(s)
Ferroptosis , Iron , Non-alcoholic Fatty Liver Disease , Non-alcoholic Fatty Liver Disease/metabolism , Ferroptosis/physiology , Humans , Iron/metabolism , Animals , Liver/metabolism , Liver/pathology , Ferritins/metabolism
8.
Molecules ; 29(5)2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38474597

ABSTRACT

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

9.
Int J Cancer ; 154(4): 723-737, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-37855385

ABSTRACT

UBR5 is a HECT domain E3 ubiquitin ligase that is frequently amplified in breast, ovarian and prostate cancers. Heightened UBR5 expression plays a profound role in tumor growth through immune-dependent mechanisms; however, its mode of action in driving tumor metastasis has not been definitively delineated. Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion. In vitro, Ubr5 knockdown induces morphological and molecular changes characteristic of epithelial-mesenchymal transition (EMT). In vivo, UBR5 promotes lung metastasis in an E3 ubiquitin ligase-dependent manner. Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73. In human triple-negative breast cancer (TNBC) patient specimens, a strong inverse correlation was observed between UBR5 and CDC73 protein levels, with reduced CDC73 expression at metastatic sites compared to primary lesions. Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.


Subject(s)
Lung Neoplasms , Triple Negative Breast Neoplasms , Animals , Humans , Male , Mice , Apoptosis , Cell Line, Tumor , Cell Proliferation , Lung Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism
10.
NPJ Parkinsons Dis ; 9(1): 157, 2023 Nov 28.
Article in English | MEDLINE | ID: mdl-38017009

ABSTRACT

The USP19 deubiquitinase is found in a locus associated with Parkinson's Disease (PD), interacts with chaperonins, and promotes secretion of α-synuclein (α-syn) through the misfolding-associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of α-syn aggregates in PD, we inactivated USP19 (KO) in mice expressing the A53T mutation of α-syn and in whom α-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. This improvement was associated with less activation of microglia and improved performance in a tail-suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF nor propagation of aggregates in the cultured neurons. We conclude that USP19 instead modulates intracellular dynamics of aggregates. At an early time following PFF injection when the number of pSyn-positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immunoprecipitation of soluble proteins from WT and KO brains with antibodies to pSyn showed higher levels of ubiquitinated oligomeric species in the KO samples. We propose that the improved pathology in USP19 KO brains may arise from decreased formation or enhanced clearance of the more ubiquitinated aggregates and/or enhanced disassembly towards more soluble oligomeric species. USP19 inhibition may represent a novel therapeutic approach that targets the intracellular dynamics of α-syn complexes.

12.
Med Image Anal ; 90: 102932, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37657365

ABSTRACT

Accurate diagnosis of neurodevelopmental disorders is a challenging task due to the time-consuming cognitive tests and potential human bias in clinics. To address this challenge, we propose a novel adversarial self-supervised graph neural network (GNN) based on graph contrastive learning, named A-GCL, for diagnosing neurodevelopmental disorders using functional magnetic resonance imaging (fMRI) data. Taking advantage of the success of GNNs in psychiatric disease diagnosis using fMRI, our proposed A-GCL model is expected to improve the performance of diagnosis and provide more robust results. A-GCL takes graphs constructed from the fMRI images as input and uses contrastive learning to extract features for classification. The graphs are constructed with 3 bands of the amplitude of low-frequency fluctuation (ALFF) as node features and Pearson's correlation coefficients (PCC) of the average fMRI time series in different brain regions as edge weights. The contrastive learning creates an edge-dropped graph from a trainable Bernoulli mask to extract features that are invariant to small variations of the graph. Experiment results on three datasets - Autism Brain Imaging Data Exchange (ABIDE) I, ABIDE II, and attention deficit hyperactivity disorder (ADHD) - with 3 atlases - AAL1, AAL3, Shen268 - demonstrate the superiority and generalizability of A-GCL compared to the other GNN-based models. Extensive ablation studies verify the robustness of the proposed approach to atlas selection and model variation. Explanatory results reveal key functional connections and brain regions associated with neurodevelopmental disorders.

13.
Int J Biol Sci ; 19(9): 2725-2739, 2023.
Article in English | MEDLINE | ID: mdl-37324942

ABSTRACT

Identification of mucin modulators is of remarkable significance to facilitate mucin-based antineoplastic therapy. However, little is known about circular RNAs (circRNAs) on regulating mucins. Dysregulated mucins and circRNAs were identified via high-throughput sequencing and their relationships with lung cancer survival were analyzed in tumor samples of 141 patients. The biological functions of circRABL2B were determined via gain- and loss-of-function experiments and exosome-packaged circRABL2B treatment in cells, patient-derived lung cancer organoids and nude mice. We identified that circRABL2B was negatively correlated with MUC5AC. Patients with low circRABL2B and high MUC5AC displayed the poorest survival (HR=2.00; 95% CI=1.12-3.57). Overexpressed circRABL2B significantly inhibited cell malignant phenotypes, while it knock-down exerted opposite effects. CircRABL2B interacted with YBX1 to inhibit MUC5AC, and subsequently suppressed integrin ß4/pSrc/p53 signaling and impoverished cell stemness, and promoted erlotinib sensitivity. Exosome-packaged circRABL2B exerted significant anti-cancer actions in cells, patient-derived lung cancer organoids and nude mice. Meanwhile, circRABL2B in plasma exosomes could distinguish early-stage lung cancer patients from healthy controls. Finally, we found circRABL2B was downregulated at the transcriptional level, and EIF4a3 involved the formation of circRABL2B. In conclusion, our data suggest that circRABL2B counteracts lung cancer progression via MUC5AC/integrin ß4/pSrc/p53 axis, which provides a rationale to enhance the efficacy of anti-MUCs treatment in lung cancer.


Subject(s)
Integrin beta4 , Lung Neoplasms , Animals , Mice , Mice, Nude , Down-Regulation/genetics , Integrin beta4/metabolism , RNA, Circular/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mucins/genetics , Mucins/metabolism
14.
Curr Psychol ; : 1-12, 2023 Mar 17.
Article in English | MEDLINE | ID: mdl-37359607

ABSTRACT

The teacher-child relationship plays an important role in children's future development. However, the existing research mainly focuses on the influence of preschool teachers' external conditions on the teacher-student relationship, while the research on the influence of teachers' internal psychological characteristics on the teacher-student relationship is relatively lacking. In this study, three hundred and seventeen preschool teachers were tested were tested with Five Facet Mindfulness Questionnaire, Emotional Intelligence Scale, Chinese Interpersonal Response Index, and Teacher-student Relationship Scale. The results showed that trait mindfulness positively predicted the quality of parent-teacher relationship (ß = 0.173, p = 0.026). Emotional intelligence played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.118, p = 0.004), and empathy played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.112, p = 0.001). Meanwhile, emotional intelligence and empathy played a chain mediating role in trait mindfulness and parent-teacher relationship quality (ß = 0.044, p = 0.038). On the one hand, this study enriches attachment theory. The conclusions of this study verify the diversity of proximal factors in attachment theory, and confirm the influence of teachers' own characteristics and abilities on the teacher-child relationship quality. On the other hand, by exploring the factors affecting the teacher-child relationship quality, we can find ways to improve teacher-child relationship from a new perspective, and then provide some new methods and approaches for improving the quality of preschool teacher-child relationship.

15.
Front Cell Infect Microbiol ; 13: 1149679, 2023.
Article in English | MEDLINE | ID: mdl-37143744

ABSTRACT

The tuberculosis (TB) burden remains a significant global public health concern, especially in less developed countries. While pulmonary tuberculosis (PTB) is the most common form of the disease, extrapulmonary tuberculosis, particularly intestinal TB (ITB), which is mostly secondary to PTB, is also a significant issue. With the development of sequencing technologies, recent studies have investigated the potential role of the gut microbiome in TB development. In this review, we summarized studies investigating the gut microbiome in both PTB and ITB patients (secondary to PTB) compared with healthy controls. Both PTB and ITB patients show reduced gut microbiome diversity characterized by reduced Firmicutes and elevated opportunistic pathogens colonization; Bacteroides and Prevotella were reported with opposite alteration in PTB and ITB patients. The alteration reported in TB patients may lead to a disequilibrium in metabolites such as short-chain fatty acid (SCFA) production, which may recast the lung microbiome and immunity via the "gut-lung axis". These findings may also shed light on the colonization of Mycobacterium tuberculosis in the gastrointestinal tract and the development of ITB in PTB patients. The findings highlight the crucial role of the gut microbiome in TB, particularly in ITB development, and suggest that probiotics and postbiotics might be useful supplements in shaping a balanced gut microbiome during TB treatment.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Mycobacterium tuberculosis , Tuberculosis, Lymph Node , Tuberculosis, Pulmonary , Humans , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Lymph Node/complications
16.
Structure ; 31(5): 541-552.e4, 2023 05 04.
Article in English | MEDLINE | ID: mdl-37040767

ABSTRACT

The human UBR5 is a single polypeptide chain homology to E6AP C terminus (HECT)-type E3 ubiquitin ligase essential for embryonic development in mammals. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis. Here, we report that UBR5 assembles into a dimer and a tetramer. Our cryoelectron microscopy (cryo-EM) structures reveal that two crescent-shaped UBR5 monomers assemble head to tail to form the dimer, and two dimers bind face to face to form the cage-like tetramer with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an "intermolecular jaw" in the dimer. We show the jaw-lining residues are important for function, suggesting that the intermolecular jaw functions to recruit ubiquitin-loaded E2 to UBR5. Further work is needed to understand how oligomerization regulates UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development and contributes to a growing appreciation of E3 ligase diversity.


Subject(s)
Antineoplastic Agents , Ubiquitin-Protein Ligases , Animals , Humans , Ubiquitin-Protein Ligases/chemistry , Cryoelectron Microscopy , Ubiquitin , Catalytic Domain , Mammals/metabolism
17.
Antioxidants (Basel) ; 12(3)2023 Mar 16.
Article in English | MEDLINE | ID: mdl-36978979

ABSTRACT

Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2-/-) mice, more sever ferroptosis and neurological deficits were detected. Dimethyl fumarate (DMF)-mediated NRF2 activation alleviated neural dysfunction in TBI mice, partly due to TBI-induced ferroptosis mitigation. Additionally, FTH-FTL and FSP1 protein levels, associated with iron metabolism and the ferroptotic redox balance, were highly NRF2-dependent post-TBI. Thus, NRF2 is neuroprotective against TBI-induced ferroptosis through both the xCT-GPX4- and FTH-FTL-determined free iron level and the FSP1-regulated redox status. This yields insights into the neuroprotective role of NRF2 in TBI-induced neuronal damage and its potential use in TBI treatment.

18.
Nat Cell Biol ; 25(2): 309-322, 2023 02.
Article in English | MEDLINE | ID: mdl-36646789

ABSTRACT

Defining drivers of tumour initiation can provide opportunities to control cancer progression. Here we report that lysophosphatidic acid receptor 4 (LPAR4) becomes transiently upregulated on pancreatic cancer cells exposed to environmental stress or chemotherapy where it promotes stress tolerance, drug resistance, self-renewal and tumour initiation. Pancreatic cancer cells gain LPAR4 expression in response to stress by downregulating a tumour suppressor, miR-139-5p. Even in the absence of exogenous lysophosphatidic acid, LPAR4-expressing tumour cells display an enrichment of extracellular matrix genes that are established drivers of cancer stemness. Mechanistically, upregulation of fibronectin via an LPAR4/AKT/CREB axis is indispensable for LPAR4-induced tumour initiation and stress tolerance. Moreover, ligation of this fibronectin-containing matrix via integrins α5ß1 or αVß3 can transfer stress tolerance to LPAR4-negative cells. Therefore, stress- or drug-induced LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix, allowing cells to survive 'isolation stress' and compensate for the absence of stromal-derived factors by creating their own tumour-initiating niche.


Subject(s)
MicroRNAs , Pancreatic Neoplasms , Receptors, Purinergic P2 , Humans , Fibronectins/genetics , Fibronectins/metabolism , Pancreatic Neoplasms/pathology , Extracellular Matrix/metabolism , Cell Transformation, Neoplastic/metabolism , Receptors, Purinergic P2/metabolism , MicroRNAs/genetics , Pancreatic Neoplasms
19.
IEEE Trans Med Imaging ; 42(4): 1197-1209, 2023 04.
Article in English | MEDLINE | ID: mdl-36449589

ABSTRACT

Segmenting the fine structure of the mouse brain on magnetic resonance (MR) images is critical for delineating morphological regions, analyzing brain function, and understanding their relationships. Compared to a single MRI modality, multimodal MRI data provide complementary tissue features that can be exploited by deep learning models, resulting in better segmentation results. However, multimodal mouse brain MRI data is often lacking, making automatic segmentation of mouse brain fine structure a very challenging task. To address this issue, it is necessary to fuse multimodal MRI data to produce distinguished contrasts in different brain structures. Hence, we propose a novel disentangled and contrastive GAN-based framework, named MouseGAN++, to synthesize multiple MR modalities from single ones in a structure-preserving manner, thus improving the segmentation performance by imputing missing modalities and multi-modality fusion. Our results demonstrate that the translation performance of our method outperforms the state-of-the-art methods. Using the subsequently learned modality-invariant information as well as the modality-translated images, MouseGAN++ can segment fine brain structures with averaged dice coefficients of 90.0% (T2w) and 87.9% (T1w), respectively, achieving around +10% performance improvement compared to the state-of-the-art algorithms. Our results demonstrate that MouseGAN++, as a simultaneous image synthesis and segmentation method, can be used to fuse cross-modality information in an unpaired manner and yield more robust performance in the absence of multimodal data. We release our method as a mouse brain structural segmentation tool for free academic usage at https://github.com/yu02019.


Subject(s)
Algorithms , Magnetic Resonance Imaging , Animals , Mice , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Neuroimaging
20.
IEEE J Biomed Health Inform ; 27(2): 1072-1083, 2023 02.
Article in English | MEDLINE | ID: mdl-36446007

ABSTRACT

Accurate neonatal brain MRI segmentation is valuable for investigating brain growth patterns and tracking the progression of neurodevelopmental disorders. However, it is a challenging task to use intensity-based methods to segment neonatal brain structures because of small contrast differences between brain regions caused by the inherent myelination process. Although convolutional neural networks offer the potential to segment brain structures in an intensity-independent manner, they suffer from lack of in-plane long-range dependency which is essential for the segmentation. To solve this problem, we propose a novel Transformer-Weighted network (TW-Net) to incorporate in-plane long-range dependency information. TW-Net employs a conventional encoder-decoder architecture with a Transformer module in the middle. The Transformer module uses a rotate-and-flip layer to better calculate the similarity between two patches in a slice to leverage similar patterns of geometrical and texture features within brain structures. In addition, a deep supervision module and squeeze-and-excitation blocks are introduced to incorporate boundary information of brain structures. Compared with state-of-the-art deep learning algorithms, TW-Net outperforms these methods for multiple-label tasks in 2D and 2.5D configurations on two independent public datasets, demonstrating that TW-Net is a promising method for neonatal brain MRI segmentation.


Subject(s)
Magnetic Resonance Imaging , Neuroimaging , Humans , Infant, Newborn , Algorithms , Brain/diagnostic imaging , Electric Power Supplies , Image Processing, Computer-Assisted
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