Cellular metabolism is at the foundation of all biological activities. The catabolic processes that support cellular bioenergetics and survival have been well studied. By contrast, how cells alter ...their metabolism to support anabolic biomass accumulation is less well understood. During the commitment to cell proliferation, extensive metabolic rewiring must occur in order for cells to acquire sufficient nutrients such as glucose, amino acids, lipids and nucleotides, which are necessary to support cell growth and to deal with the redox challenges that arise from the increased metabolic activity associated with anabolic processes. Defining the mechanisms of this metabolic adaptation for cell growth and proliferation is now a major focus of research. Understanding the principles that guide anabolic metabolism may ultimately enhance ways to treat diseases that involve deregulated cell growth and proliferation, such as cancer.
Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to ...cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
In order to protect intangible cultural heritage and promote outstanding cultural works, this article introduces innovative research on Shen Embroidery using convolutional neural networks. The ...dataset of Shen Embroidery was preprocessed to augment the data required for experimentation. Moreover, the approach of transfer learning was introduced to fine-tune the recognition network. Specifically, Spatial Pyramid Pooling (SPP) is employed by replacing the avg pool in the MobileNet V1 network, achieving the fusion of local and global features. The experimental results showed that the improved MobileNet V1 achieved a recognition accuracy of 98.45%, which was 2.3% higher than the baseline MobileNet V1 network. The experiments demonstrated that the improved convolutional neural network can efficiently recognize Shen Embroidery and provide technical support for the intelligent development of intangible cultural heritage.
Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated ...uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines, while in other cells, these enzymes are induced following cysteine deprivation. We show that both constitutive and inducible transsulfuration activities contribute to the cellular cysteine pool and redox homeostasis. The rate of transsulfuration is determined by the cellular capacity to conduct methylation reactions that convert S-adenosylmethionine to S-adenosylhomocysteine. Finally, our results demonstrate that transsulfuration-mediated cysteine synthesis is critical in promoting tumor growth in vivo.
SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes ...respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.
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•A hPSC-derived cell and organoid platform is used to study SARS-CoV-2 tissue tropism•Human pancreatic alpha and beta cells are permissive to SARS-CoV-2 infection•Human hepatocyte and cholangiocyte organoids are permissive to SARS-CoV-2 infection•hPSC-derived cells/organoids show similar chemokine responses as COVID-19 tissues
Yang et al. show that hPSC-derived cells and organoids provide valuable models to study SARS-CoV-2 tropism and to model COVID-19. They find that hPSC-derived pancreatic endocrine cells and human adult hepatocyte and cholangiocyte organoids are permissive to SARS-CoV-2 infection.
Artificial intelligence (AI) has been utilized in soft-tissue analysis and prediction in orthodontic treatment planning, although its reliability has not been systematically assessed. This scoping ...review was conducted to outline the development of AI in terms of predicting soft-tissue changes after orthodontic treatment, as well as to comprehensively evaluate its prediction accuracy. Six electronic databases (PubMed, EBSCO
host
, Web of Science, Embase, Cochrane Library, and Scopus) were searched up to March 14, 2023. Clinical studies investigating the performance of AI-based systems in predicting post-orthodontic soft-tissue alterations were included. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and Joanna Briggs Institute (JBI) appraisal checklist for diagnostic test accuracy studies were applied to assess risk of bias, while the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) assessment was conducted to evaluate the certainty of outcomes. After screening 2500 studies, four non-randomized clinical trials were finally included for full-text evaluation. We found a low level of evidence indicating an estimated high overall accuracy of AI-generated prediction, whereas the lower lip and chin seemed to be the least predictable regions. Furthermore, the facial morphology simulated by AI via the fusion of multimodality images was considered to be reasonably true. Since all of the included studies that were not randomized clinical trials (non-RCTs) showed a moderate to high risk of bias, more well-designed clinical trials with sufficient sample size are needed in future work.
There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, ...as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes
. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.
Congenital heart defect is the leading malformation in China. There may have been changes in congenital heart defect incidence because of birth policy shift in China over past years. This study aimed ...to investigate the epidemiology, prenatal diagnosis, and outcomes of congenital heart disease to improve medical and policy decisions.
Data on cases of congenital heart disease identified during 2014-2018 were taken from the Zhejiang provincial birth defects surveillance system. Chi-square test, odds ratio (OR) and 95% confidence interval (CI) were used to explore epidemiology, prenatal diagnosis, and birth outcomes of congenital heart disease.
The average incidence of congenital heart disease was 16.0 per 1000 births, which increased by 62.2% during 2014-2018(χ
= 181.41, P < 0.001). However, the average critical congenital heart incidence was 1.6 per 1000 births, which remained stable over time. Women aged ≤20 years (OR2.1, 95% CI 1.9-2.3) or ≥ 35 years (OR 1.2, 95% CI 1.2-1.3) were at higher risk of having babies with congenital heart disease than women aged 21-34 years. Women who gave birth in urban areas (OR 1.2, 95% CI 1.2-1.3), had a son (OR 1.3, 95% CI 1.3-1.4), or had multiple births (OR 4.0, 95% CI 3.7-4.4) were also at higher risk than those giving birth in rural areas, to girls, or single births, respectively. The three major subtypes of congenital heart disease were atrial septal defect (67.9%), patent ductus arteriosus (34.7%), and ventricular septal defect (6.4%). The prenatal detection rate of critical congenital heart disease was 90.0%, which was far higher than total congenital heart disease, at 22.2% (χ
= 1687.67, P < 0.001). There were 1457 (17.1%) stillbirths, 106 (1.2%) early neonatal deaths, and 6983 (81.7%) live births associated with congenital heart disease.
The high incidence of congenital heart disease in Zhejiang might be attributable to the large proportion of mild congenital heart disease. The incidence of critical congenital heart disease, the prenatal detection rate, and perinatal deaths from congenital heart disease are comparable to those in other studies.
Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from ...intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
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