ABSTRACT
Telocytes (TCs), a novel type of mesenchymal or interstitial cell with specific, very long and thin cellular prolongations, have been found in various mammalian organs and have potential biological functions. However, their existence during lung development is poorly understood. This study aimed to investigate the existence, morphological features, and role of CD34+ SCs/TCs in mouse lungs from foetal to postnatal life using primary cell culture, double immunofluorescence, transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The immunofluorescence double staining profiles revealed positive expression of CD34 and PDGFR-α, Sca-1 or VEGFR-3, and the expression of these markers differed among the age groups during lung development. Intriguingly, in the E18.5 stage of development, along with the CD34+ SCs/TCs, haematopoietic stem cells and angiogenic factors were also significantly increased in number compared with those in the E14.5, E16.5, P0 and P7. Subsequently, TEM confirmed that CD34+ SCs/TCs consisted of a small cell body with long telopodes (Tps) that projected from the cytoplasm. Tps consisted of alternating thin and thick segments known as podomers and podoms. TCs contain abundant endoplasmic reticulum, mitochondria and secretory vesicles and establish close connections with neighbouring cells. Furthermore, SEM revealed characteristic features, including triangular, oval, spherical, or fusiform cell bodies with extensive cellular prolongations, depending on the number of Tps. Our findings provide evidence for the existence of CD34+ SCs/TCs, which contribute to vasculogenesis, the formation of the airâblood barrier, tissue organization during lung development and homoeostasis.
ABSTRACT
Integrated reservoir water quantity and quality management is significant for water supply security and river ecosystem health. However, the spatiotemporal heterogeneity of water quality and the nonuniform response of multiple indicators to operation changes make it difficult to determine optimal operation schedules. This study proposes a coupled simulation-surrogate-optimization modeling approach for compromising multiple water quantity and quality targets in reservoir operations. The Environmental Fluid Dynamics Code (EFDC) was used to simulate spatiotemporal reservoir water quality dynamics. Subsequently, an ecological damage assessment method was established, accounting for the spatiotemporal heterogeneity of multiple water quality indicators and the nonlinear relationship between the water quality deterioration and ecological damage. To quickly simulate the ecological damage, a surrogate model was developed using the nonlinear autoregressive network with exogenous inputs (NARX). Finally, the surrogate model was integrated into a reservoir operation optimization model for compromising socioeconomic and ecological targets. By applying the methods to China's Danjiangkou Reservoir as a case, it was shown that more even nutrient distribution in the reservoir increased water eutrophication area while reducing concentration peak values, which helped decrease the ecological damage. Operation changes could lead to opposite effects on in-reservoir and downstream ecological targets, increasing operation optimization complexity. Both ecological and socioeconomic benefits significantly increased (by 9.4%-16.4%) during dry years under the optimized operation scheme, implying that synergies were obtained. This study offers implications and a management tool for reservoir operations to address the multiple tradeoffs among socioeconomic and ecological benefits.
ABSTRACT
Although the effects of human-enhanced atmospheric nitrogen (N) deposition are well documented, the response of dryland soils to N deposition remains unclear owing to the divergence in hydrological outputs and soil heterogeneity. We selected a typical desert steppe in western China to simulate the effects of long-term N deposition by applying 0 (CK), 3.5, 7, and 14 g N m-2 yr-1 for 12 consecutive years. We found that, compared with the CK plots, the total N content of the upper (0-10 cm) and lower (10-20 cm) soil layers in fertilized plots increased by 8.3-14.6 % and 2.4-8.2 %, respectively. Correspondingly, the available, NH4+-, and NO3--N contents in the upper soil significantly increased by 25.5-68.3 %. However, in the lower soil, available and NO3--N contents were significantly lower than those in the CK plots, and their variation trend was opposite to that of NH4+-N, implying N turnover and leaching. As a result, the upper and lower soil pH in fertilized plots significantly decreased by 0.36-0.53 and 0.31-0.37 units; however, their CaCO3 content significantly increased by 9.8-22.8 % and 7.2-30.3 %, respectively. The total phosphorus (P) content in the upper and lower soil layers in fertilized plots significantly increased and decreased by 3.6-51.3 % and 16.7-62.5 %, respectively, however, both significantly decreased along the N fertilization gradient. Furthermore, the upper and lower soil organic carbon (SOC) content in the fertilized plots significantly increased by 57.7-78.1 % and 19.2-27.4 %, respectively. Pearson's correlation analysis revealed that available soil P was significantly negatively correlated with plant shoot Mn content (a proxy for rhizosphere carboxylates), whereas dissolved OC, SOC, and CaCO3 were significantly positively correlated, suggesting that Ca cycling is involved in P cycling and SOC sequestration. Our study suggests that long-term N input exacerbates P limitation in desert steppes, however, enhances SOC sequestration.
ABSTRACT
CYP2C19*3 enzyme plays a pivotal role in drug metabolism and is tightly regulated by the CYP2C19*3 gene. Therefore, quantification of CYP2C19*3 gene holds paramount importance for achieving personalized medication guidance in precision medicine. In this project, the magnetic electrochemical biosensors were constructed for the ultra-sensitive detection of CYP2C19*3 gene. Employing magnetic α-Fe2O3/Fe3O4@Au as the matrixes for signal amplification, CYP2C19*3 complementary chains (c-ssDNA) were bound to their surfaces through gold-sulfur bonds with subsequent specific sites blockade by bovine serum albumin (BSA) to form the α-Fe2O3/Fe3O4@Au/c-ssDNA/BSA biosensors. This design enabled efficient biosensors separation, target gene capture, and self-assembly on the electrode surface, enhancing the response signal. The biosensors exhibited excellent capture capabilities with a wide linear range (1 pM-1 µM), a low detection limit of 0.2710 pM, a quantitation limit of 0.9033 pM, reproducibility with an RSD value of 1.26 %, and stable storage for at least one week. The RSD value of CYP2C19*3 in serum samples consistently remained below 4.5 %, with a recovery rate ranging 95.52 % from 102.71 %. Moreover, the target gene could be accurately identified and captured in a mixed system of multiple nucleotide mutants of the CYP2C19*3 gene, suggesting a promising applicability and popularization.
ABSTRACT
Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.
Subject(s)
Endoplasmic Reticulum , GTP Phosphohydrolases , Mitochondria , Reactive Oxygen Species , Endoplasmic Reticulum/metabolism , Mitochondria/metabolism , Humans , GTP Phosphohydrolases/metabolism , GTP Phosphohydrolases/genetics , Reactive Oxygen Species/metabolism , HeLa Cells , Microtubules/metabolism , HEK293 Cells , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Membrane Transport Proteins/genetics , Protein Binding , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Cytosol/metabolism , Mitochondrial DynamicsABSTRACT
Optical computing promises to improve the speed and energy efficiency of machine learning applications1-6. However, current approaches to efficiently train these models are limited by in silico emulation on digital computers. Here we develop a method called fully forward mode (FFM) learning, which implements the compute-intensive training process on the physical system. The majority of the machine learning operations are thus efficiently conducted in parallel on site, alleviating numerical modelling constraints. In free-space and integrated photonics, we experimentally demonstrate optical systems with state-of-the-art performances for a given network size. FFM learning shows training the deepest optical neural networks with millions of parameters achieves accuracy equivalent to the ideal model. It supports all-optical focusing through scattering media with a resolution of the diffraction limit; it can also image in parallel the objects hidden outside the direct line of sight at over a kilohertz frame rate and can conduct all-optical processing with light intensity as weak as subphoton per pixel (5.40 × 1018- operations-per-second-per-watt energy efficiency) at room temperature. Furthermore, we prove that FFM learning can automatically search non-Hermitian exceptional points without an analytical model. FFM learning not only facilitates orders-of-magnitude-faster learning processes, but can also advance applied and theoretical fields such as deep neural networks, ultrasensitive perception and topological photonics.
ABSTRACT
CD8+ T cell immunity, mediated by human leukocyte antigen (HLA) and T cell receptor (TCR), plays a critical role in conferring immune memory and protection against viral pathogens. The emergence of SARS-CoV-2 variants poses a serious challenge to the efficacy of current vaccines. Whereas numerous SARS-CoV-2 mutations associated with immune escape from CD8+ T cells have been documented, the molecular effects of most mutations on epitope-specific TCR recognition remain largely unexplored. Here, we studied an HLA-A24-restricted NYN epitope (Spike448-456) that elicits broad CD8+ T cell responses in COVID-19 patients characterized by a common TCR repertoire. Four natural mutations, N450K, L452Q, L452R, and Y453F, arose within the NYN epitope and have been transmitted in certain viral lineages. Our findings indicate that these mutations have minimal impact on the epitope's presentation by cell surface HLA, yet they diminish the affinities of their respective peptide-HLA complexes (pHLAs) for NYN peptide-specific TCRs, particularly L452R and Y453F. Furthermore, we determined the crystal structure of HLA-A24 loaded with the Y453F peptide (NYNYLFRLF), and subsequently a ternary structure of the public TCRNYN-I complexed to the original NYN-HLA-A24 (NYNYLYRLF). Our structural analysis unveiled that despite competent presentation by HLA, the mutant Y453F peptide failed to establish a stable TCR-pHLA ternary complex due to reduced peptide: TCR contacts. This study supports the idea that cellular immunity restriction is an important driving force behind viral evolution.
ABSTRACT
In this paper, a long-stroke parallel compliant tip-tilt-piston micropositioning stage driven by voice coil motors (VCMs) is proposed. The stage is equipped with three sets of driving arms, which include a spherical hinge, VCM, and parallelogram guide mechanism, evenly spaced at 120° intervals. The spherical hinge is composed of orthogonal leaf-spring beams, and the VCM is embedded into the parallelogram mechanism to form a compact design. The compliance matrix method and the geometric method facilitated the determination of compliance in all six degree-of-freedom directions of the spherical hinge and the derivation of kinematic equations for decoupling the motion of the stage. In addition, finite element analysis was utilized to determine the maximum stroke and stress of the stage. To validate the proposed design, a stage prototype was constructed and subjected to experimental testing. Furthermore, a feedback controller was designed, integrating proportional integral controller, notch filter, and sliding mode controller feedforward. The experimental results indicate that the stage can achieve a long stroke of ±50.75 mrad × ±44.2 mrad × ±4.425 mm, with the natural frequencies in the three-axis direction of 22.3 × 25.5 × 25.5 Hz3. In addition, the maximum relative tracking error was maintained below 5.25%, highlighting the effectiveness of the control technique in achieving a high tracking performance.
ABSTRACT
Neutrophils need to migrate through tight tissue spaces to eliminate pathogens, but their movement is often hindered by their large and stiff nuclei. Neutrophil migration is impaired in sepsis patients, but it is unclear whether this defect is related to the deformability of their nuclei. Herein, we designed microfluidic devices with micron-scale narrow slits to simulate biological barriers. This setup allowed us to observe and record neutrophil movement and nuclear deformation in real-time. We also developed a method for morphological analysis to quantify nucleus deformation in numerous individual cells. Our studies showed that neutrophils from healthy individuals could adjust their nuclear shape to squeeze through these constrictions, whereas those from sepsis patients demonstrated less flexibility. Neutrophils with rigid nuclei struggled to pass through narrow gaps and were more likely to rupture under pressure. These findings suggest that the migration defects of neutrophils observed in sepsis may be attributed to the inability of neutrophils to deform their nuclei, highlighting the crucial role of microfluidic technologies in offering new insights into migration defects under pathological conditions.
Subject(s)
Cell Movement , Lab-On-A-Chip Devices , Neutrophils , Sepsis , Humans , Neutrophils/cytology , Biosensing Techniques/instrumentation , Equipment Design , Cell NucleusABSTRACT
Menstrual blood-derived endometrial stem cells (MenSCs) have attracted increasing interest due to their excellent safety, and lack of ethical dilemma as well as their ability to be periodically obtained in a noninvasive manner. However, although preclinical research as shown the therapeutic potential of MenSCs in several diseases, their poor cell survival and low engraftment at disease sites reduce their clinical efficacy. Flotillins (including Flot1 and Flot2) are implicated in various cellular processes, such as vesicular trafficking, signal transduction, cell proliferation, migration and apoptosis. In this study, we aimed to determine the effects of Flotillins on MenSCs survival, proliferation and migration. Our experimental results show that MenSCs were modified to overexpress Flot1 and/or Flot2 without altering their intrinsic characteristics. Flot1 and Flot2 co-overexpression promoted MenSC viability and proliferation capacity. Moreover, Flot1 or Flot2 overexpression significantly promoted the migration and inhibited the apoptosis of MenSCs compared with the negative control group, and these effects were stronger in the Flot1 and Flot2 gene co-overexpression group. However, these effects were significantly reversed after Flot1 and/or Flot2 knockdown. In conclusion, our results indicate that Flot1 and Flot2 overexpression in MenSCs improved their proliferation and migration and inhibited their apoptosis, and this might be an effective approach to improve the efficiency of cell-based therapies.
Subject(s)
Apoptosis , Cell Movement , Cell Proliferation , Cell Survival , Membrane Proteins , Humans , Membrane Proteins/metabolism , Membrane Proteins/genetics , Female , Endometrium/cytology , Endometrium/metabolism , Stem Cells/metabolism , Stem Cells/cytology , Cells, Cultured , Signal TransductionABSTRACT
Biomarkers are crucial physiological and pathological indicators in the host. Over the years, numerous detection methods have been developed for biomarkers, given their significant potential in various biological and biomedical applications. Among these, the detection system based on functionalized DNA origami has emerged as a promising approach due to its precise control over sensing modules, enabling sensitive, specific, and programmable biomarker detection. We summarize the advancements in biomarker detection using functionalized DNA origami, focusing on strategies for DNA origami functionalization, mechanisms of biomarker recognition, and applications in disease diagnosis and monitoring. These applications are organized into sections based on the type of biomarkers - nucleic acids, proteins, small molecules, and ions - and concludes with a discussion on the advantages and challenges associated with using functionalized DNA origami systems for biomarker detection.
Subject(s)
Biomarkers , DNA , DNA/chemistry , DNA/analysis , Biomarkers/analysis , Humans , Biosensing Techniques , Nanostructures/chemistry , Proteins/analysis , Proteins/chemistry , Nucleic Acid ConformationABSTRACT
The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
Subject(s)
AMP-Activated Protein Kinases , Electron Transport Complex I , Ferroptosis , Animals , Female , Humans , Mice , AMP-Activated Protein Kinase Kinases/genetics , AMP-Activated Protein Kinases/metabolism , AMP-Activated Protein Kinases/genetics , Cell Line, Tumor , Electron Transport Complex I/metabolism , Electron Transport Complex I/genetics , Ferroptosis/genetics , Ferroptosis/drug effects , Mitochondria/metabolism , Mitochondria/genetics , Mitochondria/drug effects , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/metabolism , Neoplasms/drug therapy , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The pursuit of artificial general intelligence (AGI) continuously demands higher computing performance. Despite the superior processing speed and efficiency of integrated photonic circuits, their capacity and scalability are restricted by unavoidable errors, such that only simple tasks and shallow models are realized. To support modern AGIs, we designed Taichi-large-scale photonic chiplets based on an integrated diffractive-interference hybrid design and a general distributed computing architecture that has millions-of-neurons capability with 160-tera-operations per second per watt (TOPS/W) energy efficiency. Taichi experimentally achieved on-chip 1000-category-level classification (testing at 91.89% accuracy in the 1623-category Omniglot dataset) and high-fidelity artificial intelligence-generated content with up to two orders of magnitude of improvement in efficiency. Taichi paves the way for large-scale photonic computing and advanced tasks, further exploiting the flexibility and potential of photonics for modern AGI.
ABSTRACT
Electrostatic capacitors are foundational components of advanced electronics and high-power electrical systems owing to their ultrafast charging-discharging capability. Ferroelectric materials offer high maximum polarization, but high remnant polarization has hindered their effective deployment in energy storage applications. Previous methodologies have encountered problems because of the deteriorated crystallinity of the ferroelectric materials. We introduce an approach to control the relaxation time using two-dimensional (2D) materials while minimizing energy loss by using 2D/3D/2D heterostructures and preserving the crystallinity of ferroelectric 3D materials. Using this approach, we were able to achieve an energy density of 191.7 joules per cubic centimeter with an efficiency greater than 90%. This precise control over relaxation time holds promise for a wide array of applications and has the potential to accelerate the development of highly efficient energy storage systems.
ABSTRACT
NLRP inflammasomes are a group of cytosolic multiprotein oligomer pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) produced by infected cells. They regulate innate immunity by triggering a protective inflammatory response. However, despite their protective role, aberrant NLPR inflammasome activation and gain-of-function mutations in NLRP sensor proteins are involved in occurrence and enhancement of non-communicating autoimmune, auto-inflammatory, and neurodegenerative diseases. In the last few years, significant advances have been achieved in the understanding of the NLRP inflammasome physiological functions and their molecular mechanisms of activation, as well as therapeutics that target NLRP inflammasome activity in inflammatory diseases. Here, we provide the latest research progress on NLRP inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRP7, NLRP2, NLRP9, NLRP10, and NLRP12 regarding their structural and assembling features, signaling transduction and molecular activation mechanisms. Importantly, we highlight the mechanisms associated with NLRP inflammasome dysregulation involved in numerous human auto-inflammatory, autoimmune, and neurodegenerative diseases. Overall, we summarize the latest discoveries in NLRP biology, their forming inflammasomes, and their role in health and diseases, and provide therapeutic strategies and perspectives for future studies about NLRP inflammasomes.
Subject(s)
Inflammasomes , NLR Proteins , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , NLR Proteins/metabolism , Animals , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/metabolism , Signal Transduction/immunology , Immunity, Innate , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Inflammation/immunology , Inflammation/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/immunology , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
To avoid the difficulty of separating solids from liquids when reusing powder photocatalysts, 3D stereoscopic photocatalysts were constructed. In this study, three-dimensional S defect-rich MoS2 hierarchical aerogel was prepared by chemical cross-linking of functional ultrathin 2D MoS2. Its phase, micro-morphology and structure were characterized, and it was used in the study of photocatalytic degradation of organic pollutants. Of the samples tested, MS@CA-3 (i.e., defect-rich 3D MoS2 aerogel with a loading of 30 mg of defect-rich MoS2) exhibited the best photocatalytic activity due to its suitable load, good light transmission, and a degradation rate of up to 91.0% after 3 h. In addition, MS@CA-3 aerogel offers high recyclability and structural stability, and the degradation rate of the organic pollutant methylene blue decreases only 9.8% after more than ten cycles of photocatalytic degradation. It combines the high catalytic performance of S defect-rich 2D MoS2 and the convenient reusability of hierarchical porous aerogel. This study provides valuable data and a reference for the practical promotion and application of photocatalytic technology in the field of environmental remediation.
Subject(s)
Environmental Pollutants , Molybdenum , Porosity , Catalysis , Coloring AgentsABSTRACT
BACKGROUND: Exosomes derived from breast cancer have been reported to play a role in promoting cell proliferation, migration, and angiogenesis, which has the potential to accelerate the healing process of diabetic wounds. The aim of this investigation was to examine the function of exosomes originating from 4T1 mouse breast carcinoma cells (TEXs) in the process of diabetic wound healing. METHODS: The assessment of primary mouse skin fibroblasts cell proliferation and migration was conducted through the utilization of CCK-8 and wound healing assays, while the tube formation of HUVECs was evaluated by tube formation assay. High-throughput sequencing, RT-qPCR and cell experiments were used to detect the roles of miR-126a-3p in HUVECs functions in vitro. The in vivo study employed a model of full-thickness excisional wounds in diabetic subjects to explore the potential therapeutic benefits of TEXs. Immunohistochemical and immunofluorescent techniques were utilized to evaluate histological changes in skin tissues. RESULTS: The findings suggested that TEXs facilitate diabetic wound healing through the activation of cell migration, proliferation, and angiogenesis. An upregulation of miR-126a-3p has been observed in TEXs, and it has demonstrated efficient transferability from 4T1 cells to HUVEC cells. The activation of the PI3K/Akt pathway has been attributed to miR-126a-3p derived from TEXs. CONCLUSIONS: The promotion of chronic wound healing can be facilitated by TEXs through the activation of cellular migration, proliferation, and angiogenesis. The activation of the PI3K/Akt pathway by miR-126a-3p originating from TEXs has been discovered, indicating a potential avenue for enhancing the regenerative capabilities of wounds treated with TEXs.
Subject(s)
Cell Movement , Cell Proliferation , Exosomes , Human Umbilical Vein Endothelial Cells , Wound Healing , Animals , Exosomes/metabolism , Humans , Mice , Female , MicroRNAs/metabolism , MicroRNAs/genetics , Cell Line, Tumor , Mice, Inbred BALB C , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Diabetes Mellitus, Experimental , Fibroblasts/metabolism , Neovascularization, Physiologic , Proto-Oncogene Proteins c-akt/metabolism , Signal TransductionABSTRACT
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from patients with BRCA1-mutant breast cancer with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers. Significance: BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers. See related commentary by Alborzinia and Friedmann Angeli, p. 1372.
Subject(s)
BRCA1 Protein , Ferroptosis , Phospholipid Hydroperoxide Glutathione Peroxidase , Poly(ADP-ribose) Polymerase Inhibitors , Ferroptosis/drug effects , Humans , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , BRCA1 Protein/genetics , Female , Animals , Mice , Cell Line, Tumor , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Xenograft Model Antitumor Assays , Nuclear Receptor CoactivatorsABSTRACT
Scalable, high-capacity, and low-power computing architecture is the primary assurance for increasingly manifold and large-scale machine learning tasks. Traditional electronic artificial agents by conventional power-hungry processors have faced the issues of energy and scaling walls, hindering them from the sustainable performance improvement and iterative multi-task learning. Referring to another modality of light, photonic computing has been progressively applied in high-efficient neuromorphic systems. Here, we innovate a reconfigurable lifelong-learning optical neural network (L2ONN), for highly-integrated tens-of-task machine intelligence with elaborated algorithm-hardware co-design. Benefiting from the inherent sparsity and parallelism in massive photonic connections, L2ONN learns each single task by adaptively activating sparse photonic neuron connections in the coherent light field, while incrementally acquiring expertise on various tasks by gradually enlarging the activation. The multi-task optical features are parallelly processed by multi-spectrum representations allocated with different wavelengths. Extensive evaluations on free-space and on-chip architectures confirm that for the first time, L2ONN avoided the catastrophic forgetting issue of photonic computing, owning versatile skills on challenging tens-of-tasks (vision classification, voice recognition, medical diagnosis, etc.) with a single model. Particularly, L2ONN achieves more than an order of magnitude higher efficiency than the representative electronic artificial neural networks, and 14× larger capacity than existing optical neural networks while maintaining competitive performance on each individual task. The proposed photonic neuromorphic architecture points out a new form of lifelong learning scheme, permitting terminal/edge AI systems with light-speed efficiency and unprecedented scalability.
ABSTRACT
Soil solution pH and dissolved organic carbon (DOC) influence cadmium (Cd) uptake by hyperaccumulators but their tradeoff in calcareous soils is unclear. This study investigated the mechanisms of Solanum nigrum L. and Solanum alatum Moench in calcareous soil using a combination of concentration gradient experiments (0.6-100 mg Cd kg-1) and soil solution composition analysis. The results showed that the soil solution pH of S. nigrum remained stable despite Cd stress. On average, the soil solution pH of S. alatum was 0.23 units higher than that of S. nigrum, although pH decreased significantly under high Cd stress. In addition, the concentrations of potassium (K) and calcium (Ca) in the soil solution of S. nigrum increased and decreased under low and high levels of Cd stress, respectively. In S. alatum, the K and Ca concentrations in the soil solution generally increased with increasing Cd stress levels. Moreover, the level of DOC in the soil solution of both plants was higher under Cd stress compared to the control, and a gradually increasing trend with Cd stress level was observed in S. alatum. Consequently, the bioconcentration factors of the roots (2.62-19.35) and shoots (1.20-9.59) of both plants were >1, while the translocation factors were <1, showing an obstacle of Solanum hyperaccumulators in transferring Cd into their aboveground parts. Redundancy analysis revealed that the Cd concentration in S. nigrum roots was significantly negatively correlated with the soil solutions of K and Ca. In contrast, Cd concentrations in S. alatum roots and shoots were significantly positively correlated with soil solution DOC, K, and Ca but negatively correlated with pH. Our results suggest that calcareous soil neutralizes the acidity of released protons but does not affect cation exchange, inhibiting DOC in assisting the translocation of Cd within plants.