Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the ...accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
As postulated by life‐history theory, not all life‐history traits can be maximized simultaneously. In ectothermic animals, climate warming is predicted to increase growth rates, but at a cost to ...overall life span. Maternal effects are expected to mediate this life‐history trade‐off, but such effects have not yet been explicitly elucidated.
To understand maternal effects on the life‐history responses to climate warming in lizard offspring, we conducted a manipulative field experiment on a desert‐dwelling viviparous lacertid lizard Eremias multiocellata, using open‐top chambers in a factorial design (maternal warm climate and maternal present climate treatments × offspring warm climate and offspring present climate treatments).
We found that the maternal warm climate treatment had little impact on the physiological and life‐history traits of adult females (i.e. metabolic rate, reproductive output, growth and survival). However, the offspring warm climate treatment significantly affected offspring growth, and both maternal and offspring warm climate treatments interacted to affect offspring survival.
Offspring from the warm climate treatment grew faster than those from the present climate treatment. However, the offspring warm climate treatment significantly decreased the survival rate of offspring from maternal present climate treatment, but not for those from the maternal warm climate treatment.
Our study demonstrates that maternal effects mediate the trade‐off between growth and survival of offspring lizards, allowing them to grow fast without a concurrent cost of low survival rate (short life span). These findings stress the importance of adaptive maternal effects in buffering the impact of climate warming on organisms, which may help us to accurately predict the vulnerability of populations and species to future warming climates.
The authors fully factorial warming experiment using open‐top chambers demonstrated that maternal effects mediate the growth‐survival tradeoff of lizards under climate warming. This finding challenges a rarely tested assumption underlying life‐history tradeoff: the limitation of an energy budget, and stresses the importance of adaptive maternal effects in buffering the impact of climate warming on organisms.
Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic ...stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.
Stem cell therapy may replace lost photoreceptors and preserve residual photoreceptors during retinal degeneration (RD). Unfortunately, the degenerative microenvironment compromises the fate of ...grafted cells, demanding supplementary strategies for microenvironment regulation. Donor cells with both proper regeneration capability and intrinsic ability to improve microenvironment are highly desired. Here, we use cell surface markers (C-Kit
/SSEA4
) to effectively eliminate tumorigenic embryonic cells and enrich retinal progenitor cells (RPCs) from human embryonic stem cell (hESC)-derived retinal organoids, which, following subretinal transplantation into RD models of rats and mice, significantly improve vision and preserve the retinal structure. We characterize the pattern of integration and materials transfer following transplantation, which likely contribute to the rescued photoreceptors. Moreover, C-Kit
/SSEA4
cells suppress microglial activation, gliosis and the production of inflammatory mediators, thereby providing a healthier host microenvironment for the grafted cells and delaying RD. Therefore, C-Kit
/SSEA4
cells from hESC-derived retinal organoids are a promising therapeutic cell source.
Cervical cancer is a common cause of cancer-related mortality in women. Mounting evidence suggests that long non-coding RNAs (lncRNAs) function vitally in many cancers. In this study, we discovered ...that the regulation of the heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) in cervical cancer. RT-qPCR was conducted to detect the expression of HAND2-AS1 and microRNA-21-5p (miR-21-5p). The relationship of HAND2-AS1 and miR-21-5p was identified by dual-luciferase reporter gene assay. The roles of HAND2-AS1, miR-21-5p and tissue inhibitor of metalloproteinases-3 (TIMP3) in cervical cancer were accessed via gain- and loss-of-function approaches. The expression of related proteins in the vascular endothelial growth factor A (VEGFA) signaling pathway was detected through Western blot analysis. Finally, xenografts of cervical cancer in nude mice were established to assess the effect of HAND2-AS1 on tumorigenesis in vivo. HAND2-AS1 and TIMP3 were downregulated in cervical cancer, which were identified to be associated with a poor prognosis of patients with cervical cancer. Moreover, HAND2-AS1 was upregulated the expression of TIMP3 through competitively binding to miR-21-5p. Overexpressed HAND2-AS1 or downregulated miR-21-5p inhibited cell proliferation, migration, and invasion while promoting cell apoptosis, in association with increased expression of proteins in VEGFA signaling pathway. These changes were reversed by silencing of TIMP3. Overexpressed HAND2-AS1 reduced the tumor formation ability in nude mice. In summary, HAND2-AS1 may exert inhibitory effects on cervical cancer cell growth and cervical cancer development through its regulation on the miR-21-5p/TIMP3/VEGFA axis. This highlights that HAND2-AS1 may serve as a potential target for cervical cancer diagnosis and treatment.
As a lightweight deep neural network, MobileNet has fewer parameters and higher classification accuracy. In order to further reduce the number of network parameters and improve the classification ...accuracy, dense blocks that are proposed in DenseNets are introduced into MobileNet. In Dense-MobileNet models, convolution layers with the same size of input feature maps in MobileNet models are taken as dense blocks, and dense connections are carried out within the dense blocks. The new network structure can make full use of the output feature maps generated by the previous convolution layers in dense blocks, so as to generate a large number of feature maps with fewer convolution cores and repeatedly use the features. By setting a small growth rate, the network further reduces the parameters and the computation cost. Two Dense-MobileNet models, Dense1-MobileNet and Dense2-MobileNet, are designed. Experiments show that Dense2-MobileNet can achieve higher recognition accuracy than MobileNet, while only with fewer parameters and computation cost.
Inverse kinematics problems (IKP) are ubiquitous in robotics for improved robot control in widespread applications. However, the high non-linearity, complexity, and equation coupling of a general ...six-axis robotic manipulator pose substantial challenges in solving the IKP precisely and efficiently. To address this issue, we propose a novel approach based on neural network (NN) with numerical error minimization in this paper. Within our framework, the complexity of IKP is first simplified by a strategy called joint space segmentation, with respective training data generated by forward kinematics. Afterwards, a set of multilayer perception networks (MLP) are established to learn from the foregoing data in order to fit the goal function piecewise. To reduce the computational cost of the inference process, a set of classification models is trained to determine the appropriate forgoing MLPs for predictions given a specific input. After the initial solution is sought, being improved with a prediction error minimized, the refined solution is finally achieved. The proposed methodology is validated via simulations on Xarm6-a general 6 degrees of freedom manipulator. Results further verify the feasibility of NN for IKP in general cases, even with a high-precision requirement. The proposed algorithm has showcased enhanced efficiency and accuracy compared to NN-based approaches reported in the literature.
Tremendous progress has been made in the field of toxicology leading to the advance of developmental toxicity assessment. Conventional animal models and in vitro two-dimensional models cannot ...accurately describe toxic effects and predict actual in vivo responses due to obvious inter-species differences between humans and animals, as well as the lack of a physiologically relevant tissue microenvironment. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived three-dimensional organoids are ideal complex and multicellular organotypic models, which are indispensable in recapitulating morphogenesis, cellular interactions, and molecular processes of early human organ development. Recently, human organoids have been used for drug discovery, chemical toxicity and safety in vitro assessment. This review discusses the recent advances in the use of human organoid models, (i.e., brain, retinal, cardiac, liver, kidney, lung, and intestinal organoid models) for developmental toxicity and teratogenicity assessment of distinct tissues/organs following exposure to pharmaceutical compounds, heavy metals, persistent organic pollutants, nanomaterials, and ambient air pollutants. Combining next-generation organoid models with innovative engineering technologies generates novel and powerful tools for developmental toxicity and teratogenicity assessment, and the rapid progress in this field is expected to continue.
•Advances in stem cell techniques for toxicity assessment.•Human organoids can decipher the embryonic development and morphogenesis.•Organoid technologies for developmental toxicology assessment.•Advanced next-generation human organoids toward next-level toxicity testing.
Premise
Pollinator sharing of co‐flowering plants may result in interspecific pollen receipt with a fitness cost. However, the underlying factors that determine the effects of heterospecific pollen ...(HP) are not fully understood. Moreover, the cost of stigma closure induced by HP may be more severe for plants with special touch‐sensitive stigmas than for plants with non‐touch‐sensitive stigmas. Very few studies have assessed HP effects on stigma behavior.
Methods
We conducted hand‐pollination experiments with 10 HP donors to estimate HP effects on stigma behavior and stigmatic pollen germination in Campsis radicans (Bignoniaceae) at low and high pollen loads. We assessed the role of phylogenetic distance between donor and recipient, pollen size, and pollen aperture number in mediating HP effects. Additionally, we observed pollen tube growth to determine the conspecific pollen‐tube‐growth advantage.
Results
Stigma behavior differed significantly with HP of different species. Pollen load increased, while pollen size decreased, the percentage of permanent closure and stigmatic germination of HP. Stigmatic HP germination increased with increasing aperture number. However, HP effects did not depend on phylogenetic distance. In addition, conspecific pollen had a pollen‐tube‐growth advantage over HP.
Conclusions
Our results provide a good basis for understanding the stigma‐pollen recognition process of plant taxa with touch‐sensitive stigmas. We concluded that certain flowering traits drive the HP effects on the post‐pollination period. To better understand the impact of pollinator sharing and interspecific pollen transfer on plant evolution, we highlight the importance of evaluating more factors that determine HP effects at the community level.
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