DDX58 deficiency leads to triple negative breast cancer chemotherapy resistance by inhibiting Type I IFN-mediated signalling apoptosis.

Introduction: Triple-negative breast cancer (TNBC) is characterized by its aggressive nature and absence of specific therapeutic targets, necessitating the reliance on chemotherapy as the primary treatment modality. However, the drug resistance poses a significant challenge in the management of TNBC. In this study, we investigated the role of DDX58 (DExD/H-box helicase 58), also known as RIG-I, in TNBC chemoresistance. Methods: The relationship between DDX58 expression and breast cancer prognosis was investigated by online clinical databases and confirmed by immunohistochemistry analysis. DDX58 was knockout by CRISPR-Cas9 system (DDX58-KO), knockdown by DDX58-siRNA (DDX58-KD), and stably over expressed (DDX58-OE) by lentivirus. Western blotting, immunofluorescence and qPCR were used for related molecules detection. Apoptosis was analyzed through flow cytometry (Annexin V/7AAD apoptosis assay) and Caspase 3/7 activity assay. Results: Patients with lower expression of DDX58 led to lower rate of pathological complete response (pCR) and worse prognosis by online databases and hospital clinical data. DDX58-KD cells showed multiple chemo-drugs resistance (paclitaxel, doxorubicin, 5-fluorouracil) in TNBC cell lines. Similarly, DDX58-KO cells also showed multiple chemo-drugs resistance in a dosage-dependent manner. In the CDX model, tumours in the DDX58-KO group had a 25% reduction in the tumour growth inhibition rate (IR) compared to wild-type (WT) group after doxorubicin (Dox) treatment. The depletion of DDX58 inhibited proliferation and promoted the migration and invasion in MDA-MB-231 cells. The findings of our research indicated that DDX58-KO cells exhibit a reduction in Dox-induced apoptosis both in vivo and in vitro. Mechanistically, Dox treatment leads to a significant increase in the expression of double-stranded RNAs (dsRNAs) and activates the DDX58-Type I interferon (IFN) signaling pathway, ultimately promoting apoptosis in TNBC cells. Discussion: In the process of TNBC chemotherapy, the deficiency of DDX58 can inhibit Dox-induced apoptosis, revealing a new pathway of chemotherapy resistance, and providing a possibility for developing personalized treatment strategies based on DDX58 expression levels.

scRNA-Seq and Bulk-Seq Analysis Identifies S100A9 Plasma Cells as a Potentially Effective Immunotherapeutic Agent for Multiple Myeloma.

Purpose: Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy. Patients and Methods: In our study, we used both single-cell RNA sequencing (scRNA-seq) and bulk sequencing techniques to analyze MM patients. We analyzed each sample using gene set variation analysis (GSVA) based on immune-related gene sets. We also conducted further analyses to compare immune infiltration, clinical characteristics, and expression of immune checkpoint molecules between the H-S100A9 and L-S100A9 groups of MM patients. Results: We identified eight subpopulations of plasma cells, with S100A9 plasma cells being more abundant in patients with 1q21 gain and 1q21 diploid. CellChat analysis revealed that GAS and HGF signaling pathways were prominent in intercellular communication of S100A9 plasma cells. We identified 14 immune-related genes in the S100A9 plasma cell population, which allowed us to classify patients into the H-S100A9 group or the L-S100A9 group. The H-S100A9 group showed higher ESTIMATE, immune and stroma scores, lower tumor purity, and greater immune checkpoint expression. Patients with 1q21 gain and four or more copies had the lowest ESTIMATE score, immune score, stroma score, and highest tumor purity. Drug sensitivity analysis indicated that the H-S100A9 group had lower IC50 values and greater drug sensitivity compared to the L-S100A9 group. Quantitative reverse transcription (RT-q) PCR showed significantly elevated expression of RNASE6, LYZ, S100A8, S100A9, and S100A12 in MM patients compared to the healthy control group. Conclusion: Our study has identified a correlation between molecular subtypes of S100A9 plasma cells and the response to immunotherapy in MM patients. These findings improve our understanding of tumor immunology and provide guidance for developing effective immunotherapy strategies for this patient population.

DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT.

BACKGROUND: Chemotherapy is a primary treatment for breast cancer (BC), yet many patients develop resistance over time. This study aims to identify critical factors contributing to chemoresistance and their underlying molecular mechanisms, with a focus on reversing this resistance. METHODS: We utilized samples from the Gene Expression Omnibus (GEO) and West China Hospital to identify and validate genes associated with chemoresistance. Functional studies were conducted using MDA-MB-231 and MCF-7 cell lines, involving gain-of-function and loss-of-function approaches. RNA sequencing (RNA-seq) identified potential mechanisms. We examined interactions between DNAJC12, HSP70, and AKT using co-immunoprecipitation (Co-IP) assays and established cell line-derived xenograft (CDX) models for in vivo validations. RESULTS: Boruta analysis of four GEO datasets identified DNAJC12 as highly significant. Patients with high DNAJC12 expression showed an 8 % pathological complete response (pCR) rate, compared to 38 % in the low expression group. DNAJC12 inhibited doxorubicin (DOX)-induced cell death through both ferroptosis and apoptosis. Combining apoptosis and ferroptosis inhibitors completely reversed DOX resistance caused by DNAJC12 overexpression. RNA-seq suggested that DNAJC12 overexpression activated the PI3K-AKT pathway. Inhibition of AKT reversed the DOX resistance induced by DNAJC12, including reduced apoptosis and ferroptosis, restoration of cleaved caspase 3, and decreased GPX4 and SLC7A11 levels. Additionally, DNAJC12 was found to increase AKT phosphorylation in an HSP70-dependent manner, and inhibiting HSP70 also reversed the DOX resistance. In vivo studies confirmed that AKT inhibition reversed DNAJC12-induced DOX resistance in the CDX model. CONCLUSION: DNAJC12 expression is closely linked to chemoresistance in BC. The DNAJC12-HSP70-AKT signaling axis is crucial in mediating resistance to chemotherapy by suppressing DOX-induced ferroptosis and apoptosis. Our findings suggest that targeting AKT and HSP70 activities may offer new therapeutic strategies to overcome chemoresistance in BC.

Efficient healing of diabetic wounds by MSC-EV-7A composite hydrogel via suppression of inflammation and enhancement of angiogenesis.

Diabetes mellitus (DM) is characterized by prolonged hyperglycemia, impaired vascularization, and serious complications, such as blindness and chronic diabetic wounds. About 25% of patients with DM are estimated to encounter impaired healing of diabetic wounds, often leading to lower limb amputation. Multiple factors are attributed to the non-healing of diabetic wounds, including hyperglycaemia, chronic inflammation, and impaired angiogenesis. It is imperative to develop more efficient treatment strategies to tackle healing difficulties in diabetic wounds. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are promising for diabetic wound healing considering their anti-inflammatory, pro-angiogenic and pro-proliferative activities. A histone deacetylase 7 (HDAC7)-derived 7-amino-acid peptide (7A) was shown to be highly effective for angiogenesis. However, it has never been investigated whether MSC-EVs are synergistic with 7A for the healing of diabetic wounds. Herein, we propose that MSC-EVs can be combined with 7A to greatly promote diabetic wound healing. The combination of EVs and 7A significantly improved the migration and proliferation of skin fibroblasts. Moreover, EVs alone significantly suppressed LPS-induced inflammation in macrophages, and notably, the combination treatment showed an even better suppression effect. Importantly, the in vivo study revealed that the combination therapy consisting of EVs and 7A in an alginate hydrogel was more efficient for the healing of diabetic wounds in rats than monotherapy using either EV or 7A hydrogels. The underlying mechanisms include suppression of inflammation, improvement of skin cell proliferation and migration, and enhanced collagen fiber disposition and angiogenesis in wounds. In summary, the MSC-EV-7A hydrogel potentially constitutes a novel therapy for efficient healing of chronic diabetic wounds.

Long noncoding RNA LINC00675 drives malignancy in acute myeloid leukemia via the miR-6809 -CDK6 axis.

Hematological malignancies such as acute myeloid leukemia (AML) have a low cure rate and a high recurrence rate. Long noncoding RNAs (LNCs) are essential regulators of tumorigenesis and progression. The role of lncRNA LINC00675 in AML has rarely been reported. This study revealed elevated LINC00675 expression in AML that promotes proliferation and inhibits apoptosis. Mechanistically, LINC00675 combines with miR-6809 to promote the expression of CDK6 in vitro and in vivo. Immune-checkpoint genes were expressed more highly in LINC00675-high patients. A high level of LINC00675 expression may make patients more susceptible to palbociclib treatments. In conclusion, our study demonstrated that LINC00675 is an oncogenic lncRNA that enhances the malignancy of AML by upregulating CDK6 expression through miR-6809 sponging, providing a new perspective and feasible target for the diagnosis and treatment of AML.

Enhanced cartilage regeneration by icariin and mesenchymal stem cell-derived extracellular vesicles combined in alginate-hyaluronic acid hydrogel.

OBJECTIVE: Osteoarthritis (OA) is characterized by progressive cartilage degeneration and absence of curative therapies. Therefore, more efficient therapies are compellingly needed. Both mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) and Icariin (ICA) are promising for repair of cartilage defect. This study proposes that ICA may be combined to potentiate the cartilage repair capacity of MSC-EVs. MATERIALS AND METHODS: MSC-EVs were isolated from sodium alginate (SA) and hyaluronic acid (HA) composite hydrogel (SA-HA) cell spheroid culture. EVs and ICA were combined in SA-HA hydrogel to test therapeutic efficacy on cartilage defect in vivo. RESULTS: EVs and ICA were synergistic for promoting both proliferation and migration of MSCs and inflammatory chondrocytes. The combination therapy led to strikingly enhanced repair on cartilage defect in rats, with mechanisms involved in the concomitant modulation of both cartilage degradation and synthesis makers. CONCLUSION: The MSC-EVs-ICA/SA-HA hydrogel potentially constitutes a novel therapy for cartilage defect in OA.

FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA.

BACKGROUND: Parkinson's disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra and striatum of brain, seriously threatens human health, and is still lack of effective treatment. Dysregulation of N6-methyladenosine (m6A) modification has been implicated in PD pathogenesis. However, how m6A modification regulates dopaminergic neuronal death in PD remains elusive. Mesenchymal stem cell-derived exosomes (MSC-Exo) have been shown to be effective for treating central nervous disorders. We thus propose that the m6A demethylase FTO-targeted siRNAs (si-FTO) may be encapsulated in MSC-Exo (Exo-siFTO) as a synergistic therapy against dopaminergic neuronal death in PD. METHODS: In this study, the effect of m6A demethylase FTO on dopaminergic neuronal death was evaluated both in vivo and in vitro using a MPTP-treated mice model and a MPP + -induced MN9D cellular model, respectively. The mechanism through which FTO influences dopaminergic neuronal death in PD was investigated with qRT-PCR, western blot, immumohistochemical staining, immunofluorescent staining and flow cytometry. The therapeutic roles of MSC-Exo containing si-FTO were examined in PD models in vivo and in vitro. RESULTS: The total m6A level was significantly decreased and FTO expression was increased in PD models in vivo and in vitro. FTO was found to promote the expression of cellular death-related factor ataxia telangiectasia mutated (ATM) via m6A-dependent stabilization of ATM mRNA in dopaminergic neurons. Knockdown of FTO by si-FTO concomitantly suppressed upregulation of α-Synuclein (α-Syn) and downregulation of tyrosine hydroxylase (TH), and alleviated neuronal death in PD models. Moreover, MSC-Exo were utilized to successfully deliver si-FTO to the striatum of animal brain, resulting in the significant suppression of α-Syn expression and dopaminergic neuronal death, and recovery of TH expression in the brain of PD mice. CONCLUSIONS: MSC-Exo delivery of si-FTO synergistically alleviates dopaminergic neuronal death in PD via m6A-dependent regulation of ATM mRNA.

Improved Prediction of Knee Osteoarthritis by the Machine Learning Model XGBoost.

Objectives: The accurate prediction of osteoarthritis (OA) severity in patients can be helpful to make the proper decision of intervention. This study aims to build up a powerful model to assess predictive risk factors and severity of knee osteoarthritis (KOA) in the clinical scenario. Methods: A total of 4796 KOA cases and 1205 features were selected by feature selections from the public OA database, Osteoarthritis Initiative (OAI). Six machine learning-based models were constructed and compared for the accuracy of OA prediction. The gradient-boosting decision tree was used to identify important prediction features in the extreme gradient boosting (XGBoost) model. The performance of models was evaluated by F1-score. Results: Twenty features were determined as predictors for KOA risk and severity, including the subject characteristics, knee symptoms/risk factors and physical exam. The XGBoost model demonstrated 100% prediction accuracy for 54.7% of examined samples, and the remaining 45.3% of samples showed Kellgren and Lawrence (KL) gradings very close to the actual levels. It showed the highest prediction accuracy with an F1-score of 0.553 among the tested six models. Conclusions: We demonstrate that the XGBoost is the best model for the prediction of KOA severity in the six examined models. In addition, 20 risk features were determined as the essential predictors of KOA, including the physical exam, knee symptoms/risk factors and subject characteristics, which may be useful for the identification of high-risk KOA cases and for making appropriate treatment decisions as well.

Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway.

The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.

Biological potential of Bacillus subtilis BS45 to inhibit the growth of Fusarium graminearum through oxidative damage and perturbing related protein synthesis.

Fusarium root rot (FRR) caused by Fusarium graminearum poses a threat to global food security. Biological control is a promising control strategy for FRR. In this study, antagonistic bacteria were obtained using an in-vitro dual culture bioassay with F. graminearum. Molecular identification of the bacteria based on the 16S rDNA gene and whole genome revealed that the species belonged to the genus Bacillus. We evaluated the strain BS45 for its mechanism against phytopathogenic fungi and its biocontrol potential against FRR caused by F. graminearum. A methanol extract of BS45 caused swelling of the hyphal cells and the inhibition of conidial germination. The cell membrane was damaged and the macromolecular material leaked out of cells. In addition, the mycelial reactive oxygen species level increased, mitochondrial membrane potential decreased, oxidative stress-related gene expression level increased and oxygen-scavenging enzyme activity changed. In conclusion, the methanol extract of BS45 induced hyphal cell death through oxidative damage. A transcriptome analysis showed that differentially expressed genes were significantly enriched in ribosome function and various amino acid transport pathways, and the protein contents in cells were affected by the methanol extract of BS45, indicating that it interfered with mycelial protein synthesis. In terms of biocontrol capacity, the biomass of wheat seedlings treated with the bacteria increased, and the BS45 strain significantly inhibited the incidence of FRR disease in greenhouse tests. Therefore, strain BS45 and its metabolites are promising candidates for the biological control of F. graminearum and its related root rot diseases.

Environmental impact of adult incontinence products in China in the context of population aging.

With the rise of the aging population, the demand for adult incontinence products keeps increasing in developing countries. The increasing market demand for adult incontinence products will inevitably drive up upstream production, leading to more resources and energy consumption, carbon emissions, and heavier environmental pollution. It is imperative to explore the environmental impact of those products and seek opportunities to reduce the environmental impact, which is insufficient. This study aims to fill the gap in research on comparative analysis of energy consumption, carbon emissions, and the environmental impact of adult incontinence products from a life cycle perspective under different energy saving and emission reduction scenarios in the context of aging in China. Based on empirical data from a top papermaking manufacturer in China, this study applies Life Cycle Assessment (LCA) method to analyze the impact of adult incontinence products from cradle to grave. Then different scenarios in the future are set to explore the potential of and the possible pathways for energy-saving and emission-reduction of adult incontinence products from the perspective of the whole life cycle. The results indicate that the energy and materials inputs are the environmental hotspots of adult incontinence products. Under the future trend of the aging population, the predictable optimization of energy structure, optimization of material composition, and final disposal methods are far from being able to cope with the enormous environmental burden brought by the increase in the consumption of adult incontinence products, especially in 2060 which shows 3.33 to 18.40 times the annual environmental burden under the optimal energy saving and emission reduction scenario, compared to the base year 2020. Research on new environmentally friendly materials and recycling technology should be the focus of the technological development of adult incontinence products.

Non-thermal plasma synthesis of supported Cu-Mn-Ce mixed oxide catalyst towards highly improved catalytic performance for volatile organic compound oxidation.

Compared with that of the transition metal mixed oxide pellet catalyst, the catalytic activity of the supported mixed oxide catalyst was significantly reduced, which was limited in practical industrial applications. In this work, supported Cu-Mn-Ce mixed oxide catalysts were prepared by non-thermal plasma. Catalyst characterization result demonstrated that plasma treatment could promote the proportion of oxygen vacancy and enhance the adsorptive strength of VOCs on the surface of catalyst. Meanwhile, plasma treatment process exerted a slight influence on the pore structure and morphological property of the catalyst. Consequently, CMC/SiO2-P exhibited much higher catalytic activity than CMC/SiO2 prepared by the incipient wetness impregnation method for the catalytic oxidation of toluene and n-hexane. Among the catalysts prepared, the 15%CMC/SiO2-P catalyst even exhibited a high catalytic activity comparable to that of the supported noble metal catalyst for the oxidation of the inert hexane. The T98 of toluene and n-hexane over 15%CMC/SiO2-P was 260 and 280°C under the conditions of VOC concentration at 1000 ppm and WHSV at 20,000 mL·g-1·h-1, respectively. This work provided a novel method for the preparation of the supported transition metal mixed oxide catalyst.

Exports Widen the Regional Inequality of Health Burdens and Economic Benefits in India.

Both the ever-complex international and subnational supply chains could relocate health burdens and economic benefits across India, leading to the widening of regional inequality. Here, we simultaneously track the unequal distribution of fine particle matter (PM2.5) pollution, health costs, and value-added embodied in inter- and intranational exports for Indian states in 2015 by integrating a nested multiregional input-output (MRIO) table constructed based on EXIOBASE and an Indian regional MRIO table, Emissions Database for Global Atmospheric Research (EDGAR), the Community Multi-Scale Air Quality (CMAQ) model, and a concentration-response function. The results showed that the annual premature deaths associated with PM2.5 pollution embodied in inter- and intranational exports were 757,356 and 388,003 throughout India, accounting for 39% and 20% of the total premature deaths caused by PM2.5 pollution, respectively. Richer south and west coastal states received around half of the national Gross Domestic Product (GDP) induced by exports with a quarter of the health burden, while poorer central and east states bear approximately 60% of the health burden with less than a quarter of national GDP. Our findings highlight the role of exports in driving the regional inequality of health burdens and economic benefits. Therefore, tailored strategies (e.g., air pollution compensation, advanced technology transfer, and export structure optimization) could be formulated.

Pulmonary Delivery of Extracellular Vesicle-Encapsulated Dinaciclib as an Effective Lung Cancer Therapy.

The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the killing of cancer cells with the potent cyclin-dependent kinase (CDK) inhibitor Dinaciclib (Dina). However, both optimal drug formulations and delivery strategies are yet to be established to facilitate the clinical application of the combination of EV-T and Dina. We hypothesize that Dina can be encapsulated into EV-T to produce a complexed formulation, designated EV-T-Dina, which can be nebulized for pulmonary delivery to treat lung cancer with potentially improved efficacy and safety. The prepared EV-T-Dina shows good stability both in vitro and in vivo and is very efficient at killing two highly TRAIL-resistant cancer lines. The ability to overcome TRAIL resistance is associated with the concomitant downregulation of the expression of cFLIP, MCL-1, and Survivin by Dina. The EV-T-Dina solution is nebulized for inhalation, showing unique deposition in animal lungs and importantly it demonstrates a significant suppression of the growth of orthotopic A549 tumors without any detectable adverse side events. In conclusion, the aerosolized EV-T-Dina constitutes a novel therapy, which is highly effective and safe for the treatment of lung cancers.

Analysis of microRNA expression profiles in exosomes derived from acute myeloid leukemia by p62 knockdown and effect on angiogenesis.

Objectives: In this study, we aimed to investigate the effect of p62 on angiogenesis and microRNA (miRNA) expression profiles in acute myeloid leukemia (AML) exosomes. Methods: An Exiqon v19.0 microRNA MicroArray was used to profile miRNAs in exosomes derived from parental and p62-knockdown U937 cells. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to predict the biological functions and potential mechanisms of differentially expressed miRNAs in AML exosomes. Endothelial cell tube formation assays using human umbilical vein endothelial cells (HUVECs) were performed to investigate the effect of AML exosomes on angiogenesis. Results: We demonstrated that 2,080 miRNAs were expressed in exosomes derived from our cultured cell samples, of which 215 and 208 miRNAs were upregulated and downregulated, respectively, in p62-knockdown U937 cells (fold change ≥ 2, P < 0.05). GO analysis indicated that miRNAs were most enriched in the intercellular pathways. Biological process analysis revealed that 1460 biological processes were associated with downregulated transcripts, including 19 pathways related to vesicles, and 1,515 pathways were upregulated, including 8 pathways related to vesicles. Molecular function analysis indicated that protein binding, transcription regulator activity, and DNA-binding transcription factor activity were enriched (P < 0.05). Pathway analysis indicated that 84 pathways corresponded to upregulated transcripts, and 55 pathways corresponded to downregulated transcripts (P < 0.05). We also found that exosomes derived from U937 cells promoted angiogenesis in HUVECs. Conclusions: Our data suggest that exosomal miRNAs may play important roles in the pathogenesis of AML, which may be treated by p62 knockdown with exosomal miRNAs to inhibit angiogenesis.

Comparison of three administration modes for establishing a zebrafish seizure model induced by N-Methyl-D-aspartic acid.

BACKGROUND: Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures resulting from the sudden abnormal discharge of brain neurons. It leads to transient brain dysfunction, manifested by abnormal physical movements and consciousness. It can occur at any age, affecting approximately 65 million worldwide, one third of which are still estimated to suffer from refractory seizures. There is an urgent need for further establishment of seizure models in animals, which provides an approach to model epilepsy and could be used to identify novel anti-epileptic therapeutics in the future. AIM: To compare three administration modes for establishing a seizure model caused by N-Methyl-D-aspartic acid (NMDA) in zebrafish. METHODS: Three administration routes of NMDA, including immersion, intravitreal injection and intraperitoneal injection, were compared with regard to their effects on inducing seizure-like behaviors in adult zebrafish. We evaluated neurotoxicity by observing behavioral changes in zebrafish and graded those behaviors with a seizure score. In addition, the protective effects of MK-801 (Dizocilpine) and natural active constituent resveratrol against NMDA-induced alterations were studied. RESULTS: The three NMDA-administration methods triggered different patterns of the epileptic process in adult zebrafish. Seizure scores were increased after increasing NMDA concentration regardless of the mode of administration. However, the curve of immersion continuously rose to a high plateau (after 50 min), while the curves of intravitreal injection and intraperitoneal injection showed a spike in the early stage (10-20 min) followed by a steady decrease in seizure scores. Furthermore, pretreatment with resveratrol and MK-801 significantly delayed seizure onset time and lowered seizure scores. CONCLUSION: By comparing the three methods of administration, intravitreal injection of NMDA was the most suitable for establishing an acute epileptic model in zebrafish. Thus, intraperitoneal injection in zebrafish can be applied to simulate diseases such as epilepsy. In addition, NMDA immersion may be an appropriate method to induce persistent seizures. Moreover, MK-801 and resveratrol showed strong anti-epileptic effects; thus, both of them may be clinically valuable treatments for epilepsy.

Sustainability evaluation based on the Three-dimensional Ecological Footprint and Human Development Index: A case study on the four island regions in China.

Sustainable development emphasizes the sustainability of natural resources and the environment as well as the development of social welfare. Under the background of resource scarcity and environmental constraints, maximizing social welfare is an inevitable choice to achieve sustainable development. Ecological Wellbeing Performance (EWP) can comprehensively reflect the efficiency of natural capital conversion into social welfare, and improving EWP is a feasible measure to achieve sustainable development. Moreover, island areas are the extremely complicated ecological-social-economic systems due to the traits that are geographical isolation, scarce resources, and frequent natural disasters, so that emphasizing the sustainability of island systems is a key step for achieving sustainable development goals. This study developed the EWP model based on the improved Three-dimensional Ecological Footprint (EF) and urban-scale Human Development Index (HDI), to synthetically evaluate and analyze the sustainable development of four major island regions in China with the data in 2017. Results found that: (1) The four regions are all in ecological deficits, being in exchange for overdraft natural capital for economic development. The EFdepth is greater than the original length 1 indicating the excessive consumption of the natural capital stock. The EFsize reflects the abundance and liquidity of regional natural capital, all the four regions are with the generally low level of flow capital utilization. Hainan with highest EFsize 0.428 is due to its comparatively sparse population density, abundant resources, and strong ecological capacity, while the relatively large population density and more restricted natural capital flows make Taiwan in the lowest value. (2) Judging from the evaluation results of the HDI, Chongming (0.796) and Hainan (0.773) high development level are relatively behind Taiwan (0.912) and Zhoushan (0.827) very high development level, for the impact of income is greater, that is, economic development in Hainan and Chongming is slightly weak. (3) Taiwan, with the highest EWP 3.646, shows the excellent natural resource utilization efficiency and sustainability, followed by Zhoushan, Chongming, and Hainan. In general, increasing HDI while reducing EF can be an ideal way to improve the efficiency of ecological resources and achieve sustainable urban development.

Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina.

It is currently believed that aging is closely linked with mitochondrial dysfunction, and that resveratrol exhibits anti-aging and neuroprotective effects by improving mitochondrial function, even though the mechanisms are not well defined. This study explored mitochondrial quality (mitochondrial DNA integrity and copy number), mitochondrial function (fusion/fission, mitophagy/autophagy), antioxidant system and activity of the Akt/mTOR and Ampk/Sirt1/Pgc1α pathways, and inflammation in aging zebrafish retinas to identify the probable mechanisms of resveratrol's anti-aging and neuroprotective effects. mtDNA integrity, mtDNA copy number, mitochondrial fusion regulators, mitophagy, and antioxidant-related genes were all decreased whereas Akt/mTOR activity and inflammation was increased upon aging in zebrafish retinas. Resveratrol was shown to not only increase mitochondrial quality and function, but also to suppress Akt/mTOR activity in zebrafish retinas. These results support the notion that mitochondrial dysfunction and increased Akt/mTOR activity are major players in age-related retinal neuropathy in zebrafish, and demonstrate a trend towards mitochondrial fragmentation in the aging retina. Importantly, resveratrol promoted mitochondrial function, up-regulating Ampk/Sirt1/Pgc1α, and down-regulated Akt/mTOR pathway activity in zebrafish retinas, suggesting that it may be able to prevent age-related oculopathy.