Development of an accelerated cellular model for early changes in Alzheimer's disease.

Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. Progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aß42 to Aß40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening.

Research on the development and testing methods of physical education and agility training equipment in universities.

Introduction: Because of the problems of insufficient funds and traditional training methods in college sports agile training, an agile training system based on a wireless ad hoc network was developed to evaluate the effect of improving the sensitive quality of ordinary college students. Based on the ESP-MESH network, the lower computer realizes automatic networking between devices and tests the performance of the mesh network. Fourteen male college students received 9 weeks of agility training, with seven students in each of two groups: traditional agility training and agile equipment training. The researchers evaluated the performance of both groups in rapid disguise, body coordination, changing movements, and predictive decision-making. Results: There was no significant difference between the groups before training, but there were significant differences in the four abilities after training (p < 0.01). The experimental group had significant differences in rapid direction change and physical coordination (p < 0.05), and in changing movement and predictive decision-making ability (p < 0.01). Conclusion: Both traditional training and agile equipment training improve the agility quality of college students, and the latter shows better results in certain abilities. However, limited by other physical qualities, the improvement of motor changes and predictive decision-making ability is not as obvious as the other two abilities.

Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disease that accelerates atherosclerosis. With a limited pool of HGPS patients, clinical trials face unique challenges and require reliable preclinical testing. We previously reported a 3D tissue engineered blood vessel (TEBV) microphysiological system fabricated with iPSC-derived vascular cells from HGPS patients. HGPS TEBVs exhibit features of HGPS atherosclerosis including loss of smooth muscle cells, reduced vasoactivity, excess extracellular matrix (ECM) deposition, inflammatory marker expression, and calcification. We tested the effects of HGPS therapeutics Lonafarnib and Everolimus separately and together, currently in Phase I/II clinical trial, on HGPS TEBVs. Everolimus decreased reactive oxygen species levels, increased proliferation, reduced DNA damage in HGPS vascular cells, and improved vasoconstriction in HGPS TEBVs. Lonafarnib improved shear stress response of HGPS iPSC-derived endothelial cells (viECs) and reduced ECM deposition, inflammation, and calcification in HGPS TEBVs. Combination treatment with Lonafarnib and Everolimus produced additional benefits such as improved endothelial and smooth muscle marker expression and reduced apoptosis, as well as increased TEBV vasoconstriction and vasodilation. These results suggest that a combined trial of both drugs may provide cardiovascular benefits beyond Lonafarnib, if the Everolimus dose can be tolerated.

Impaired LEF1 Activation Accelerates iPSC-Derived Keratinocytes Differentiation in Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a detrimental premature aging disease caused by a point mutation in the human LMNA gene. This mutation results in the abnormal accumulation of a truncated pre-lamin A protein called progerin. Among the drastically accelerated signs of aging in HGPS patients, severe skin phenotypes such as alopecia and sclerotic skins always develop with the disease progression. Here, we studied the HGPS molecular mechanisms focusing on early skin development by differentiating patient-derived induced pluripotent stem cells (iPSCs) to a keratinocyte lineage. Interestingly, HGPS iPSCs showed an accelerated commitment to the keratinocyte lineage than the normal control. To study potential signaling pathways that accelerated skin development in HGPS, we investigated the WNT pathway components during HGPS iPSCs-keratinocytes induction. Surprisingly, despite the unaffected ß-catenin activity, the expression of a critical WNT transcription factor LEF1 was diminished from an early stage in HGPS iPSCs-keratinocytes differentiation. A chromatin immunoprecipitation (ChIP) experiment further revealed strong bindings of LEF1 to the early-stage epithelial developmental markers K8 and K18 and that the LEF1 silencing by siRNA down-regulates the K8/K18 transcription. During the iPSCs-keratinocytes differentiation, correction of HGPS mutation by Adenine base editing (ABE), while in a partial level, rescued the phenotypes for accelerated keratinocyte lineage-commitment. ABE also reduced the cell death in HGPS iPSCs-derived keratinocytes. These findings brought new insight into the molecular basis and therapeutic application for the skin abnormalities in HGPS.

Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate M1 Microglial Activation in Brain Injury of Mice With Subarachnoid Hemorrhage via microRNA-140-5p Delivery.

BACKGROUND: It is documented that mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs) to modulate subarachnoid hemorrhage (SAH) development. miR-140-5p expression has been detected in MSC-derived EVs, while the mechanism of MSC-derived EVs containing miR-140-5p in SAH remains unknown. We aim to fill this void by establishing SAH mouse models and extracting MSCs and MSC-EVs. METHODS: After ALK5 was silenced in SAH mice, neurological function was evaluated, neuron apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling with NeuN staining, and expression of serum inflammatory factors (interleukin-6, interleukin-1ß, and tumor necrosis factor-α) was determined by enzyme-linked immunosorbent assay. The effect of ALK5 on NOX2 expression was assessed by western-blot analysis. Targeting the relationship between miR-140-5p and ALK5 was evaluated by dual luciferase assay. Following extraction of MSCs and MSC-EVs, EVs and miR-140-5p were labeled by PKH67 and Cy3, respectively, to identify the transferring of miR-140-5p by MSC-EVs. SAH mice were treated with EVs from miR-140-5p mimic/inhibitor-transfected MSCs to detect effects of MSC-EV-miR-140-5p on brain injury and microglial polarization. RESULTS: ALK5 silencing increased the neurological score and reduced neuron apoptosis and neuroinflammation in SAH mice. ALK5 silencing inhibited M1 microglia activation by inactivating NOX2. ALK5 was a target gene of miR-140-5p. MSC-derived EVs contained miR-140-5p and transferred miR-140-5p into microglia. MSC-EV-delivered miR-140-3p reduced ALK5 expression to contribute to repression of brain injury and M1 microglia activation in SAH mice. CONCLUSIONS: MSC-derived EVs transferred miR-140-5p into microglia to downregulate ALK5 and NOX2, thus inhibiting M1 microglia activation in SAH mice.

The Potentials of Methylene Blue as an Anti-Aging Drug.

Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increaseding oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. This review summarizes the recent studies on the applications of MB in treating age-related conditions, including neurodegeneration, memory loss, skin aging, and a premature aging disease, progeria.

Effect of astaxanthin on neuron damage, inflammatory factors expressions and oxidative stress in mice with subarachnoid hemorrhage.

OBJECTIVE: This study aimed to explore the effect of astaxanthin (ATX) on neuron damage, inflammatory factor expression and oxidative stress in mice with subarachnoid hemorrhage (SAH). METHODS: Specific-pathogen-free, 'Institute of Cancer Research', male mice were randomly divided into four groups: SAH group, sham group, SAH + placebo group (SAH + Vehicle group) and SAH + ATX group. Neurological function was scored in each group. Brain water content, reactive oxygen species (ROS) content and inflammatory factor levels in the brain were detected by wet-dry weighting method, DCFH-DA fluorescent probe staining method and ELISA, respectively. Expression of NADPH oxidase 2 (NOX2), glial fibrillary acidic protein (GFAP) and apoptosis-related proteins Bax and Bcl-2 were detected by Western blot and quantitative real-time polymerase chain reaction. Neuronal apoptosis was detected by TUNEL staining. RESULTS: Compared with sham group, neurological score, brain water content and ROS content in the other three groups increased significantly (all P<0.05). Neurological score, brain water content and ROS content in SAH + ATX group were lower than those in SAH group (all P<0.05). Compared with the sham group, there was increased expression of interleukin (IL)-6, IL-17 and tumor necrosis factor α (TNF-α), and increased neuronal apoptosis, as well as enhanced expression of NOX2, GFAP and Bax; while there was decreased IL-10 expression, and declined Bcl-2 expression, in the other three groups (all P<0.05). There was decreased expression of IL-6, IL-17 and TNF-α, declined expressions of NOX2, GFAP and Bax, and lowered neuronal apoptosis; while there was increased IL-10 expression, and enhanced Bcl-2 expression, in SAH + ATX group as compared to SAH group (all P<0.05). All indicators between SAH group and SAH + Vehicle group showed no significant differences (all P>0.05). CONCLUSION: Astaxanthin can decrease neuron damage, inhibit inflammatory response, and improve oxidative stress in SAH mice. Thus, astaxanthin is a method for treating SAH.

Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a de novo point mutation in the LMNA gene (c.1824C>T; p.G608G) resulting in progerin, a toxic lamin A protein variant. Children with HGPS typically die from coronary artery diseases or strokes at an average age of 14.6 years. Endothelial dysfunction is a known driver of cardiovascular pathogenesis; however, it is currently unknown how progerin antagonizes normal angiogenic function in HGPS. Here, we use human iPSC-derived endothelial cell (iPSC-EC) models to study angiogenesis in HGPS. We cultured normal and HGPS iPSC-ECs under both static and fluidic culture conditions. HGPS iPSC-ECs show reduced endothelial nitric oxide synthase (eNOS) expression and activity compared with normal controls and concomitant decreases in intracellular nitric oxide (NO) level, which result in deficits in capillary-like microvascular network formation. Furthermore, the expression of matrix metalloproteinase 9 (MMP-9) was reduced in HGPS iPSC-ECs, while the expression of tissue inhibitor metalloproteinases 1 and 2 (TIMP1 and TIMP2) was upregulated relative to healthy controls. Finally, we used an adenine base editor (ABE7.10max-VRQR) to correct the pathogenic c.1824C>T allele in HGPS iPSC-ECs. Remarkably, ABE7.10max-VRQR correction of the HGPS mutation significantly reduced progerin expression to a basal level, rescued nuclear blebbing, increased intracellular NO level, normalized the misregulated TIMPs, and restored angiogenic competence in HGPS iPSC-ECs. Together, these results provide molecular insights of endothelial dysfunction in HGPS and suggest that ABE could be a promising therapeutic approach for correcting HGPS-related cardiovascular phenotypes.

Gene targeting techniques for Huntington's disease.

Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.

Ultraviolet radiation protection potentials of Methylene Blue for human skin and coral reef health.

Methylene blue (MB) is a century-old medicine, a laboratory dye, and recently shown as a premier antioxidant that combats ROS-induced cellular aging in human skins. Given MB's molecular structure and light absorption properties, we hypothesize that MB has the potential to be considered as a sunscreen active for UV radiation protection. In this study, we tested the effects of MB on UVB ray-induced DNA double-strand breaks in primary human keratinocytes. We found that MB treatment reduced DNA damages caused by UVB irradiation and subsequent cell death. Next, we compared MB with Oxybenzone, which is the most commonly used chemical active ingredient in sunscreens but recently proven to be hazardous to aquatic ecosystems, in particular to coral reefs. At the same concentrations, MB showed more effective UVB absorption ability than Oxybenzone and significantly outperformed Oxybenzone in the prevention of UVB-induced DNA damage and the clearance of UVA-induced cellular ROS. Furthermore, unlike Oxybenzone, MB-containing seawater did not affect the growth of the coral species Xenia umbellata. Altogether, our study suggests that MB has the potential to be a coral reef-friendly sunscreen active ingredient that can provide broad-spectrum protection against UVA and UVB.

A targeted antisense therapeutic approach for Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1-4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

Predictive Factors and Nomogram to Evaluate the Risk of Symptomatic Intracerebral Hemorrhage for Stroke Patients Receiving Thrombectomy.

BACKGROUND: Symptomatic intracerebral hemorrhage (sICH) is a severe complication of mechanical thrombectomy (MT). This study is to identify predictive factors and create a nomogram to evaluate the risk of sICH after MT treatment. METHODS: We conducted a retrospective analysis on 127 consecutive stroke patients treated by MT therapy. We evaluated multiple predictive factors for the incidence of sICH using univariate and multivariate logistic regressions. Based on the identified and other possible factors, a nomogram was constructed to predict the risk of sICH. RESULTS: We identified several predictive factors for sICH in the univariate analysis, including thrombectomy maneuvers >3 (odds ratio [OR], 4.42; 95% confidence interval [CI], 1.25-15.6; P = 0.0211), admission blood glucose (OR, 1.29; 95% CI, 1.13-1.48; P = 0.0002), diabetes mellitus (OR, 4.44; 95% CI, 1.64-12.0; P = 0.0033), and admission National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.05; 95% CI, 1.01-1.10; P = 0.0263). The multivariate analysis showed that admission NIHSS score and blood glucose significantly affected the prognosis. Moreover, the proposed nomogram showed reliable identification ability with an area under the curve of 0.82 (95% CI, 0.71-0.93), specificity of 0.745, sensitivity of 0.762, accuracy of 0.748, and negative predictive value of 0.941. CONCLUSIONS: Our study identified the admission NIHSS score and admission blood glucose level as predictive factors for sICH. Moreover, the proposed nomogram based on possible factors showed reliable predictive performance in evaluating the risk of sICH.

Peroxisomal abnormalities and catalase deficiency in Hutchinson-Gilford Progeria Syndrome.

Peroxisomes are small, membrane-enclosed eukaryotic organelles that house various enzymes with metabolic functions. One important feature in both Hutchinson-Gilford Progeria Syndrome (HGPS) and normal aging is the elevated levels of Reactive Oxygen Species (ROS), which are generated from metabolic pathways with the capacity to cause oxidative damage to macromolecules within the cells. Although peroxisomal bioreactions can generate free radicals as their byproducts, many metabolic enzymes within the peroxisomes play critical roles as ROS scavengers, in particular, catalase. Here, we observed impaired peroxisomes-targeting protein trafficking, which suggested that the poorly assembled peroxisomes might cause high oxidative stress, contributing to the premature senescent phenotype in HGPS. We then investigated the ROS clearance efficiency by peroxisomal enzymes and found a significantly decreased expression of catalase in HGPS. Furthermore, we evaluated the effects of two promising HGPS-treatment drugs Methylene Blue and RAD001 (Everolimus, a rapamycin analog) on catalase in HGPS fibroblasts. We found that both drugs effectively reduced cellular ROS levels. MB, as a well-known antioxidant, did not affect catalase expression or activity. Interestingly, RAD001 treatment significantly upregulated catalase activity in HGPS cells. Our study presents the first characterization of peroxisomal function in HGPS and provides new insights into the cellular aspects of HGPS and the ongoing clinical trial.

iPSC-Derived Endothelial Cells Affect Vascular Function in a Tissue-Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder caused by a point mutation in the Lamin A gene that produces the protein progerin. Progerin toxicity leads to accelerated aging and death from cardiovascular disease. To elucidate the effects of progerin on endothelial cells, we prepared tissue-engineered blood vessels (viTEBVs) using induced pluripotent stem cell-derived smooth muscle cells (viSMCs) and endothelial cells (viECs) from HGPS patients. HGPS viECs aligned with flow but exhibited reduced flow-responsive gene expression and altered NOS3 levels. Relative to viTEBVs with healthy cells, HGPS viTEBVs showed reduced function and exhibited markers of cardiovascular disease associated with endothelium. HGPS viTEBVs exhibited a reduction in both vasoconstriction and vasodilation. Preparing viTEBVs with HGPS viECs and healthy viSMCs only reduced vasodilation. Furthermore, HGPS viECs produced VCAM1 and E-selectin protein in TEBVs with healthy or HGPS viSMCs. In summary, the viTEBV model has identified a role of the endothelium in HGPS.

Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts.

Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed Tert heterozygous knockout mice (mTert+/- ) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts from mTert+/+ and mTert-/- progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, both mTert+/+ and mTert-/- fibroblasts showed comparable and extremely short telomere length. However, mTert-/- cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than mTert+/+ cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was detected in mTert+/+ cells at the presenescence stage. Moreover, removal or down-regulation of TERT expression in mTert+/+ and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated mTert-/- phenotypes of accelerated senescence and transformation, and overexpression of TERT in mTert-/- cells rescued these phenotypes. Taking these data together, this study suggests that TERT has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.

A Facile Approach for Preparing Ag Functionalized Nonwoven Polypropylene Membrane to Improve Its Electrical Conductivity and Electromagnetic Shielding Performance.

The commonly used preparation methods of polypropylene functionalization require special equipment to be put into use or take a long time, which limits its application. Therefore, a simple and economical method for preparing silver functionalized nonwoven polypropylene membrane was studied herein. Triethanolamine was first coated on the surface of the polypropylene, and then Ag was deposited on the surface of polypropylene using a continuous reduction reaction of triethanolamine and silver ions. Surface morphology, crystal structure, and surface chemistry during the preparation of Ag functionalized nonwoven polypropylene were investigated. The electrical conductivity, electromagnetic shielding properties, and washing durability of the treated nonwoven polypropylene were also studied. It was found that Ag was uniformly deposited on the surface of the nonwoven polypropylene, and the coating reaction did not change the chemical structure of the polypropylene. The crystallinity and thermal stability of polypropylene were improved after silver coated polypropylene. The washing experiment results showed that the weight gain rate of the treated nonwoven relative to the untreated sample after the 90 min washing ranged from 6.72% to 9.64%. The resistance test results showed that the maximum surface resistivity of Ag coated nonwoven polypropylene was about 1.95 × 105 Ω, which was 64,615 times lower than the original. In addition, the results showed that the maximum electromagnetic shielding effectiveness of the Ag coated nonwoven polypropylene was about 71.6 dB, showing a very good electromagnetic shielding effect.

Evaluation of the oxidative stress in liver of crucian carp (Carassius auratus) exposed to 3,4,4'-tri-CDE, 2-MeO-3',4,4'-tri-CDE, and 2-HO-3',4,4'-tri-CDE.

Polychlorinated diphenyl ethers (PCDEs) are a class of potential persistent organic contaminants, which have been widely detected in aquatic environment. In the present study, the effects of 3,4,4'-tri-CDE and its two possible metabolites (2-MeO-3',4,4'-tri-CDE and 2-HO-3',4,4'-tri-CDE) on oxidative stress biomarkers in liver of Carassius auratus were evaluated. The fish were treated with these three compounds at different doses (0.1, 1, and 10 µg/L) via semi-static water exposure. The liver samples were individually taken at 3, 7, and 21 days for analysis of oxidative stress indicators, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), and malondialdehyde (MDA). Compare to the control group, the hepatic antioxidant enzyme activity and GSH contents showed significant decreases (p < 0.05) at high-dose treatment (10 µg/L) and prolonged exposure time (21 days) in most of the toxicant-treated groups, indicating the occurrence of oxidative stress in fish liver. However, no consistent trend of the variations of antioxidant parameters was observed at low doses (0.1 and 1 µg/L). Meanwhile, the lipid peroxidation was significantly induced with extending exposure time and increasing dose. In addition, the toxicity order of three compounds was discussed using the integrated biomarker response (IBR) index. Notably, 2-HO-3',4,4'-tri-CDE was indicated to cause the most severe hepatic oxidative stress.

Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases.

Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases.