Stigmasterol Activates the mTOR Signaling Pathway by Inhibiting ORP5 Ubiquitination to Promote Milk Synthesis in Bovine Mammary Epithelial Cells.

Stigmasterol (ST), a phytosterol found in food, has various biological activities. However, the effect of ST on milk synthesis in dairy cows remains unclear. Therefore, bovine primary mammary epithelial cells (BMECs) were isolated, cultured, and treated with ST to determine the effect of ST on milk synthesis. The study revealed that 10 µM ST significantly increased milk synthesis in BMECs by activating the mammalian target of rapamycin (mTOR) signaling pathway. Further investigation revealed that this activation depends on the regulatory role of oxysterol binding protein 5 (ORP5). ST induces the translocation of ORP5 from the cytoplasm to the lysosome, interacts with the mTOR, recruits mTOR to target the lysosomal surface, and promotes the activation of the mTOR signaling pathway. Moreover, ST was found to increase ORP5 protein levels by inhibiting its degradation via the ubiquitin-proteasome pathway. Specifically, the E3 ubiquitin ligase membrane-associated cycle-CH-type finger 4 (MARCH4) promotes the ubiquitination and subsequent degradation of ORP5. ST mitigates the interaction between MARCH4 and ORP5, thereby enhancing the structural stability of ORP5 and reducing its ubiquitination. In summary, ST stabilizes ORP5 by inhibiting the interaction between MARCH4 and ORP5, thereby activating mTOR signaling pathway and enhancing milk synthesis.

Pathological Asymmetry-Guided Progressive Learning for Acute Ischemic Stroke Infarct Segmentation.

Quantitative infarct estimation is crucial for diagnosis, treatment and prognosis in acute ischemic stroke (AIS) patients. As the early changes of ischemic tissue are subtle and easily confounded by normal brain tissue, it remains a very challenging task. However, existing methods often ignore or confuse the contribution of different types of anatomical asymmetry caused by intrinsic and pathological changes to segmentation. Further, inefficient domain knowledge utilization leads to mis-segmentation for AIS infarcts. Inspired by this idea, we propose a pathological asymmetry-guided progressive learning (PAPL) method for AIS infarct segmentation. PAPL mimics the step-by-step learning patterns observed in humans, including three progressive stages: knowledge preparation stage, formal learning stage, and examination improvement stage. First, knowledge preparation stage accumulates the preparatory domain knowledge of the infarct segmentation task, helping to learn domain-specific knowledge representations to enhance the discriminative ability for pathological asymmetries by constructed contrastive learning task. Then, formal learning stage efficiently performs end-to-end training guided by learned knowledge representations, in which the designed feature compensation module (FCM) can leverage the anatomy similarity between adjacent slices from the volumetric medical image to help aggregate rich anatomical context information. Finally, examination improvement stage encourages improving the infarct prediction from the previous stage, where the proposed perception refinement strategy (RPRS) further exploits the bilateral difference comparison to correct the mis-segmentation infarct regions by adaptively regional shrink and expansion. Extensive experiments on public and in-house NCCT datasets demonstrated the superiority of the proposed PAPL, which is promising to help better stroke evaluation and treatment.

Environmental endocrine disrupting chemical 4-tert-butylphenol induced calcium overload and subsequent autophagy impairment via miRNA-363/CACNA1D Axis in epithelioma papulosum cyprini cells.

Environmental endocrine disrupting chemical 4-tert-butylphenol (4-tBP), a widely-utilized surfactant in various industries, poses potential risks to aquatic organisms. Our previous sequencing results suggested that 4-tBP-induced common carp liver injury might be associated with Ca2+ signaling and autophagy. However, the intricate involvement of these pathways in 4-tBP-induced cytotoxic mechanisms remained unexplored. To bridge these knowledge gaps, this study focused on epithelioma papulosum cyprini (EPC) cells, a significant cell type in fish biology. Initial observations showed that 4-tBP induced a dose-dependent perturbation in Ca2+ levels. Further investigations, with siRNA and L-type Ca2+ channel agonist (BAYK8644), identified L-type calcium channel gene CACNA1D as a critical regulator of 4-tBP-induced Ca2+ overload. Predictive analysis using miRanda platform suggested a potential interaction between miR-363 and CACNA1D, which was subsequently verified through dual-luciferase reporter gene assays. We then established miR-363 mimic/inhibitor models, along with miR-363 and CACNA1D co-suppression models in EPC cells. Through TEM observation, immunofluorescence assay, Ca2+ staining, and qRT-PCR analysis, we evaluated the role of miR-363/CACNA1D axis in modulating the effects of 4-tBP on Ca2+ signaling and autophagy. Results showed that miR-363 inhibitor exacerbated 4-tBP-induced increase in CALM2, CAMKII, Calpain2, and p62 expression and also led to decrease in ATG5, ATG7, and LC3b expression. In contrast, miR-363 mimic notably alleviated these changes. Notably, siRNA CACNA1D effectively modulating miR-363 inhibitor's effect. Our study revealed that 4-tBP induced Ca2+ overload and subsequent autophagy impairment via miR-363/CACNA1D axis. These findings illuminated a profound understanding of molecular mechanisms underlying 4-tBP-induced cytotoxicity and spotlighted a potential therapeutic target.

Nationwide trends and features of human salmonellosis outbreaks in China.

Salmonellosis is one of the most common causes of diarrhea, affecting 1/10 of the global population. Salmonellosis outbreaks (SO) pose a severe threat to the healthcare systems of developing regions. To elucidate the patterns of SO in China, we conducted a systematic review and meta-analysis encompassing 1,134 reports across 74 years, involving 89,050 patients and 270 deaths. A rising trend of SO reports has been observed since the 1970s, with most outbreaks occurring east of the Hu line, especially in coastal and populated regions. It is estimated to have an overall attack rate of 36.66% (95% CI, 33.88-39.45%), and antimicrobial resistance towards quinolone (49.51%) and beta-lactam (73.76%) remains high. Furthermore, we developed an online website, the Chinese Salmonellosis Outbreak Database (CSOD), for visual presentation and data-sharing purposes. This study indicated that healthcare-associated SO required further attention, and our study served as a foundational step in pursuing outbreak intervention and prediction.

Tetrahedral framework nucleic acid-based small-molecule inhibitor delivery for ecological prevention of biofilm.

Biofilm formation constitutes the primary cause of various chronic infections, such as wound infections, gastrointestinal inflammation and dental caries. While preliminary achievement of biofilm inhibition is possible, the challenge lies in the difficulty of eliminating the bactericidal effects of current drugs that lead to microbiota imbalance. This study, utilizing in vitro and in vivo models of dental caries, aims to efficiently inhibit biofilm formation without inducing bactericidal effects, even against pathogenic bacteria. The tetrahedral framework nucleic acid (tFNA) was employed as a delivery vector for a small-molecule inhibitor (smI) specifically targeting the activity of glucosyltransferases C (GtfC). It was observed that tFNA loaded smI in a small-groove binding manner, efficiently transferring it into Streptococcus mutans, thereby inhibiting GtfC activity and extracellular polymeric substances formation without compromising bacterial survival. Furthermore, smI-loaded tFNA demonstrated a reduction in the severity of dental caries in vivo without adversely affecting oral microbial diversity and exhibited desirable topical and systemic biosafety. This study emphasizes the concept of 'ecological prevention of biofilm', which is anticipated to advance the optimization of biofilm prevention strategies and the clinical application of DNA nanocarrier-based drug formulations.

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.

DNA-PKcs/AKT1 inhibits epithelial-mesenchymal transition during radiation-induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1.

INTRODUCTION: Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive, irreversible lung interstitial disease that develops after radiotherapy. Although several previous studies have focused on the mechanism of epithelial-mesenchymal transition (EMT) in lung epithelial cells, the essential factors involved in this process remain poorly understood. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) exhibits strong repair capacity when cells undergo radiation-induced damage; whether DNA-PKcs regulates EMT during RIPF remains unclear. OBJECTIVES: To investigate the role and molecular mechanism of DNA-PKcs in RIPF and provide an important theoretical basis for utilising DNA-PKcs-targeted drugs for preventing RIPF. METHODS: DNA-PKcs knockout (DPK-/-) mice were generated via the Cas9/sgRNA technique and subjected to whole chest ionizing radiation (IR) at a 20 Gy dose. Before whole chest IR, the mice were intragastrically administered the DNA-PKcs-targeted drug VND3207. Lung tissues were collected at 1 and 5 months after IR. RESULTS: The expression of DNA-PKcs is low in pulmonary fibrosis (PF) patients. DNA-PKcs deficiency significantly exacerbated RIPF by promoting EMT in lung epithelial cells. Mechanistically, DNA-PKcs deletion by shRNA or inhibitor NU7441 maintained the protein stability of Twist1. Furthermore, AKT1 mediated the interaction between DNA-PKcs and Twist1. High Twist1 expression and EMT-associated changes caused by DNA-PKcs deletion were blocked by insulin-like growth factor-1 (IGF-1), an AKT1 agonist. The radioprotective drug VND3207 prevented IR-induced EMT and alleviated RIPF in mice by stimulating the kinase activity of DNA-PKcs. CONCLUSION: Our study clarified the critical role and mechanism of DNA-PKcs in RIPF and showed that it could be a potential target for preventing RIPF.

An Improved Method to Compute the Mutual Capacitance between Interdigital Transducers in Radio Frequency Surface Acoustic Wave Filters.

This paper proposes an improved method to calculate the mutual capacitance between interdigital transducer (IDT) electrodes to enhance the accuracy of the traditional coupling-of-modes (COM) model, which is commonly used to simulate surface acoustic wave (SAW) filters and duplexers. In this method, the boundary element method (BEM) is adopted to obtain the capacitance per unit length in a layered medium, while the partial capacitance (PC) method is used to derive the effective relative permittivity of the multi-layered IDT. Numerical results from commercially available software are provided for comparison with the results calculated using the proposed method. The consistent results verify the validity and accuracy of this method, which also demonstrates significantly faster calculation speed compared to commercially available software. Precise electrical response prediction of a dual-mode SAW (DMS) filter can be achieved by applying this method to the COM model, and this ultra-fast calculation method can also be included in filter design optimization.

Oxygen vacancy enhanced photocatalytic activity of Cu2O/TiO2 heterojunction.

In this study, a method was developed to create oxygen vacancies in Cu2O/TiO2 heterojunctions. By varying the amounts of ethylenediaminetetraacetic acid (EDTA), sodium citrate, and copper acetate, Cu2O/TiO2 with different Cu ratios were synthesized. Tests on CO2 photocatalytic reduction revealed that Cu2O/TiO2's performance is influenced by Cu content. The ideal Cu mass fraction in Cu2O/TiO2, determined by inductively coupled plasma (ICP), is between 0.075% and 0.55%, with the highest CO yield being 10.22 µmol g-1 h-1, significantly surpassing pure TiO2. High-resolution transmission electron microscopy and electron paramagnetic resonance studies showed optimal oxygen vacancy in the most effective heterojunction. Density functional theory (DFT) calculations indicated a 0.088 eV lower energy barrier for ∗CO2 to ∗COOH conversion in Cu2O/TiO2 with oxygen vacancy compared to TiO2, suggesting that oxygen vacancies enhance photocatalytic activity.

Research on the Resource Recovery of Medium-Chain Fatty Acids from Municipal Sludge: Current State and Future Prospects.

The production of municipal sludge is steadily increasing in line with the production of sewage. A wealth of organic contaminants, including nutrients and energy, are present in municipal sludge. Anaerobic fermentation can be used to extract useful resources from sludge, producing hydrogen, methane, short-chain fatty acids, and, via further chain elongation, medium-chain fatty acids. By comparing the economic and use values of these retrieved resources, it is concluded that a high-value resource transformation of municipal sludge can be achieved via the production of medium-chain fatty acids using anaerobic fermentation, which is a hotspot for future research. In this study, the selection of the pretreatment method, the method of producing medium-chain fatty acids, the influence of the electron donor, and the technique used to enhance product synthesis in the anaerobic fermentation process are introduced in detail. The study outlines potential future research directions for medium-chain fatty acid production using municipal sludge. These acids could serve as a starting point for investigating other uses for municipal sludge.

Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Regulating Sulfur Redox Kinetics by Coupling Photocatalysis for High-Performance Photo-Assisted Lithium-Sulfur Batteries.

Challenges such as shuttle effect have hindered the commercialization of lithium-sulfur batteries (LSBs), despite their potential as high-energy-density storage devices. To address these issues, we explore the integration of solar energy into LSBs, creating a photo-assisted lithium-sulfur battery (PA-LSB). The PA-LSB provides a novel and sustainable solution by coupling the photocatalytic effect to accelerate sulfur redox reactions. Herein, a perovskite quantum dot-loaded MOF material serves as a cathode for the PA-LSB, creating built-in electric fields at the micro-interface to extend the lifetime of photo-generated charge carriers. The band structure of the composite material aligns well with the electrochemical reaction potential of lithium-sulfur, enabling precise regulation of polysulfides in the cathode of the PA-LSB system. This is attributed to the selective catalysis of the liquid-solid reaction stage in the lithium-sulfur electrochemical process by photocatalysis. These contribute to the outstanding performance of PA-LSBs, particularly demonstrating a remarkably high reversible capacity of 679 mAh g-1 at 5 C, maintaining stable cycling for 1500 cycles with the capacity decay rate of 0.022 % per cycle. Additionally, the photo-charging capability of the PA-LSB holds the potential to compensate for non-electric energy losses during the energy storage process, contributing to the development of lossless energy storage devices.

Comparison of the mesodermal differentiation potential between embryonic stem cells and scalable induced pluripotent stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) have promising potential in clinical application, whereas their limited amount and sources hinder their bioavailability. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have become prominent options in regenerative medicine as both possess the ability to differentiate into MSCs. METHODS: Recently, our research team has successfully developed human leukocyte antigen (HLA)-homozygous iPSC cell lines with high immune compatibility, covering 13.5% of the Taiwanese population. As we deepen our understanding of the differences between these ESCs and HLA-homozygous iPSCs, our study focused on morphological observations and flow cytometry analysis of specific surface marker proteins during the differentiation of ESCs and iPSCs into MSCs. RESULTS: The results showed no significant differences between the two pluripotent stem cells, and both of them demonstrated the equivalent ability to further differentiate into adipose, cartilage, and bone cells. CONCLUSION: Our research revealed that these iPSCs with high immune compatibility exhibit the same differentiation potential as ESCs, enhancing the future applicability of highly immune-compatible iPSCs.

Gaussian Process-Gated Hierarchical Mixtures of Experts.

In this paper, we propose novel Gaussian process-gated hierarchical mixtures of experts (GPHMEs). Unlike other mixtures of experts with gating models linear in the input, our model employs gating functions built with Gaussian processes (GPs). These processes are based on random features that are non-linear functions of the inputs. Furthermore, the experts in our model are also constructed with GPs. The optimization of the GPHMEs is performed by variational inference. The proposed GPHMEs have several advantages. They outperform tree-based HME benchmarks that partition the data in the input space, and they achieve good performance with reduced complexity. Another advantage is the interpretability they provide for deep GPs, and more generally, for deep Bayesian neural networks. Our GPHMEs demonstrate excellent performance for large-scale data sets, even with quite modest sizes.

Recent progress and prospects for chain elongation of transforming biomass waste into medium-chain fatty acids.

Chain elongation technology utilises microorganisms in anaerobic digestion to transform waste biomass into medium-chain fatty acids that have greater economic value. This innovative technology expands upon traditional anaerobic digestion methods, requiring abundant substrates that serve as electron donors and acceptors, and inoculating microorganisms with chain elongation functions. While this process may result in the production of by-products and elicit competitive responses, toxicity suppression of microorganisms by substrates and products remains a significant obstacle to the industrialisation of chain elongation technology. This study provides a comprehensive overview of existing research on widely employed electron donors and their synthetic reactions, competitive reactions, inoculum selection, toxicity inhibition of substrates and products, and increased chain elongation approaches. Additionally, it presents actionable recommendations for future research and development endeavours in this domain, intending to inspire and guide researchers in advancing the frontiers of chain elongation technology.

A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation.

BACKGROUND: This article reports an extremely rare case of lipoprotein glomerulopathy (LPG) with apolipoprotein E gene (APOE) Chicago mutation in a young Chinese male. Only five cases or families with APOE Chicago mutations have been reported in the literature. CASE PRESENTATION: The young male patient is manifested with nephrotic syndrome, accompanied by hyperlipidemia with a preferable increase in triglycerides and elevated ApoE level. Renal biopsy of the patient showed highly dilated glomerular capillaries filled with vacuolar lipids, segmentally fused podocyte foot processes, vacuolar degeneration of renal tubular epithelial cells and absence of electron-dense material, which indicates the diagnosis of LPG. Whole-exome gene sequencing identified the heterozygous mutation of NM_000041.4:c.494G > C (p.Arg165Pro), which is in the exon 4 of the APOE gene and also known as APOE Chicago mutation, a rare mutation of LPG. Further family pedigree gene analysis clarified that the mutation was inherited from the patient's mother, who does not have high ApoE levels or renal manifestations. This is also consistent with the incomplete penetrance of APOE gene mutations in LPG. Under lipid-lowering treatments, including a low-fat diet and fenofibrate, the patient's urinary protein was partially controlled, and the albumin level was recovered. CONCLUSION: Patients with nephrotic syndrome and elevated ApoE levels should be prompted into renal biopsy to avoid delay of appropriate treatment and unnecessary use of glucocorticoids. This case of LPG was diagnosed by renal biopsy and further verified with genetic sequencing. The timely diagnosis and treatment improved the patient's symptoms. This case is one of only six reported LPG cases or families with APOE Chicago mutation in the world.

Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury.

Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12ß, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17-NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17-NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH-IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2-GPx1-GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.

Dysregulation of the circRNA_0087207/miR-548c-3p/PLSR1-TGFB2 axis in Leber hereditary optic neuropathy in vitro.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction. METHODS: Using LHON patient-specific induced pluripotent stem cells (iPSCs) as the in vitro disease model, we previously demonstrated that circRNA_0087207 had the most significantly higher expression level in the LHON patient-iPSC-derived RGCs compared with the unaffected carrier-iPSC-derived RGCs. To elaborate the underlying pathologies regulated by circRNA_008720 mechanistically, bioinformatics analysis was conducted and elucidated that circRNA_0087207 could act as a sponge of miR-548c-3p and modulate PLSCR1/TGFB2 levels in ND4 mutation-carrying LHON patient-iPSC-derived RGCs. RESULTS: Using LHON iPSC-derived RGCs as the disease-based platform, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on targeted mRNA of miR-548c-3p showed the connection with apoptosis, suggesting downregulation of miR548c-3p contributes to the apoptosis of LHON patient RGCs. CONCLUSION: We showed that the downregulation of miR548c-3p plays a critical role in modulating cellular dysfunction and the apoptotic program of RGCs in LHON.

Molecular mechanism of selenium against lead-induced apoptosis in chicken brainstem relating to heat shock protein, selenoproteins, and inflammatory cytokines.

Extensive application of lead (Pb) brought about environmental pollution and toxic reactions of organisms. Selenium (Se) has the effect of antagonizing Pb poisoning in humans and animals. However, it is still unclear how Pb causes brainstem toxicity. In the present study, we wanted to investigate whether Se can alleviate Pb toxicity in chicken brainstems by reducing apoptosis. One hundred and eighty chickens were randomly divided into four groups, namely the control group, the Se group, the Pb group, and the Se/Pb group. Morphological examination, ultrastructural observation, relative mRNA expressions of genes on heat shock proteins (HSPs); selenoproteins; inflammatory cytokines; and apoptosis-related factors were investigated. The results showed that Pb exposure led to tissue damage and apoptosis in chicken brainstems. Furthermore, an atypical expression of HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90); selenoprotein family glutathione peroxidase (GPx) 1, GPx2, GPx3, and GPx4), thioredoxin reductases (Txnrd) (Txnrd1, Txnrd2, and Txnrd3), dio selenoprotein famliy (diodothyronine deiodinases (Dio)1, Dio2, and Dio3), as well as other selenoproteins (selenoprotein (Sel)T, SelK, SelS, SelH, SelM, SelU, SelI, SelO, Selpb, selenoprotein n1 (Sepn1), Sepp1, Sepx1, Sepw1, 15-kDa selenoprotein (Sep15), and selenophosphate synthetases 2 (SPS2)); inflammatory cytokines (Interleukin 2 (IL-2), IL-4, IL-6, IL-12ß, IL-17, and Interferon-γ (IFN-γ)); and apoptosis-related genes (B-cell lymphoma-2 (Bcl-2), tumor protein 53 (p53), Bcl-2 Associated X (Bax), Cytochrome c (Cyt c), and Caspase-3) were identified. An inflammatory reaction and apoptosis were induced in chicken brainstems after exposure to Pb. Se alleviated the abnormal expression of HSPs, selenoproteins, inflammatory cytokines, and apoptosis in brainstem tissues of chickens treated with Pb. The results indicated that HSPs, selenoproteins, inflammatory, and apoptosis were involved in Se-resisted Pb poisoning. Overall, Se had resistance effect against Pb poisoning, and can be act as an antidote for Pb poisoning in animals.

Understanding Water Diffusion Behaviors in Epoxy Resin through Molecular Simulations and Experiments.

The unclear understanding of the water diffusion behavior posts a big challenge to the manipulation of water absorption properties in epoxy resins. Herein, we investigated the water diffusion behavior and its relationship with molecule structures inside an epoxy resin mainly by the nonequilibrium molecular dynamics and experiments. It is found that at the initial rapid water absorption stage, bound water and free water both contribute, while at the later slow water absorption stage, free water plays a dominant role. The observed evolution of free water and bound water cannot be explained by the traditional Langmuir model. In addition, molecule polarity, free volume, and segment mobility can all influence the water diffusion process. Hence, the epoxy resin with low polarity and high molecular segment mobility is endowed with higher diffusion coefficients. The saturated water absorption content is almost dependent on the polarity. The understanding of how water diffuses and what decides the diffusion process is critical to the rational design of molecule structures for improving the water resistance in epoxy resin.