Massively Enhanced Charge Selectivity, Ion Transport, and Osmotic Energy Conversion by Antiswelling Nanoconfined Hydrogels.

Developing a nanofluidic membrane with simultaneously enhanced ion selectivity and permeability for high-performance osmotic energy conversion has largely been unexplored. Here, we tackle this issue by the confinement of highly space-charged hydrogels within an orderedly aligned nanochannel array membrane. The nanoconfinement effect endows the hydrogel-based membrane with excellent antiswelling property. Furthermore, experimental and simulation results demonstrate that such a nanoconfined hydrogel membrane exhibits massively enhanced cation selectivity and ion transport properties. Consequently, an amazingly high power density up to ∼52.1 W/m2 with an unprecedented energy conversion efficiency of 37.5% can be reached by mixing simulated salt-lake water (5 M NaCl) and river water (0.01 M NaCl). Both efficiency indexes surpass those of most of the state-of-the-art nanofluidic membranes. This work offers insights into the design of highly ion-selective membranes to achieve ultrafast ion transport and high-performance osmotic energy harvesting.

Temporal and Spatial Variations in Zebrafish Hairy/E(spl) Gene Expression in Response to Mib1-Mediated Notch Signaling During Neurodevelopment.

Notch signaling is a conserved pathway crucial for nervous system development. Disruptions in this pathway are linked to neurodevelopmental disorders, neurodegenerative diseases, and brain tumors. Hairy/E(spl) (HES) genes, major downstream targets of Notch, are commonly used as markers for Notch activation. However, these genes can be activated, inhibited, or function independently of Notch signaling, and their response to Notch disruption varies across tissues and developmental stages. MIB1/Mib1 is an E3 ubiquitin ligase that enables Notch receptor activation by processing ligands like Delta and Serrate. We investigated Notch signaling disruption using the zebrafish Mib1 mutant line, mib1ta52b, focusing on changes in the expression of Hairy/E(spl) (her) genes. Our findings reveal significant variability in her gene expression across different neural cell types, regions, and developmental stages following Notch disruption. This variability questions the reliability of Hairy/E(spl) genes as universal markers for Notch activation, as their response is highly context-dependent. This study highlights the complex and context-specific nature of Notch signaling regulation. It underscores the need for a nuanced approach when using Hairy/E(spl) genes as markers for Notch activity. Additionally, it provides new insights into Mib1's role in Notch signaling, contributing to a better understanding of its involvement in Notch signaling-related disorders.

Novel SARS-CoV-2 inhibition properties of the anti-cancer Kang Guan Recipe herbal formula.

The ongoing COVID-19 pandemic is a persistent challenge, with continued breakthrough infections despite vaccination efforts. This has spurred interest in alternative preventive measures, including dietary and herbal interventions. Previous research has demonstrated that herbal medicines can not only inhibit cancer progression but also combat viral infections, including COVID-19 by targeting SARS-CoV-2, indicating a multifaceted potential to address both viruses and cancer. Here, we found that the Kang Guan Recipe (KGR), a novel herbal medicine formula, associates with potent inhibition activity against the SARS-CoV-2 viral infection. We demonstrate that KGR exhibits inhibitory activity against several SARS-CoV-2 variants of concern (VOCs). Mechanistically, we found that KGR can block the interaction of the viral spike and human angiotensin-converting enzyme 2 (ACE2). Furthermore, we assessed the inhibitory effect of KGR on SARS-CoV-2 viral entry in vivo, observing that serum samples from healthy human subjects having taken KGR exhibited suppressive activity against SARS-CoV-2 variants. Our investigation provides valuable insights into the potential of KGR as a novel herbal-based preventive and therapeutic strategy against COVID-19.

Sex difference in the association between creatinine-to-cystatin C ratio and metabolic syndrome among Chinese adults.

Background: Metabolic syndrome (MetS), characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, affects 20-25% of the global population. The creatinine-to-cystatin C ratio (CCR) is an indicator of skeletal muscle mass. While CCR may play a role in MetS development, sex differences in these associations are not fully understood. Therefore, this study aimed to investigate how CCR levels are associated with MetS in a Chinese adult population, focusing on possible sex disparities. Method: We conducted a retrospective cross-sectional analysis of 9,376 adults from Xiamen Chang Gung Hospital between 2014 to 2016. We examined the relationship between CCR and MetS, adjusting for cardiometabolic risk factors. Results: The prevalence of MetS was 24.7% in males and 18.0% in females. Interestingly, we observed significant sex differences in the association between CCR quartiles and MetS. Females in the lowest CCR quartile had a significantly higher risk of MetS (odds ratio=1.84). Receiver operating characteristic curve analysis revealed acceptable diagnostic power of CCR for MetS in females (area under the curve=0.65) but not in males. Conclusion: Our findings suggest that CCR is an independent risk factor for MetS in females, highlighting the importance of sex-specific assessments when evaluating MetS risk.

Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery.

Traumatic injury to the spinal cord can lead to significant, permanent disability. Mammalian spinal cords are not capable of regeneration; in contrast, adult zebrafish are capable of such regeneration, fully recovering motor function. Understanding the mechanisms underlying zebrafish neuroregeneration may provide useful information regarding endogenous regenerative potential and aid in the development of therapeutic strategies in humans. DELTEX proteins (DTXs) regulate a variety of cellular processes. However, their role in neural regeneration has not been described. We found that zebrafish dtx2, encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous dtx2 mutant fish motor function recovered quicker than that of the wild-type controls. The mutant fish displayed increased ependymo-radial glial cell proliferation and augmented motor neuron formation. Moreover, her gene expression, downstream of Notch signaling, increased in Dtx2 mutants. Notch signaling inactivation by dominant-negative Rbpj abolished the increased ependymo-radial glia proliferation caused by Dtx2 deficiency. These results indicate that ependymo-radial glial proliferation is induced by Dtx2 deficiency by activating Notch-Rbpj signaling to improve spinal cord regeneration and motor function recovery.

Unplanned emergency department visits within 90 days of hip hemiarthroplasty for osteoporotic femoral neck fractures: Reasons, risks, and mortalities.

Objectives: Bipolar hemiarthroplasty is commonly performed to treat displaced femoral neck fractures in osteoporotic patients. This study aimed to assess the occurrence and outcomes of unplanned return visits to the emergency department (ED) within 90 days following bipolar hemiarthroplasty for displaced femoral neck fractures. Methods: The clinical data of 1322 consecutive patients who underwent bipolar hemiarthroplasty for osteoporotic femoral neck fractures at a tertiary medical center were analyzed. Data from the patients' electronic medical records, including demographic information, comorbidities, and operative details, were collected. The risk factors and mortality rates were analyzed. Results: Within 90 days after surgery, 19.9% of patients returned to the ED. Surgery-related reasons accounted for 20.2% of the patient's returns. Older age, a high Charlson comorbidity index score, chronic kidney disease, and a history of cancer were identified as significant risk factors for unplanned ED visits. Patients with uncemented implants had a significantly greater risk of returning to the ED due to periprosthetic fractures than did those with cemented implants (P = 0.04). Patients who returned to the ED within 90 days had an almost fivefold greater 1-year mortality rate (15.2% vs 3.1%, P < 0.001) and a greater overall mortality rate (26.2% vs 10.5%, P < 0.001). Conclusions: This study highlights the importance of identifying risk factors for unplanned ED visits after bipolar hemiarthroplasty, which may contribute to a better prognosis. Consideration should be given to the use of cemented implants for hemiarthroplasty, as uncemented implants are associated with a greater risk of periprosthetic fractures.

Long-term mortality after isolated coronary artery bypass grafting and risk factors for mortality.

BACKGROUND: Patients requiring coronary artery bypass grafting (CABG) have multiple co-morbidities which need to be considered in totality when determining surgical risks. The objective of this study is to evaluate short-term and long-term mortality rates of CABG surgery, as well as to identify the most significant risk factors for mortality after isolated CABG. METHODS: All patients with complete dataset who underwent isolated CABG between January 2008 and December 2017 were included. Univariate and multivariate Cox regression was performed to determine the risk factors for all-cause mortality. Classification and regression tree analysis was performed to identify the relative importance of these risk factors. RESULTS: 3,573 patients were included in the study. Overall mortality rate was 25.7%. In-hospital mortality rate was 1.62% overall. 30-day, 1-year, 5-year, 10-year and 14.5-year mortality rates were 1.46%, 2.94%, 9.89%, 22.79% and 36.30% respectively. Factors associated with death after adjustment for other risk factors were older age, lower body mass index (BMI), hypertension, diabetes mellitus, chronic obstructive pulmonary disease, pre-operative renal failure on dialysis, higher last pre-operative creatinine level, lower estimated glomerular filtration rate (eGFR), heart failure, lower left ventricular ejection fraction and New York Heart Association class II, III and IV. Additionally, female gender and logistic EuroSCORE were associated with death on univariate Cox analysis, but not associated with death after adjustment with multivariate Cox analysis. Using CART analysis, the strongest predictor of mortality was pre-operative eGFR < 46.9, followed by logistic EuroSCORE ≥ 2.4. CONCLUSION: Poorer renal function, quantified by a lower eGFR, is the best predictor of post-CABG mortality. Amongst other risk factors, logistic EuroSCORE, age, diabetes and BMI had a relatively greater impact on mortality. Patients with chronic kidney disease stage 3B and above are at highest risk for mortality. We hope these findings heighten awareness to optimise current medical therapy in preserving renal function upon diagnosis of any atherosclerotic disease and risk factors contributing to coronary artery disease.

Impacts of audiovisual simultaneity perception on single-task and dual-task gaits in middle-aged and older adults.

BACKGROUND: While dual-task walking requires the ability to integrate sensory information from multiple ongoing sources, it remains unknown whether dual-task walking is more affected than single-task walking by the multisensory integration ability. RESEARCH QUESTION: How does the audiovisual temporal integration ability affect single-task and dual-task gaits in the aging population? METHODS: One hundred and thirty healthy middle-aged and older adults (age = 64.7 ± 6.4 years) completed an audiovisual simultaneity judgment (AVSJ) task and underwent single-task, motor dual-task, and cognitive dual-task gait assessments. In the AVSJ task, participants judged whether a flash and an auditory stimulus presented at different stimulus onset asynchronies were simultaneous. The accuracy and precision of the AVSJ performance were assessed using the point of subjective simultaneity (PSS) and the temporal binding window (δ), respectively. A lower absolute PSS and δ indicated better performance. Participants held a cup of water and performed serial-7 subtraction for motor and cognitive dual-task gait assessments, respectively. The spatiotemporal gait parameters and their variability were calculated. The influences of PSS and δ on the gait parameters of the three gaits were examined with multiple hierarchical regressions. RESULTS: Only the cognitive dual-task gait was significantly affected by PSS and δ. Greater PSS predicted a longer single support time (ß = 0.195, p = 0.024) and its variability (ß = 0.224, p = 0.011). Greater δ predicted greater step time variability (ß = 0.198, p = 0.022). SIGNIFICANCE: Declined perception of audiovisual simultaneity particularly degrades temporal control of cognitive dual-task walking, highlighting the importance of assessing and training this ability after midlife.

Structural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB.

The K+ uptake system KtrAB is essential for bacterial survival in low K+ environments. The activity of KtrAB is regulated by nucleotides and Na+. Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na+ activates KtrAB and the Na+ binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na+, as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na+ binding stabilizes the ATP-bound BsKtrAB complex and enhances its K+ flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na+ in activating BsKtrAB is likely applicable to Na+-activated K+ channels in central nervous system.

Preparation of (S)-epichlorohydrin using a novel halohydrin dehalogenase by selective conformation adjustment.

Chiral epichlorohydrin (ECH) is an attractive intermediate for chiral pharmaceuticals and chemicals preparation. The asymmetric synthesis of chiral ECH using 1,3-dicholoro-2-propanol (1,3-DCP) catalyzed by a haloalcohol dehalogenase (HHDH) was considered as a feasible approach. However, the reverse ring opening reaction caused low optical purity of chiral ECH, thus severely restricts the industrial application of HHDHs. In the present study, a novel selective conformation adjustment strategy was developed with an engineered HheCPS to regulate the kinetic parameters of the forward and reverse reactions, based on site saturation mutation and molecular simulation analysis. The HheCPS mutant E85P was constructed with a markable change in the conformation of (S)-ECH in the substrate pocket and a slight impact on the interaction between 1,3-DCP and the enzyme, which resulted in the kinetic deceleration of the reverse reactions. Compared with HheCPS, the catalytic efficiency (kcat(S)-ECH/Km(S)-ECH) of the reversed reaction dropped to 0.23-fold (from 0.13 to 0.03 mM-1 s-1), while the catalytic efficiency (kcat(1,3-DCP)/Km(1,3-DCP)) of the forward reaction only reduced from 0.83 to 0.71 mM-1 s-1. With 40 mM 1,3-DCP as substrate, HheCPS E85P catalyzed the synthesis of (S)-ECH with the yield up to 55.35% and the e.e. increased from 92.54 to >99%. Our work provided an effective approach for understanding the stereoselective catalytic mechanism as well as the green manufacturing of chiral epoxides.

Within-Session Reliability of fNIRS in Robot-Assisted Upper-Limb Training.

Functional near-infrared spectroscopy (fNIRS) seems opportune for neurofeedback in robot-assisted rehabilitation training due to its noninvasive, less physical restriction, and no electromagnetic disturbance. Previous research has proved the cross-session reliability of fNIRS responses to non-motor tasks (e.g., visual stimuli) and fine-motor tasks (e.g., finger tapping). However, it is still unknown whether fNIRS responses remain reliable 1) in gross-motor tasks, 2) within a training session, and 3) for different training parameters. Hence, this study aimed to investigate the within-session reliability of fNIRS responses to gross-motor tasks for different training parameters. Ten healthy participants were recruited to conduct right elbow extension-flexion in three robot-assisted modes. The Passive mode was fully motor-actuated, while Active1 and Active2 modes involved active engagement with different resistance levels. FNIRS data of three identical runs were used to assess the within-session reliability in terms of the map- ( R2 ) and cluster-wise ( Roverlap ) spatial reproducibility and the intraclass correlation (ICC) of temporal features. The results revealed good spatial reliability ( R2 up to 0.69, Roverlap up to 0.68) at the subject level. Besides, the within-session temporal reliabilities of Slope, Max/Min, and Mean were between good and excellent ( ICC < 0.86). We also found that the within-session reliability was positively correlated with the intensity of the training mode, except for the temporal reliability of HbO in Active2 mode. Overall, our results demonstrated good within-session reliability of fNIRS responses, suggesting fNIRS as reliable neurofeedback for constructing closed-loop robot-assisted rehabilitation systems.

Leaching kinetics and bioaccumulation potential of additive-derived organophosphate esters in microplastics.

Considerable research has been conducted to evaluate microplastics (MPs) as vehicles for the transfer of hazardous pollutants in organisms. However, little effort has been devoted to the chemical release of hazardous additive-derived pollutants from MPs in gut simulations. This study looked at the leaching kinetics of organophosphate esters (OPFRs) from polypropylene (PP) and polystyrene (PS) MPs in the presence of gut surfactants, specifically sodium taurocholate, at two biologically relevant temperatures for marine organisms. Diffusion coefficients of OPFRs ranged from 1.71 × 10-20 to 4.04 × 10-18 m2 s-1 in PP and 2.91 × 10-18 to 1.51 × 10-15 m2 s-1 in PS. The accumulation factors for OPFRs in biota-plastic and biota-sediment interactions ranged from 1.52 × 10-3-69.1 and 0.02-0.7, respectively. Based on B3LYP/6-31G (d,p) calculations, the biodynamic model analysis revealed a slight increase in the bioaccumulation of OPFRs at a minor dose of 0.05% MPs. However, at higher concentrations (0.5% and 5% MPs), there was a decrease in bioaccumulation compared to the lower concentration for most OPFR compounds. In general, the ingestion of PE MPs notably contributed to the bioaccumulation of OPFRs in lugworms, whereas the contribution of PP and PS MPs was minimal. This could vary among sites exhibiting varying levels of MP concentrations or MPs displaying stronger affinities towards chemicals.

Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

[Pollution Characteristics and Ecological Risk Assessment of Microplastics in the Yangtze River Basin].

The Yangtze River, the largest river in China, has not been comprehensively studied for its basin's microplastic pollution status. Therefore, a comprehensive investigation and assessment system of microplastics was developed at the river basin scale to characterize the spatial distribution and composition of microplastics in the Yangtze River Basin in order to analyze their influencing factors and assess their ecological risks. The results showed that the microplastic abundance in the study area ranged from 21 to 44 080 n·m-3, with an average abundance of 4 483 n·m-3. The spatial distribution of microplastic abundance was higher in the tributaries than in the main streams (except the Ganjiang Basin), with the Chengdu of the Minjiang Basin being the tributary area with the highest abundance of microplastics detected. The size of microplastics in the river basin was concentrated in the 0-1 mm range; the shapes were mainly fiber and fragment; and the colors were mainly colored and transparent. Further, introducing the diversity index of microplastics, it was found that both the Simpson index and the Shannon-Wiener index could quantify the diversity of microplastic characteristic composition in the river basin, but there were certain differences in the changing trends between the two. Regression analysis showed that anthropogenic activities were significantly and positively correlated with microplastic abundance (P<0.05), and among the eight anthropogenic activity factors, civilian vehicle ownership and tourism income were the most strongly correlated with microplastic abundance, indicating that transportation and tourism were the main factors influencing microplastic distribution. From the perspective of the potential ecological risk index of microplastics, microplastics in the Yangtze River Basin posed a certain ecological risk, with 68.97% of the area falling within risk zones III and IV, with the ecological risk of microplastics in Taihu Lake warranting more widespread attention.

Reliable quantitative detection of uric acid in urine by surface-enhanced Raman spectroscopy with endogenous internal standard.

Abnormal levels of uric acid (UA) in urine serve as warning signs for gout and metabolic cardiovascular diseases, necessitating the monitoring of UA levels for early prevention. However, the current analytical methods employed suffer from limitations in terms of inadequate suitability for home-based applications and the requirement of non-invasive procedures. In this approach, creatinine, a metabolite with a constant excretion rate, was incorporated as an endogenous internal standard (e-IS) for calibration, presenting a rapid, pretreatment-free, and accurate strategy for quantitative determination of UA concentrations. By utilizing urine creatinine as an internal reference value to calibrate the signal fluctuation of surface-enhanced Raman spectroscopy (SERS) of UA, the quantitative accuracy can be significantly improved without the need for an external internal standard. Due to the influence of the medium, UA, which carries a negative charge, is selectively adsorbed by Au@Ag nanoparticles functionalized with hexadecyltrimethylammonium chloride (CTAC) in this system. Furthermore, a highly convenient detection method was developed, which eliminates the need for pre-processing and minimizes matrix interference by simple dilution. The method was applied to the urine detection of different volunteers, and the results were highly consistent with those obtained using the UA colorimetric kit (UACK). The detection time of SERS was only 30 s, which is 50 times faster than UACK. This quantitative strategy of using urinary creatinine as an internal standard to correct the SERS intensity of uric acid is also expected to be extended to the quantitative detection needs of other biomarkers in urine.

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

Increased Risk of Coronary Artery Disease in People with Diagnosis of Neuromuscular Disorders: A Nationwide Retrospective Population-Based Case-Control Study.

The existing literature has explored carpal tunnel syndrome (CTS) and determined that it could be a risk for coronary artery disease (CAD), but there has been little research comparing the relevance of CAD with other neuromuscular disorders (NMDs) to CTS. This case-control study explored the association between CTS, stenosing tenosynovitis (ST), and ulnar side NMDs and CAD. The study utilized data from Taiwan's National Health Insurance Research Database, focusing on health insurance claims. Between January 2000 and December 2011, we employed the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes to identify 64,025 CAD patients as the case group. The control group consisted of an equal number of individuals without CAD, matched for age, sex, and index year of CAD. Logistic regression analysis was employed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for each variable. Multivariate analysis, after adjusting for sociodemographic factors and comorbidities, revealed a significantly higher likelihood of a previous diagnosis of CTS in the CAD group compared to the comparison control group. However, neither ST nor the ulnar side NMDs had any statistical significance. These results indicated that median nerve injury, rather than other NMDs, may uniquely serve as a predisposing factor of CAD.

Exploring quantitative measures in metacognition of emotion.

Metacognition of emotion (meta-emotion) refers to the ability to evaluate and identify one's emotional feelings. No previous study has defined and measured this construct through objective and quantitative procedures. We established a reliable method to measure meta-emotion. With a two-interval forced-choice procedure, participants selected which of two pictures elicited stronger positive emotion; via the Law of Comparative Judgment, their responses were used to compute individual psychological distances for the emotional responses triggered by the pictures. Then, participants were asked to judge whether a pre-exposed picture induced a stronger positive emotion than the median of that elicited by the whole picture set, followed by a confidence rating. By utilizing each individual's psychological distance, the correctness of a participant's emotional experience was quantified by d', and meta-emotion was quantified using meta-d', M-ratio, and M-diff as indices of metacognitive sensitivity and efficiency based on Signal-Detection Theory. Test-retest reliabilities, validated by Spearman correlation, were observed in meta-d', M-ratio, and marginally with M-diff, suggesting the stability of meta-emotion in the current design. This study unveils a validated procedure to quantify meta-emotion, extendable for assessing metacognition of other subjective feelings. Nevertheless, caution is warranted in interpretation, as the measured processes may be influenced by non-metacognitive factors.

Chronic neurotoxicity of Tetrabromobisphenol A: Induction of oxidative stress and damage to neurons in Caenorhabditis elegans.

Tetrachlorobisphenol A (TCBPA) has been used as an alternative flame retardant in various fields. However, the long-term effects of TCBPA on the nervous system remain unclear. Thus, Caenorhabditis elegans (L4 larvae) were selected as a model animal to investigate the neurotoxic effects and underlying mechanisms after 10 d of TCBPA exposure. Exposure to TCBPA (0.01-100 µg/L) decreased locomotive behavior in a concentration-dependent manner. In addition, reactive oxygen species (ROS) formation and lipofuscin accumulation were significantly increased, and the expression of sod-3 was upregulated in the exposed nematodes, indicating that TCBPA exposure induced oxidative damage. Furthermore, 100 µg/L TCBPA exposure caused a reduction in dopamine and serotonin levels, and damage in dopaminergic and serotoninergic neurons, which was further confirmed by the downregulated expression of related genes (e.g., dop-1, dop-3, cat-1, and mod-1). Molecular docking analysis demonstrated the potential of TCBPA to bind to the neurotransmitter receptor proteins DOP-1, DOP-3, and MOD-1. These results indicate that chronic exposure to TCBPA induces neurotoxic effects on locomotive behavior, which is associated with oxidative stress and damage to dopaminergic and serotoninergic neurons.

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.