Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method.

Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using 'off-the-shelf' products, such as allogeneic CAR natural killer T (AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced AlloCAR-NKT cells with high yield and purity. We generated AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of AlloCAR-NKT cells support their potential for clinical translation.

[Annual review of capillary electrophoresis technology in 2023].

This paper serves as an annual review of capillary electrophoresis (CE) technology for 2023. The journals were selected based on their impact factor (IF), a universally recognized academic performance metric, combined with experimental work closely related to CE technology, to facilitate the rapid acquisition of significant research and application advancements in CE technology in 2023. A thematic search of the ISI Web of Science database yielded 669 research papers on CE technology published in 2023. This review highlights five experimental papers published in journals with IFs greater than 10.0, including Nature Communications, Nucleic Acids Research, Engineering, Journal of Medical Virology, and Carbohydrate Polymers, and 31 experimental papers from representative journals with IFs between 5.0 and 10.0, such as Analytical Chemistry, Analytica Chimica Acta, Talanta, and Food Chemistry. It also provides an overview of experimental research in journals with focused reporting on CE technology but with IFs less than 5.0, such as Journal of Chromatography A and Electrophoresis, as well as significant experimental research from key domestic Chinese core journals (Peking University). In 2023, all the latest scientific advancements reported in journals with an IF greater than 10.0 utilized previously reported CE methods, offering new breakthroughs for the promotion and application of CE technology. Additionally, new applications of CE in conjunction with mass spectrometry remained a hot topic. An increase in reports on the hardware aspects of CE, such as 3D printing and underwater systems, and significant breakthroughs in the analysis of non-solution samples, such as solid particles, cell vesicles, cells, viruses, and bacteria, was noted. CE is advantageous for the analysis of drugs and their components. In Chinese journals, the number of papers on CE applications exceeded that in previous years, with particular focus on the field of printing for new applications.

Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.

Evaluation of spatial and temporal changes in illicit drug use in the Taipei metropolitan area via wastewater-based epidemiology.

Taiwan, identified as pivotal in the Asian drug trafficking chain, has been experiencing a surge in illicit drug-related issues. Wastewater-based epidemiology (WBE) has emerged as a promising approach for comprehensive evaluation of actual illicit drug usage. This study presents the first WBE investigation of illicit drug consumption in Taiwan based on the analysis of wastewater from four wastewater treatment plants (WWTPs) in the Taipei metropolitan area. Additionally, it demonstrates a high correlation between the amounts of illicit drugs seized and influent concentrations over an extended period of time. The reliability of solid-phase extraction and analysis via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was validated for 16 illicit drugs (methamphetamine, ketamine, cocaine, codeine, methadone, morphine, meperidine, fentanyl, sufentanil, para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 3,4-methylenedioxymethamphetamine (MDMA), cathinone, methcathinone, mephedrone (MEPH), and 4-methylethcathinone (4-MEC)). Methamphetamine, ketamine, and 4-MEC were consistently detected in all wastewater samples, underscoring their prevalence in the Taipei metropolitan area. Biochemical oxygen demand (BOD) and ammonia nitrogen (ammonia N) were employed to reduce uncertainty in estimations of population size during back-calculation of illicit drug consumption. The results indicate that methamphetamine was the most consumed drug (175-740 mg day-1 1000 people-1), followed by ketamine (22-280 mg day-1 1000 people-1). In addition, urban-related WWTPs exhibited higher consumption of methamphetamine and ketamine than did the suburban-related WWTP, indicating distinct illicit drug usage patterns between suburban and urban regions. Moreover, an examination of temporal trends in wastewater from the Dihua WWTP revealed a persistent predominance of ketamine and methamphetamine, consistent with statistical data pertaining to seizure quantities and urine test results. The study provides encouraging insight into spatial and temporal variations in illicit drug usage in the Taipei metropolitan area, emphasizing the complementary role of WBE in understanding trends in illicit drug abuse.

Assessing mortality risk in Type 2 Diabetes patients with prolonged ASCVD risk factors: the inclusive Poh-Ai predictive scoring system with CAC Score integration.

PURPOSE: To enhance the predictive risk model for all-cause mortality in individuals with Type 2 Diabetes (T2DM) and prolonged Atherosclerotic Cardiovascular Disease (ASCVD) risk factors. Despite the utility of the Coronary Artery Calcium (CAC) score in assessing cardiovascular risk, its capacity to predict all-cause mortality remains limited. METHODS: A retrospective cohort study included 1929 asymptomatic T2DM patients with ASCVD risk factors, aged 40-80. Variables encompassed demographic attributes, clinical parameters, CAC scores, comorbidities, and medication usage. Factors predicting all-cause mortality were selected to create a predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: In our analysis of all-cause mortality in T2DM patients with extended ASCVD risk factors over 5 years, we identified significant risk factors, their adjusted hazard ratios (aHR), and scores: e.g., CAC score > 1000 (aHR: 1.57, score: 2), CAC score 401-1000 (aHR: 2.05, score: 2), and more. These factors strongly predict all-cause mortality, with varying risk groups (e.g., very low-risk: 2.0%, very high-risk: 24.0%). Significant differences in 5-year overall survival rates were observed among these groups (log-rank test < 0.001). CONCLUSION: The Poh-Ai Predictive Scoring System excels in forecasting mortality and cardiovascular events in individuals with Type 2 Diabetes Mellitus and extended ASCVD risk factors.

Interpretation of a paint cross-transfer on a burglary scene - A case report.

In forensic paint examination, paint traces retrieved on a crime scene are regularly compared to painted objects seized from a suspect. Less often, traces are only observed on the seized objects and compared to a damaged painted object on the crime scene. In some specific cases, paint traces may be found both on the crime scene and on one or multiple seized painted objects. The latter may be the result of a cross-transfer that occurred during the illicit act. However, mere coincidence is another possible explanation for these observations and may not be neglected. Proper consideration of the relevant populations and sufficient analytical data permits the evaluation of the results given activity level propositions. This allows the forensic expert to present a transparent and well-balanced statement on the value of their findings concerning the disputed issues in court.

Spin Crossover in [Fe(qsal-5-Brq)2]+ Complexes with a Quinoline-Substituted Qsal Ligand.

Using a quinoline substituted Qsal ligand, Hqsal-5-Brq (Hqsal-5-Brq = N-(5-bromo-8-quinolyl)salicylaldimine), four FeIII complexes, [Fe(qsal-5-Brq)2]A·CH3OH (Y = NO3- (1NO3), BF4- (2BF4), PF6- (3PF6), OTf- (4OTf), were prepared and characterized. Structure analysis revealed that complex 2BF4 contained two species (2BF4(P1̅) and 2BF4(C2/c)). In these compounds except 3PF6, the [Fe(qsal-5-Brq)2]+ cations form 1D chains through π-π interactions and other weak interactions. Adjacent chains are connected to form the 2D "Chain Layer" structures and 3D structures through various supramolecular interactions. For 3PF6, a "Dimer Chain" structure is formed from the loosely connected dimers. Magnetic studies revealed that compounds 1NO3 and 2BF4(P1̅) displayed abrupt hysteretic SCO with the transition temperature T1/2↓ = 235 K, T1/2↑ = 240 K for 1NO3 and T1/2↓ = 230 K, T1/2↑ = 235 K for 2BF4(P1̅), while compounds 3PF6 and 4OTf are in the HS state. Desolvation of the complexes significantly modifies their SCO properties: the desolvated 1NO3 and 2BF4 show a gradual SCO, desolvated 3PF6 undergoes a two-step SCO, and desolvated 4OTf exhibits a hysteretic transition. Overall, this work reported the FeIII-SCO complexes of the quinoline-substituted Hqsal ligand and highlighted the potential of these ligands for the development of interesting FeIII-SCO materials.

Fermented Gracilaria lemaneiformis polysaccharides alleviate food allergy by regulating Treg cells and gut microbiota.

Food allergy has a significant impact on the health and well-being of individuals, affecting both their physical and mental states. Research on natural bioactive compounds, such as polysaccharides extracted from seaweeds, holds great promise in the treatment of food allergies. In this study, fermented Gracilaria lemaneiformis polysaccharides (F-GLSP) were prepared using probiotic fermentation. Probiotic fermentation of Gracilaria lemaneiformis reduces the particle size of polysaccharides. To compare the anti-allergic activity of F-GLSP with unfermented Gracilaria lemaneiformis polysaccharides (UF-GLSP), an OVA-induced mouse food allergy model was established. F-GLSP exhibited a significant reduction in OVA-specific IgE and mMCP levels in allergic mice. Moreover, it significantly inhibited Th2 differentiation and IL-4 production and significantly promoted Treg differentiation and IL-10 production in allergic mice. In contrast, UF-GLSP only reduced OVA-specific IgE and mMCP in the serum of allergic mice. Furthermore, F-GLSP demonstrated a more pronounced regulation of intestinal flora abundance compared to UF-GLSP, significantly influencing the populations of Firmicutes, Bacteroidetes, Lactobacillus, and Clostridiales in the intestines of mice with food allergy. These findings suggest that F-GLSP may regulate food allergies in mice through multiple pathways. In summary, this study has promoted further development of functional foods with anti-allergic properties based on red algae polysaccharides.

Programmed Death Ligand-1 and Tumor Burden Score Dictate Treatment Responses in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The significance of tumor burden for survival is unknown for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The purpose of our study was to evaluate the prognostic impact of programmed death ligand-1 (PD-L1) and tumor burden score (TBS) in patients with R/M HNSCC. PATIENTS AND METHODS: R/M HNSCC patients who were treated with cisplatin, 5-fluorouracil plus cetuximab (EPF) or pembrolizumab (PPF) as first-line treatment were included in our study. PD-L1 and TBS were estimated and correlated with treatment responses. Kaplan-Meier curves were plotted for outcomes estimation. RESULTS: A total of 252 R/M HNSCC patients were included, with 126 high tumor burden (HTB) and 126 low tumor burden (LTB) patients. Median progression-free survival (PFS) was 7.1 months in LTB and 3.9 months in HTB (p < 0.001) and median overall survival (OS) was 14.2 months in LTB and 9.2 months in HTB (p = 0.001). Patients with LTB had better PFS and OS than those with HTB independent of PD-L1 status. Subgroup analysis showed HTB patients treated with EPF had better survival than those treated with PPF, regardless of PD-L1 expression. For LTB PD-L1 positive patients, there was a longer survival with PPF than EPF, while for LTB PD-L1 negative patients, survival was similar between PPF and EPF. Multivariate analysis exhibited that tumor burden was significantly correlated with OS. CONCLUSIONS: Tumor burden is significantly correlated with survival in patients with R/M HNSCC. PD-L1 and TBS should be taken into consideration to determine first-line treatment.

Microstructure and Perfusion Alterations of Globus Pallidus in Neonates with Hyperbilirubinemia.

BACKGROUND: Previous studies have indicated the abnormality of the globus pallidus in neonates with hyperbilirubinemia. OBJECTIVE: This study aims to explore the microstructure and cerebral perfusion of globus pallidus in neonatal hyperbilirubinemia by using Diffusion Tensor Imaging (DTI) and Arterial Spin Labeling (ASL) approaches. METHODS: Thirty-seven neonates were enrolled in this study, which were classified into Bilirubin-Induced Neurologic Dysfunction (BIND) group (hyperbilirubinemia with BIND, n=12), non-BIND group (hyperbilirubinemia without BIND, n=15), and healthy controls (HC) group (n=10). The quantitative values of globus pallidus were calculated from DTI, including the Apparent Diffusion Coefficient (ADC), the Fractional Anisotropy (FA), and Volume Ratio (VR) values. Additionally, the relative Cerebral Blood Flow (rCBF) values were obtained from ASL. RESULTS: It was observed that the mean DTI signal of globus pallidus was significantly different among the three groups (p < 0.05). However, there were no significant differences in the rCBF of globus pallidus among the three groups (p > 0.05). A positive correlation was also observed between the fractional anisotropy (FA) value and serum bilirubin level (r = 0.561, p = 0.002), while the VR value showed a negative correlation with serum bilirubin level (r=-0.484, p=0.011). The area under the curve (AUC) of FA, VR, and FA and VR combined was 0.897, 0.858, and 0.933, respectively. CONCLUSION: The alterations of microstructure in globus pallidus, especially FA and VR value, may be valuable and sensitive at the early stage of hyperbilirubinemia encephalopathy, suggesting that early hyperbilirubinemia may lead to cytotoxic edema and decreased permeability of the cell membrane.

Impact of Hearing Aids on Language Outcomes in Preschool Children With Mild Bilateral Hearing Loss.

This study aimed to investigate the role of hearing aid (HA) usage in language outcomes among preschool children aged 3-5 years with mild bilateral hearing loss (MBHL). The data were retrieved from a total of 52 children with MBHL and 30 children with normal hearing (NH). The association between demographical, audiological factors and language outcomes was examined. Analyses of variance were conducted to compare the language abilities of HA users, non-HA users, and their NH peers. Furthermore, regression analyses were performed to identify significant predictors of language outcomes. Aided better ear pure-tone average (BEPTA) was significantly correlated with language comprehension scores. Among children with MBHL, those who used HA outperformed the ones who did not use HA across all linguistic domains. The language skills of children with MBHL were comparable to those of their peers with NH. The degree of improvement in audibility in terms of aided BEPTA was a significant predictor of language comprehension. It is noteworthy that 50% of the parents expressed reluctance regarding HA use for their children with MBHL. The findings highlight the positive impact of HA usage on language development in this population. Professionals may therefore consider HAs as a viable treatment option for children with MBHL, especially when there is a potential risk of language delay due to hearing loss. It was observed that 25% of the children with MBHL had late-onset hearing loss. Consequently, the implementation of preschool screening or a listening performance checklist is recommended to facilitate early detection.

Associations between Physical Activity and the Incidence of Cerebrovascular Disease or All-Cause Mortality among 146,742 Older Adults: A 13-Year Prospective Cohort Study.

OBJECTIVES: Although studies have indicated that physical activity (PA) is related to cardiovascular disease, the specific association between PA and incident cerebrovascular disease (CBVD) remains uncertain. The current study aimed to investigate the associations between PA levels and the CBVD incidence or all-cause mortality. DESIGN: Prospective cohort study. SETTINGS AND PARTICIPANTS: Older participants (aged >60 years) from the UK Biobank. METHODS: The baseline PA was classified as total, light, moderate, and vigorous PA based on the metabolic equivalent-minutes per week (MET-min/wk) and considered as exposures, whereas CBVD incidence and all-cause mortality were considered as the outcomes. Cox proportional hazards were used to calculate the hazard ratios (HRs) and 95% CIs for the influence of the association between PA and CBVD incidence and all-cause mortality. RESULTS: A total of 146,742 participants aged 60 years and older were included. During a median follow-up period of 13.5 years (interquartile range of 12.8-14.2), 9338 older individuals developed CBVD and 3033 death were recorded (including 767 CBVD-related deaths). High volumes of PA were consistently associated with lower risks of CBVD and all-cause mortality. The lowest risk of CBVD incidence was observed at 2001-2500 MET-min/wk of total PA (HR 0.61, 95% CI 0.53-0.70), and the lowest risk of all-cause mortality was observed at 2501-5000 MET-min/wk (HR 0.52, 95% CI 0.43-0.63) in older adults. Total PA at 2001-2500 MET-min/wk significantly reduced the CBVD incidence in older women (HR 0.57, 95% CI 0.46-0.71), which was more pronounced than that in older men (HR for 2001-2500 MET-min/wk: 0.64, 95% CI 0.50-0.77). CONCLUSIONS AND IMPLICATIONS: Total PA at 2001-2500 MET-min/wk significantly reduced the risk of incident CBVD and all-cause mortality in adults aged >60 years, although the extents of risk reduction vary in men and women.

Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

Association between the stress-hyperglycemia ratio and all-cause mortality in community-dwelling populations: An analysis of the National Health and Nutrition Examination Survey (NHANES) 1999-2014.

BACKGROUND: Reportedly, the stress-hyperglycemia ratio (SHR) is closely associated with poor prognosis in patients with severe acute disease. However, the community-dwelling may also be in a state of stress due to environmental exposure. Our study aimed to explore the association between SHR and all-cause mortality in the community-dwelling population. METHODS: A total of 18 480 participants were included out of 82 091 from the NHANES 1999-2014 survey. The Kaplan-Meier survival analyses were used to assess the disparities in survival rates based on SHR, and the log-rank test was employed to investigate the distinctions between groups. The multivariate Cox regression analysis and restricted cubic spline (RCS) analysis were performed to assess the association of SHR with all-cause mortality. A subgroup analysis was also conducted. RESULTS: A total of 3188 deaths occurred during a median follow-up period of 11.0 (7.7; 15.4) years. The highest risk for all-cause mortality was observed when SHR≤ 0.843 or SHR ≥0.986 (log-rank p < .001). After adjusting for the confounding factors, compared with subjects in the second SHR quartile (Q2), participants in the highest (Q4, adjusted hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.28-1.73) and lowest quartiles (Q1, adjusted HR 1.37, 95% CI 1.16-1.60) have a higher probability of all-cause death. The RCS observed a dose-response U-shaped association between SHR and all-cause mortality. The U-shaped association between SHR and all-cause mortality was similar across subgroup analysis. CONCLUSIONS: The SHR was significantly associated with all-cause mortality in the community-dwelling population, and the relationship was U-shaped.

Inhalable spray-dried porous microparticles containing dehydroandrographolide succinate phospholipid complex capable of improving and prolonging pulmonary anti-inflammatory efficacy in mice.

Due to the unique physiological barriers within the lungs, there are considerable challenges in developing drug delivery systems enabling prolonged drug exposure to respiratory epithelial cells. Here, we report a PulmoSphere-based dry powder technology that incorporates a drug-phospholipid complex to promote intracellular retention of dehydroandrographolide succinate (DAS) in respiratory epithelial cells following pulmonary delivery. The DAS-phospholipid complex has the ability to self-assemble into nanoparticles. After spray-drying to produce PulmoSphere microparticles loaded with the drug-phospholipid complex, the rehydrated microparticles discharge the phospholipid complex without altering its physicochemical properties. The microparticles containing the DAS-phospholipid complex exhibit remarkable aerodynamic properties with a fine particle fraction of ∼ 60% and a mass median aerodynamic diameter of ∼ 2.3 µm. These properties facilitate deposition in the alveolar region. In vitro cell culture and lung tissue explants experiments reveal that the drug-phospholipid complex prolongs intracellular residence time and lung tissue retention due to the slow intracellular disassociation of drug from the complex. Once deposited in the lungs, the DAS-phospholipid complex loaded microparticles increase and extend drug exposure to the lung tissues and the immune cells compared to the free DAS counterpart. The improved drug exposure to airway epithelial cells, but not immune cells, is related to a prolonged duration of pulmonary anti-inflammation at decreased doses in a mouse model of acute lung injury induced by lipopolysaccharide. Overall, the phospholipid complex loaded microparticles present a promising approach for improved treatment of respiratory diseases, e.g. pneumonia and acute respiratory distress syndrome.

An Organodiphosphate-Containing Polyoxoniobate Ring and Its Assembly into a Three-Dimensional Framework through Hydrogen Bonding.

In this work, a novel organodiphosphate-containing inorganic-organic hybrid polyoxoniobate (PONb) ring {(PO3CH2CH2PO3H)4Nb8O16}4- (Nb8P8) has been achieved by a one-pot hydrothermal method. The ring is constructed from a tetragonal {Nb8O36} motif and four {PO3CH2CH2PO3H} ligands. Interestingly, Nb8P8 can be joined together via K-H2O clusters {K2(H2O)4(OH)2} to form one-dimensional chains {[K2(H2O)4(OH)2]Nb8P8}n and further linked by {Cu(en)2}2+ (en = ethylenediamine) complexes, resulting in a three-dimensional supramolecular framework {[Cu(en)2]2[K2(H2O)4(OH)2]Nb8P8}·3en·H2O (1). 1 exhibits good chemical and thermal stability and has a high water vapor adsorption capacity of ≤224 cm3 g-1 (22.71 mol·mol-1) at 298 K, outperforming most of the known polyoxometalate-based materials. Impedance measurements prove that 1 can transfer protons with moderate conductivity. This study not only contributes to the structural diversity of organodiphosphate-containing PONbs and PONb rings but also provides a reference for the development of PONb-based materials with unique performance.

BDNF mimetics recover palmitic acid-induced injury in cardiomyocytes by ameliorating Akt-dependent mitochondrial impairments.

Cardiac lipotoxicity is a prevalent consequence of lipid metabolism disorders occurring in cardiomyocytes, which in turn precipitates the onset of heart failure. Mimetics of brain-derived neurotrophic factor (BDNF), such as 7,8-dihydroxyflavone (DHF) and 7,8,3'-trihydroxyflavone (THF), have demonstrated significant cardioprotective effects. However, it remains unclear whether these mimetics can protect cardiomyocytes against lipotoxicity. The aim of this study was to examine the impact of DHF and THF on the lipotoxic effects induced by palmitic acid (PA), as well as the concurrent mitochondrial dysfunction. H9c2 cells were subjected to treatment with PA alone or in conjunction with DHF or THF. Various factors such as cell viability, lactate dehydrogenase (LDH) release, death ratio, and mitochondrial function including mitochondrial membrane potential (MMP), mitochondrial-derived reactive oxygen species (mito-SOX) production, and mitochondrial respiration were assessed. PA dose-dependently reduced cell viability, which was restored by DHF or THF. Additionally, both DHF and THF decreased LDH content, death ratio, and mito-SOX production, while increasing MMP and regulating mitochondrial oxidative phosphorylation in cardiomyocytes. Moreover, DHF and THF specifically activated Akt signaling. The protective effects of DHF and THF were abolished when an Akt inhibitor was used. In conclusion, BDNF mimetics attenuate PA-induced injury in cardiomyocytes by alleviating mitochondrial impairments through the activation of Akt signaling.

Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Computational Study on Interlocked-Ferroelectricity-Contributed High-Performance Memristors Based on Two-Dimensional van der Waals Ferroelectric Semiconductors.

In order to realize the prevailing artificial intelligence technology, memristor-implemented in-memory or neuromorphic computing is highly expected to break the bottleneck of von Neumann computers. Although high-performance memristors have been vigorously developed in labs or in industry, systematic computational investigations on memristors are seldom. Hence, it is urgent to provide theoretical or computational support for the exploration of memristor operating mechanisms or the screening of memristor materials. Here, a computational method based on the main input parameters learned from the first-principles calculations was developed to measure resistance switching of two-terminal memristors with sandwiched metal/ferroelectric semiconductor/metal architectures, which strikingly agrees with the experimental measurements. Based on our developed method, the diverse multiterminal memristors were designed to fully exploit the application of interlocked ferroelectricity of a ferroelectric semiconductor and realize their heterosynaptic plasticity, and their heterosynaptic behaviors can still be well described. Our developed method can provide a paradigm for the emulation of ferroelectric memristors and inspire subsequent computational exploration. Furthermore, our study also supplies a device optimization strategy based on the interlocked ferroelectricity and easy processing of two-dimensional van der Waals ferroelectric semiconductors, and our proposed heterosynaptic memristors still await further experimental exploration.