Parallel process latent growth curve mediation models (PP-LGCMMs) are frequently used to longitudinally investigate the mediation effects of treatment on the level and change of outcome through the level and change of mediator. An important but often violated assumption in empirical PP-LGCMM analysis is the absence of omitted confounders of the relationships among treatment, mediator, and outcome. In this study, we analytically examined how omitting pretreatment confounders impacts the inference of mediation from the PP-LGCMM. Using the analytical results, we developed three sensitivity analysis approaches for the PP-LGCMM, including the frequentist, Bayesian, and Monte Carlo approaches. The three approaches help investigate different questions regarding the robustness of mediation results from the PP-LGCMM, and handle the uncertainty in the sensitivity parameters differently. Applications of the three sensitivity analyses are illustrated using a real-data example. A user-friendly Shiny web application is developed to conduct the sensitivity analyses.
INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.
This study investigated how 40 Chinese learners of English as a foreign language (EFL learners) differed from 40 native English speakers in the production of four English tense-lax contrasts, /i-ɪ/, /u-Ê/, /É-Ê/, and /æ-ε/, by examining the acoustic measurements of duration, the first three formant frequencies, and the slope of the first formant movement (F1 slope). The dynamic formant trajectory was modeled using discrete cosine transform coefficients to demonstrate the time-varying properties of formant trajectories. A discriminant analysis was employed to illustrate the extent to which Chinese EFL learners relied on different acoustic parameters. This study found that: (1) Chinese EFL learners overemphasized durational differences and weakened spectral differences for the /i-ɪ/, /u-Ê/, and /É-Ê/ pairs, although they maintained sufficient spectral differences for /æ-ε/. In contrast, native English speakers predominantly used spectral differences across all four pairs; (2) in non-low tense-lax contrasts, unlike native English speakers, Chinese EFL learners failed to exhibit different F1 slope values, indicating a non-nativelike tongue-root placement during the articulatory process. The findings underscore the contribution of dynamic spectral patterns to the differentiation between English tense and lax vowels, and reveal the influence of precise articulatory gestures on the realization of the tense-lax contrast.
Multilingualism , Phonetics , Speech Acoustics , Humans , Male , Female , Young Adult , Speech Production Measurement , Adult , Language , Acoustics , Learning , Voice Quality , Sound Spectrography , East Asian People
Far-red cyanobacteriochromes (CBCRs) are bilin-based photosensory proteins that promise to be novel optical agents in optogenetics and deep tissue imaging. Recent structural studies of a far-red CBCR 2551g3 have revealed a unique all-Z,syn chromophore conformation in the far-red-absorbing Pfr state. Understanding the photoswitching mechanism through bilin photoisomerization is important for developing novel biomedical applications. Here, we employ femtosecond spectroscopy and site-directed mutagenesis to systematically characterize the dynamics of wild-type 2551g3 and four critical mutants in the 15Z Pfr state. We captured local relaxations in several picoseconds and isomerization dynamics in hundreds of picoseconds. Most mutants exhibited faster local relaxation, while their twisting dynamics and photoproducts depend on specific protein-chromophore interactions around the D-ring and C-ring. These results collectively reveal a unique dynamic pattern of excited-state evolution arising from a relatively rigid protein environment, thereby elucidating the molecular mechanism of Pfr-state photoisomerization in far-red CBCRs.
1,2-Dichloroethane (1,2-DCA), a widely utilized chemical intermediate and organic solvent in industry, frequently enters the environment due to accidental leaks and mishandling during application processes. Thus, the in-situ remediation of contaminated sites has become increasingly urgent. However, traditional remediation methods are inefficient and costly, while bioremediation presents a green, efficient, and non-secondary polluting alternative. In this study, an engineered strain capable of completely degrading 1,2-DCA was constructed. We introduced six exogenous genes of the 1,2-DCA degradation pathway into E. coli and confirmed their normal transcription and efficient expression in this engineered strain through qRT-PCR and proteomics. The degradation experiments showed that the strain completely degraded 2 mM 1,2-DCA within 12 h. Furthermore, the results of isotope tracing verified that the final degradation product, malic acid, entered the tricarboxylic acid cycle (TCA) of E. coli and was ultimately fully metabolized. Also, morphological changes in the engineered strain and control strain exposed to 1,2-DCA were observed under SEM, and the results revealed that the engineered strain is more tolerant to 1,2-DCA than the control strain. In conclusion, this study paved a new way for humanity to deal with the increasingly complex environmental challenges.
Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.
Extracellular Vesicles , Macrophage Activation , Macrophages , Neoplasms , Humans , Extracellular Vesicles/immunology , Extracellular Vesicles/metabolism , Macrophages/immunology , Macrophages/metabolism , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/pathology , Neoplasms/metabolism , Animals , Macrophage Activation/immunology , Tumor Microenvironment/immunology , Cell Communication/immunology , Cytokines/metabolism
The present 21-day daily diary study (conducted 2021-2022) tested anger and racism-related vigilance as potential transdiagnostic mediators linking exposure to racial and ethnic discrimination (RED) to distress (negative affect and stress, respectively). The data analytic sample included N = 317 Mexican-origin adolescents (Mage = 13.5 years; 50.8% male, 46.7% female; 2.5% non-binary) from the Midwestern United States. Results from longitudinal mediation models revealed significant mediation effects through anger and racism-related vigilance, respectively, in the association between daily RED and daily distress, both within and across adolescents. Implications for theory, research, and practice are discussed so that future work can leverage these novel findings toward promoting the well-being of Mexican-origin adolescents, especially those who live in contexts of ethnoracial adversity.
Sarcopenia is a systemic skeletal muscle disease that is more prevalent in older adults. The role of exercise in improving the disease has been demonstrated. However, due to the variety of exercise modalities, it is not clear what type of exercise provides the best benefit. The aim of this meta-analysis was to analyze the effects of different exercise modalities on grip strength, appendicular skeletal muscle index, skeletal muscle index, and knee extensor strength in elderly patients with sarcopenia. The protocol for this evaluation was registered on the PROSPERO website and the databases PubMed, WOS, Cochrane Library, and Embase were searched. Thirteen studies were included in the analysis. The results showed that exercise interventions had positive effects on grip strength and knee extension muscle strength, with resistance training being the most effective. There was no significant improvement in appendicular skeletal muscle index or skeletal muscle index. This study still has limitations. For example, age group and exercise duration were not considered. Future studies should further explore benefits in age groups as well as other relevant outcome indicators.
In this work, magnetic molecularly imprinted polymers (MIPs) for specific recognition of Hydroxytyrosol (HT) were designed by vinyl-modified magnetic particles (Fe3O4@SiO2@VTEOs) as carrier, ternary deep eutectic solvent (DES) as functional monomer, while ethylene glycol dimethacrylate (EGDMA) as crosslinker. The optimum amount of DES was obtained by adsorption experiments (molar ratio, caffeic acid: choline chloride: formic acid = 1:6:3) which were 140 µL in total. Under the optimized amount of DES, the maximum adsorption capacity of the MIPs particles was 42.43 mg g-1, which was superior to non-imprinted polymer (4.64 mg g-1) and the imprinting factor (IF) is 9.10. Syringin and Oleuropicrin were used as two reference molecules to test the selectivity of the DES-MIPs particles. The adsorption capacity of HT was 40.11 mg g-1. Three repeated experiments show that the polymer has high stability and repeatability (RSD = 5.50).
Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.
B7-H1 Antigen , Neoplasms , Humans , B7-H1 Antigen/metabolism , Programmed Cell Death 1 Receptor/metabolism , Proteolysis Targeting Chimera , Neoplasms/drug therapy , Immunotherapy
BACKGROUND: We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC. METHODS: Metabolite quantitative trait loci were derived from two published metabolomics genome-wide association studies (GWASs), and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (100,204 cases; 154,587 controls) and the FinnGen cohort (4,957 cases; 304,197 controls). Mendelian randomization (MR) and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable MR and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC. RESULTS: The study identified 30 plasma metabolites and four urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, Olipudase alfa, Tilactase). Thirteen modifiable risk factors were associated with nine metabolites and eight of these modifiable risk factors were associated with CRC risk. These nine metabolites mediated the effect of modifiable risk factors (Actinobacteria, BMI, waist-hip ratio, fasting insulin, smoking initiation) on CRC. CONCLUSION: This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.
Geological bodies are important sources of greenhouse gas (GHG) emissions. Organic-rich oil shale in sedimentary basins is a good gas source rock, the GHG in which will be released into the atmosphere during crushing to affect climate change. Quantitative calculations of GHG emissions during oil shale crushing were carried out on oil shales from the Yaojie (YJ) and Fushun (FS) mining areas in China. Organic geochemistry, X-ray diffraction, and pore structure analysis experiments, as well as the relationship between storage time and GHG emissions, were analyzed to investigate the main controlling factors of GHG release in different types of oil shales. The results showed that the CH4 and CO2 released from the YJ oil shale were 0.002-0.145 mL/g and 0.011-0.054 mL/g, respectively; the CH4 and CO2 released from the FS oil shale were 0.0001-0.0008 mL/g and 0.002-0.045 mL/g, respectively. Residual CH4 release was closely related to total organic carbon (TOC) and maturity: the CH4 released from the organic-rich and mature YJ oil shale was much higher than that of the FS oil shale, which is relatively organic-lean and immature. The control factors of the released CO2 vary in different regions: CO2 released from the YJ oil shale was somewhat affected by the TOC, while that released from the FS oil shale was mainly controlled by carbonate minerals and their contributing pores. The results of pore structure and organic maceral analyses indicated that both organic and inorganic pores of the YJ oil shale are occupied by asphaltenes, forming a key gas preservation mechanism of residual CH4 and CO2 as solutes dissolved in asphaltenes. In addition, CO2 has a greater absorptive capacity than CH4 and is therefore more difficult to release during the same crushing time. As oil shale is stored for longer periods, residual CH4 will be preferentially released to the atmosphere, while residual CO2 will be released in large quantities during crushing.
Objective: It aimed to investigate the difference in clinical efficacy between posterior cervical endoscopic discectomy (PCED) and Fenestration laminectomy discectomy (FLD) in cervical disc herniation (CDH). Methods: This retrospective study analyzed 100 CDH patients undergoing nucleotomy and assigned them into the FLD and PCED groups, 50 cases for each group. The differences in operation time, intraoperative blood loss, skin incision, off-bed time, and hospital stay were evaluated. Numeric rating scales (NRS), Oswestry disability Index (ODI), Japanese Orthopaedic Association (JOA), excellent and good clinical efficacy, quality of life (QoL) SF-36 score, and complication rate were compared. Results: The results showed that compared with the FLD group, the PCED group had increased operation time, decreased intraoperative blood loss, skin incision length, off-bed time, and hospital stay (P < .01). Compared with the FLD group, the PCED group had decreased NRS and ODI scores and increased JOA scores at 1 d, 3 d, 1 month, 3 months, 6 months, 12 months, and 24 months after operation (P < .05). Compared with the FLD group, the excellent and good rate of the PCED group increased significantly after 6 months, 1 year, and 2 years (52.0% vs 64.0%, 58.0% vs. 80.0%, 68.0% vs 90.0%, P < .05). Relative to the FLD group, the physical function, emotional function, vitality, social function, and mental health score of the PCED group increased obviously at 2 years after operation (P < .01). The postoperative complication rate was 0% in both FLD and PCED groups. PCED has good long-term clinical efficacy in the treatment of CDH, with excellent recovery and high safety. Conclusion: PCED showed favorable long-term clinical efficacy in the treatment of CDH, with excellent recovery and high safety. Compared to FLD, PCED resulted in reduced intraoperative blood loss, shorter incision length, and faster recovery. It also led to improved pain scores, functional outcomes, and quality of life measures. The absence of postoperative complications further supports the use of PCED as an effective treatment option for CDH.
OBJECTIVE: To investigate the associations across genetic and lifestyle factors with lifespan. DESIGN: A longitudinal cohort study. SETTING: UK Biobank. PARTICIPANTS: 353 742 adults of European ancestry, who were recruited from 2006 to 2010 and were followed up until 2021. EXPOSURES: A polygenic risk score for lifespan with long (
The use of edible packaging films to delay food spoilage has attracted widespread attention. In this study, partridge tea extract (PTE) was added to cassia gum (CG) to prepare CG/PTE films. The microstructure, optical, mechanical, barrier, and antioxidant properties of CG/PTE films were investigated, and the effect of PTE on CG films was shown. The films had high transparency and smooth surface structure. Additionally, PTE significantly improved the elongation at break and antioxidant activity of films. At 2.5% of PTE, the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging rate of the film was 46.88% after diluting 50 times, indicating excellent antioxidant property, which could be applied to food preservation. After 9 days of storage, the thiobarbituric acid reactive substances values (TBARS) of chicken jerk packaged with films containing 0% and 2.5% PTE increased from 0.12% to 1.04% and 0.11% to 0.40%, respectively. This study suggests that CG/PTE films can be used to preserve cooked meat.
L-Cysteine and L-methionine, as the only two sulfur-containing amino acids among the canonical 20 amino acids, possess distinct characteristics and find wide-ranging industrial applications. The use of different organisms for fermentative production of L-cysteine and L-methionine is gaining increasing attention, with Escherichia coli being extensively studied as the preferred strain. This preference is due to its ability to grow rapidly in cost-effective media, its robustness for industrial processes, the well-characterized metabolism, and the availability of molecular tools for genetic engineering. This review focuses on the genetic and molecular mechanisms involved in the production of these sulfur-containing amino acids in E. coli. Additionally, we systematically summarize the metabolic engineering strategies employed to enhance their production, including the identification of new targets, modulation of metabolic fluxes, modification of transport systems, dynamic regulation strategies, and optimization of fermentation conditions. The strategies and design principles discussed in this review hold the potential to facilitate the development of strain and process engineering for direct fermentation of sulfur-containing amino acids.
Triple-negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer. Despite the recognized interplay between tumors and tumor-associated macrophages in fostering drug resistance and disease progression, the precise mechanisms leading these interactions remain elusive. Our study revealed that the upregulation of collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, was closely linked to an unfavorable prognosis. Functional assays unequivocally demonstrated that COL5A1 played a pivotal role in fueling cancer growth, metastasis, and resistance to doxorubicin, both in vitro and in vivo. Furthermore, we found that the cytokine IL-6, produced by COL5A1-overexpressing TNBC cells actively promoted M2 macrophage polarization. In turn, TGFß from M2 macrophages drived TNBC doxorubicin resistance through the TGFß/Smad3/COL5A1 signaling pathway, establishing a feedback loop between TNBC cells and macrophages. Mechanistically, COL5A1 interacted with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation, thereby enhancing chemoresistance and increasing IL-6 secretion. In summary, our findings underscored the significant contribution of COL5A1 upregulation to TNBC progression and chemoresistance, highlighting its potential as a diagnostic and therapeutic biomarker for TNBC.
Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.
The current study evaluated cultural values and family processes that may moderate associations between daily racial-ethnic discrimination and distress among Mexican-origin youth. Integrating micro-time (daily diary) and macro-time (longitudinal survey) research design features, we examined familism, family cohesion, and ethnic-racial socialization from youth-, mother-, and father- reports as potential buffers of daily associations between youth racial-ethnic discrimination and youth distress (negative affect and anger). The analytic sample, drawn from the Seguimos Avanzando study, included 317 Mexican-origin adolescents (Mage = 13.5 years) and their parents, recruited from the Midwestern United States. Results indicated that youth-reported familism and family cohesion significantly buffered daily associations between youth racial-ethnic discrimination and youth distress. In contrast, parent-reported familism and family cohesion and some aspects of ethnic-racial socialization exacerbated the discrimination to distress link. The implications of these results are discussed to inform efforts supporting the healthy development of Mexican-origin youth and their families.
BACKGROUND: This study aims to investigate the impact of age and sex on high-sensitivity cardiac troponin T (hs-cTnT) and establish 99th percentile upper reference limits (URLs) in older individuals utilizing large-scale real-world data. METHODS: 40,530 outpatient hs-cTnT results were obtained from the laboratory database from January 1, 2018, to December 31, 2023. Our study included 4,199 elderly outpatients (aged ≥ 60) without cardiovascular disease or other heart-related chronic conditions. Nested analysis of variance was used to explore the necessity of partitioning reference intervals (RIs) by sex and age groups. RIs were established by the refineR algorithm and assessed based on ≤ 10% test results of validation data set outside the new RIs. RESULTS: RIs for hs-cTnT in the older population needed to be partitioned by sex and age groups ([standard deviation ratio] SDRage = 0.75; SDRsex = 0.49). URLs in older Chinese adults were 21.8 ng/L for males, 16.5 ng/L for females, and 20.7 ng/L for the overall participant group. URLs for males aged 60-69, 70-79, and ≥ 80 were 13.7, 19.4, and 31.0 ng/L, respectively. Female values were 10.1, 17.2, and 22.0 ng/L. Importantly, manufacturer-reported RIs do not suffice for Chinese individuals aged ≥ 70. Validation data showed that 2.7-5.2% of test results fell outside the new RIs, confirming the validity of the results. CONCLUSION: This study establishes age- and sex-specific 99th percentile URLs for hs-cTnT in Chinese older individuals, thereby enhancing the accuracy of clinical assessments.
Data Mining , Troponin T , Humans , Troponin T/blood , Female , Male , Aged , Aged, 80 and over , Middle Aged , Reference Values , Sex Factors , Data Mining/methods , China , Age Factors , Asian People , East Asian People
