[Hypothetical Alcohol Consumption Interventions and Hepatic Steatosis: A Longitudinal Study in a Large Cohort]. / æ¨¡æ‹Ÿé¥®é ’å¹²é¢„ä¸Žè‚è„‚è‚ªå˜æ€§ï¼šä¸€é¡¹å¤§åž‹é˜Ÿåˆ—çš„çºµå‘ç ”ç©¶.

Objective: Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (ALD) are the most common chronic liver diseases. Hepatic steatosis is an early histological subtype of both NAFLD and ALD. Excessive alcohol consumption is widely known to lead to hepatic steatosis and subsequent liver damage. However, reported findings concerning the association between moderate alcohol consumption and hepatic steatosis remain inconsistent. Notably, alcohol consumption as a modifiable lifestyle behavior is likely to change over time, but most previous studies covered alcohol intake only once at baseline. These inconsistent findings from existing studies do not inform decision-making concerning policies and clinical guidelines, which are of greater interest to health policymakers and clinician-scientists. Additionally, recommendations on the types of alcoholic beverages are not available. Usually, assessing the effects of two or more hypothetical alcohol consumption interventions on hepatic steatosis provides answers to questions concerning the population risk of hepatic steatosis if everyone changes from heavy drinking to abstinence, or if everyone keeps on drinking moderately, or if everyone of the drinking population switches from red wine to beer? Thus, we simulated a target trial to estimate the effects of several hypothetical interventions, including changes in the amount of alcohol consumption or the types of alcoholic beverages consumed, on hepatic steatosis using longitudinal data, to inform decisions about alcohol-related policymaking and clinical care. Methods: This longitudinal study included 12687 participants from the UK Biobank (UKB), all of whom participated in both baseline and repeat surveys. We excluded participants with missing data related to components of alcohol consumption and fatty liver index (FLI) in the baseline and the repeat surveys, as well as those who had reported liver diseases or cancer at the baseline survey. We used FLI as an outcome indicator and divided the participants into non-, moderate, and heavy drinkers. The surrogate marker FLI has been endorsed by many international organizations' guidelines, such as the European Association for the Study of the Liver. The calculation of FLI was based on laboratory and anthropometric data, including triglyceride, gamma-glutamyl transferase, body mass index, and waist circumference. Participants responded to questions about the types of alcoholic beverages, which were defined in 5 categories, including red wine, white wine/fortified wine/champagne, beer or cider, spirits, and mixed liqueurs, along with the average weekly or monthly amounts of alcohol consumed. Alcohol consumption was defined as pure alcohol consumed per week and was calculated according to the amount of alcoholic beverages consumed per week and the average ethanol content by volume in each alcoholic beverage. Participants were categorized as non-drinkers, moderate drinkers, and heavy drinkers according to the amount of their alcohol consumption. Moderate drinking was defined as consuming no more than 210 g of alcohol per week for men and 140 g of alcohol per week for women. We defined the following hypothetical interventions for the amount of alcohol consumed: sustaining a certain level of alcohol consumption from baseline to the repeat survey (e.g., none to none, moderate to moderate, heavy to heavy) and changing from one alcohol consumption level to another (e.g., none to moderate, moderate to heavy). The hypothetical interventions for the types of alcoholic beverages were defined in a similar way to those for the amount of alcohol consumed (e.g., red wine to red wine, red wine to beer/cider). We applied the parametric g-formula to estimate the effect of each hypothetical alcohol consumption intervention on the FLI. To implement the parametric g-formula, we first modeled the probability of time-varying confounders and FLI conditional on covariates. We then used these conditional probabilities to estimate the FLI value if the alcohol consumption level of each participant was under a specific hypothetical intervention. The confidence interval was obtained by 200 bootstrap samples. Results: For the alcohol consumption from baseline to the repeat surveys, 6.65% of the participants were sustained non-drinkers, 63.68% were sustained moderate drinkers, and 14.74% were sustained heavy drinkers, while 8.39% changed from heavy drinking to moderate drinking. Regarding the types of alcoholic beverages from baseline to the repeat surveys, 27.06% of the drinkers sustained their intake of red wine. Whatever the baseline alcohol consumption level, the hypothetical interventions for increasing alcohol consumption from the baseline alcohol consumption were associated with a higher FLI than that of the sustained baseline alcohol consumption level. When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to moderate drinking, the mean ratio of FLI was 1.027 (95% confidence interval [CI]: 0.997-1.057). When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to heavy drinking, the mean ratio of FLI was 1.075 (95% CI: 1.042-1.108). When comparing sustained heavy drinking with the hypothetical intervention of changing from heavy drinking to moderate drinking, the mean ratio of FLI was 0.953 (95% CI: 0.938-0.968). The hypothetical intervention of changing to red wine in the UKB was associated with lower FLI levels, compared with sustained consumption of other types of alcoholic beverages. For example, when comparing sustaining spirits with the hypothetical intervention of changing from spirits to red wine, the mean ratio of FLI was 0.981 (95% CI: 0.948-1.014). Conclusions: Regardless of the current level of alcohol consumption, interventions that increase alcohol consumption could raise the risk of hepatic steatosis in Western populations. The findings of this study could inform the formulation of future practice guidelines and health policies. If quitting drinking is challenging, red wine may be a better option than other types of alcoholic beverages in Western populations.

Nitro-functionalization on MIL-53(Fe) for PCMX degradation: Elevating Fenton-like catalytic propelled by abundant reaction sites and iron cycle.

To address the issue of excessive residues of 4-chloro-3,5-dimethylphenol (PCMX) in the water environment. In a one-step solvothermal process, iron-based metal-organic frameworks (Fe-MOFs) material MIL-53(Fe) undergoes a synthetic modification strategy. 2-Nitroterephthalic acid as an organic ligand reacted with Fe3+ in a solvothermal process lasting 18 h to yield the nitro-functionalized MIL-53(Fe)-NO2(18h). The objective was to augment the abundance of Fe central unsaturated coordination sites (Fe CUCs) and expedite the Fe(III)/Fe(II) redox cycle, thereby enhancing the heterogeneous Fenton-like treatment capability of pollutants. MIL-53(Fe)-NO2(18h) has excellent hydrogen peroxide (H2O2) catalytic activity and PCMX degradation across a broad pH spectrum (4.0∼8.0). Almost complete removal of PCMX was achieved within 30 min, while pseudo-first-order kinetic rate constants (kobs) increased 4.37 times over MIL-53(Fe). The confirmation of increased Fe CUCs abundance in MIL-53(Fe)-NO2(18h) was achieved through Lewis acidity, oxygen vacancies (OVs) signals, and Fe-O coordination characterization results. Density functional theory (DFT) calculations revealed that Fe CUCs in MIL-53(Fe)-NO2(18h) exhibits heightened affinity for H2O2 adsorption, showcasing stronger charge transfer and enhanced H2O2 dissociation ability. The Fe(III)/Fe(II) redox cycle, a driving force of Fenton-like reactions, was notably improved in the nitro-modified materials. These enhancements significantly expedited the Fenton-like process, resulting in the generation of increased amounts of reactive oxygen species (ROSs), with hydroxyl radicals (OH·) being pivotal components in degradation. The MIL-53(Fe)-NO2(18h)/H2O2 system has demonstrated versatility in treating a variety of emerging contaminants, achieving removal efficiencies exceeding 99.7% for other antibiotics and endocrine disruptors within 60 min. Furthermore, MIL-53(Fe)-NO2(18h) demonstrated outstanding reusability and adaptability in actual water environments. This study introduces a straightforward and environmentally friendly strategy for remediating environmental pollution using Fe-MOF-catalysed heterogeneous Fenton-like technology.

Brainstem Gliomas With Isocitrate Dehydrogenase Mutation: Natural History, Clinical-Radiological Features, Management Strategy, and Long-Term Outcome.

BACKGROUND AND OBJECTIVES: This study aimed to investigate the clinical, radiological, pathological features, treatment options, and outcomes of isocitrate dehydrogenase (IDH)-mutant brainstem gliomas (BSG-IDHmut). METHODS: A retrospective analysis of 22 patients diagnosed with BSG-IDHmut and treated at our institution from January 2011 to January 2017 was performed. Their clinical, radiological data, and long-term outcomes were collected and analyzed. RESULTS: The median age of patients was 38.5 years, with a male predominance (63.6%). All patients had IDH1 and TP53 mutations, with noncanonical IDH mutations in 59.1% of cases, 06-methylguanine-DNA methyltransferase promoter methylation in 55.6%, and alpha-thalassemia mental retardation X-linked loss in 63.2%, respectively. Tumors were primarily located in the pontine-medullary oblongata (54.5%) and frequently involved the pontine brachium (50%). Most tumors exhibited ill-defined boundaries (68.2%), no T2-FLAIR mismatch (100%), and no contrast enhancement (86.3%). Two radiological growth patterns were also identified: focal and extensively infiltrative, which were associated with the treatment strategy when tumor recurred. Seven patients (31.8%) received surgery only and 15 (68.2%) surgery plus other therapy. The median overall survival was 124.8 months, with 1-year, 2-year, 5-year, and 10-year survival rates of 81.8%, 68.2%, 54.5%, and 13.6%, respectively. Six patients experienced tumor recurrence, and all retained their radiological growth patterns, with 2 transformed into central nervous system World Health Organization grade 4. CONCLUSION: BSG-IDHmut represents a unique subgroup of brainstem gliomas with distinctive features and more favorable prognosis compared with other brainstem gliomas. Further research is required to better understand the molecular mechanisms and optimize treatment strategies for this rare and complex disease.

Temporal relationship between hepatic steatosis and blood pressure elevation and the mediation effect in the development of cardiovascular disease.

The temporal relationship between non-alcoholic fatty liver disease (NAFLD) and hypertension remains highly controversial, with ongoing debates on whether NAFLD induces hypertension or vice versa. We employed cross-lagged panel models to investigate the temporal relationship between hepatic steatosis (assessed by Fatty Liver Index [FLI] in the main analysis, and by Proton Density Fat Fraction [PDFF] in the validation study) and blood pressure (systolic and diastolic blood pressure [SBP/ DBP]). Subsequently, we employed causal mediation models to explore the mediation effect in CVD development, including ischemic heart disease and stroke. The main analysis incorporated repeated measurement data of 5,047 participants from the China Multi-Ethnic Cohort (CMEC) and 5,685 participants from the UK Biobank (UKB). In both cohorts, the path coefficients from FLI to blood pressure were significant and greater than the path from blood pressure to FLI, with ßFLI→SBP = 0.081, P < 0.001 versus ßSBP→FLI = 0.020, P = 0.031; ßFLI→DBP = 0.082, P < 0.001 versus ßDBP→FLI = -0.006, P = 0.480 for CEMC, and ßFLI→SBP = 0.057, P < 0.001 versus ßSBP→FLI = -0.001, P = 0.727; ßFLI→DBP = 0.061, P < 0.001, versus ßDBP→FLI = -0.006, P = 0.263 for UKB. The validation study with 962 UKB participants using PDFF consistently supported these findings. In the mediation analyses encompassing 11,108 UKB participants, SBP and DBP mediated 12.2% and 5.2% of the hepatic steatosis-CVD association, respectively. The proportions were lower for ischemic heart disease (SBP: 6.1%, DBP: non-statistically significant -6.8%), and relatively stronger for stroke (SBP: 19.4%, DBP: 26.1%). In conclusion, hepatic steatosis more strongly contributes to elevated blood pressure than vice versa. Blood pressure elevation positively mediates the hepatic steatosis-CVD association, particularly in stroke compared to ischemic heart disease.

The Trends of Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Systemic Immunoinflammatory Index in Patients with Intracerebral Hemorrhage and Clinical Value in Predicting Pneumonia 30 Days After Surgery.

BACKGROUND: Inflammatory response is closely associated with secondary brain injury and pneumonia in intracerebral hemorrhage (ICH). In this study, we aimed to investigate the value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immunoinflammatory index (SII) in the development of pneumonia in ICH patients 30 days after surgery. METHODS: We retrospectively collected clinical data on patients with ICH who underwent surgical treatment at our institution from January 2016 to December 2022, mainly including NLR, PLR, and SII at different time points. Receiver operating characteristic curves were used to compare the value of different inflammatory indicators in predicting the development of postoperative pneumonia 30 days after surgery in ICH patients, and multivariate logistic regression analyses were used to identify independent risk factors for pneumonia 30 days after surgery. RESULTS: Among 112 patients with ICH undergoing surgical treatment, 31 (27.7%) developed pneumonia postoperatively. The results of the univariate analysis demonstrated that patients in the pneumonia group experienced significantly higher blood glucose, NLR at 72 hours postoperatively, PLR at 72 hours postoperatively, and SII at 72 hours postoperatively (SII3) than those in the nonpneumonia group, and significantly lower admission Glasgow Coma Scale scores than those in the nonpneumonia group (all P < 0.05). NLR, PLR, and SII showed increasing and then decreasing in the disease process of ICH and peaked at 48 hours postoperatively. Multivariable logistic regression analysis revealed that SII3 was an independent risk factor for postoperative pneumonia 30 days after surgery in ICH patients (odds ratio = 1.001, 95% confidence interval: 1.000-1.002, P = 0.008). The area under the curve of the developed nomogram model was 0.895 (95% confidence interval = 0.823-0.967), with a sensitivity and specificity of 0.903 and 0.815, respectively, providing good predictive power. CONCLUSIONS: In the course of ICH, NLR, PLR, and SII increased and then decreased and peaked at 48 hours postoperatively. The SII3 was the best predictor of the occurrence of pneumonia postoperatively in ICH patients.

The Insular Cortex: An Interface Between Sensation, Emotion and Cognition.

The insula is a complex brain region central to the orchestration of taste perception, interoception, emotion, and decision-making. Recent research has shed light on the intricate connections between the insula and other brain regions, revealing the crucial role of this area in integrating sensory, emotional, and cognitive information. The unique anatomical position and extensive connectivity allow the insula to serve as a critical hub in the functional network of the brain. We summarize its role in interoceptive and exteroceptive sensory processing, illustrating insular function as a bridge connecting internal and external experiences. Drawing on recent research, we delineate the insular involvement in emotional processes, highlighting its implications in psychiatric conditions, such as anxiety, depression, and addiction. We further discuss the insular contributions to cognition, focusing on its significant roles in time perception and decision-making. Collectively, the evidence underscores the insular function as a dynamic interface that synthesizes diverse inputs into coherent subjective experiences and decision-making processes. Through this review, we hope to highlight the importance of the insula as an interface between sensation, emotion, and cognition, and to inspire further research into this fascinating brain region.

[Alcohol Abstinence and Accelerated Biological Aging Among Middle-Aged and Older Adults: Evidence From the UK Biobank]. / ä¸­è€å¹´ç¾¤ä½“é ’ç²¾æˆ’æ–­ä¸Žç”Ÿç‰©è¡°è€åŠ é€Ÿçš„å ³ç³»ï¼šåŸºäºŽè‹±å›½ç”Ÿç‰©é“¶è¡Œæ•°æ®åº“çš„ç ”ç©¶.

Objective: To investigate the longitudinal association between alcohol abstinence and accelerated biological aging among middle-aged and older adults and to explore the potential effect modifiers influencing the association. Methods: Utilizing the clinico-biochemical and anthropometric data from the baseline and first repeat survey of the UK Biobank (UKB), we employed the Klemera and Doubal method (KDM) to construct the biological age (BA) and calculate BA acceleration. Change analysis based on multivariate linear regression models was employed to explore the association between changes in alcohol abstinence and changes in BA acceleration. Age, sex, smoking status, tea and coffee consumption, and body mass index were considered as the stratification factors for conducting stratified analysis. Results: A total of 5 412 participants were included. Short-term alcohol abstinence (ß=1.00, 95% confidence interval [CI]: 0.15-1.86) was found to accelerate biological aging when compared to consistent never drinking, while long-term abstinence (ß=-0.20, 95% CI: -1.12-0.71) did not result in a significant acceleration of biological aging. Body mass index may be a potential effect modifier. Conclusion: Short-term alcohol abstinence was associated with accelerated biological aging, but the effect gradually diminishes over extended periods of abstinence.

Development of a nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis.

In this study, we aimed to investigate the risk factors associated with in-hospital mortality in patients with cirrhosis and sepsis, establish and validate the nomogram. This retrospective study included patients diagnosed with liver cirrhosis and sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV). Models were compared by the area under the curve (AUC), integrated discriminant improvement (IDI), net reclassification index (NRI) and decision curve analysis (DCA). A total of 1,696 patients with cirrhosis and sepsis were included in the final cohort. Our final model included the following 9 variables: age, heartrate, total bilirubin (TBIL), glucose, sodium, anion gap (AG), fungal infections, mechanical ventilation, and vasopressin. The nomogram were constructed based on these variables. The AUC values of the nomograms were 0.805 (95% CI 0.776-0.833), which provided significantly higher discrimination compared to that of SOFA score [0.684 (95% CI 0.647-0.720)], MELD-Na [0.672 (95% CI 0.636-0.709)] and ABIC [0.674(95% CI 0.638-0.710)]. We established the first nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis based on these factors. This nomogram can performs well and facilitates clinicians to identify people at high risk of in-hospital mortality.

Alcohol consumption and accelerated biological ageing in middle-aged and older people: A longitudinal study from two cohorts.

BACKGROUND AND AIMS: The relationship between alcohol consumption and age-related diseases is inconsistent. Biological age (BA) serves as both a precursor and a predictor of age-related diseases; however, longitudinal associations between alcohol consumption and BA in middle-aged and older people remain unclear. We measured whether there was a longitudinal association between drinking frequency and pure alcohol intake with BA among middle-aged and older people. DESIGN AND SETTING AND PARTICIPANTS: This study involved two prospective cohort studies, set in Southwestern China and the United Kingdom. A total of 8046 participants from the China Multi-Ethnic Cohort study (CMEC) and 5412 participants from the UK Biobank (UKB), aged 30-79 years, took part, with complete data from two waves of clinical biomarkers. MEASUREMENTS: BA was calculated by the Klemera Doubal's method. Accelerated BA equalled BA minus chronological age. Drinking frequency and pure alcohol intake were obtained through self-reported questionnaires. Drinking frequency in the past year was classified as current non-drinking, occasional (monthly drinking) and regular (weekly drinking). FINDINGS: Compared with consistent current non-drinkers, more frequent drinkers [CMEC: ß = 0.46, 95% confidence interval (CI) = 0.13-0.80; UKB: ß = 0.65, 95% CI = 0.01-1.29)], less frequent drinkers (CMEC: ß = 0.62, 95% CI = 0.37-0.87; UKB: ß = 0.54, 95% CI = -0.01-1.09), consistent occasional drinkers (CMEC: ß = 0.51, 95% CI = 0.23-0.79; UKB: ß = 0.63, 95% CI = 0.13-1.13) and consistent regular drinkers (CMEC: ß = 0.56, 95% CI = 0.17-0.95; UKB: ß = 0.46, 95% CI = 0.00-0.91) exhibited increased accelerated BA. A non-linear relationship between pure alcohol intake and accelerated BA was observed among consistent regular drinkers. CONCLUSIONS: In middle-aged and older people, any change in drinking frequency and any amount of pure alcohol intake seem to be positively associated with acceleration of biological ageing, compared with maintaining abstinence.

Impact of immune checkpoint inhibitors (ICIs) therapy on interferon-γ release assay (IGRA) and diagnostic value in non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Tuberculosis (TB), a highly contagious respiratory disease, presents a significant global health threat, with a notable increase in incidence reported by the WHO in 2022. Particularly, the interplay between TB and non-small cell lung cancer (NSCLC) gains attention, especially considering the rising use of immune checkpoint inhibitors (ICIs) in cancer treatment. This interplay may influence TB diagnostics and reactivation, warranting a closer examination. METHODS: A retrospective analysis was conducted on clinical data of NSCLC patients with positive T-SPOT results before undergoing anti-tumor treatment at Zhongshan Hospital (Xiamen), Fudan University, from January 1, 2021 to December 31, 2022. We assessed the incidence of tuberculosis reactivation and treatment outcomes among these patients. Moreover, we compared the differences in tuberculosis activity between the ICIs and non-ICIs treatment groups. Additionally, we observed the changes in T-SPOT spot count before and after immunotherapy, analyzing their association with tuberculosis activity and prognosis. RESULTS: A total of 40 NSCLC patients with positive T-SPOT results before treatment were included in the study, with 26 patients in the ICIs treatment group and 14 patients in the non-ICIs treatment group. The study found no significant differences between the two groups in terms of gender, age, stage, histological type, performance status, driver gene expression, and distant metastasis. With a median follow-up time of 10.0 (6.0-14.5) months, three cases (11.5%) in the ICIs treatment group developed tuberculosis activity, diagnosed at 2, 3, and 12 months after ICIs treatment initiation. Conversely, no tuberculosis activity was observed in the non-ICIs treatment group, and the difference between the two groups was not significant (P = 0.186). Among the 32 patients who received ICIs treatment, spot count dynamics were diverse: four cases (12.5%) showed an increase, 12 cases (37.5%) had no change, and 16 cases (50.0%) had a decrease. During the follow-up, the progression rate (PD) was 50.0%, 75.0%, and 62.5% in the three groups, respectively (P = 0.527). Similarly, the mortality rate was 0%, 25.0%, and 25.0%, respectively (P = 0.106). Interestingly, among the patients with decreased spot counts, three cases (18.75%) were diagnosed with active pulmonary tuberculosis. CONCLUSIONS: For NSCLC patients with a positive T-SPOT response undergoing ICIs treatment, our study observed indications of active tuberculosis. The varied T-SPOT spot count changes post-ICIs treatment suggest a complex interaction, potentially linking T-SPOT spot count reduction to tuberculosis reactivation risk. These preliminary findings underscore the importance of further research to more accurately assess T-SPOT's diagnostic utility in this context.

High Glucose Is a Stimulation Signal of the Salt-Tolerant Yeast Zygosaccharomyces rouxii on Thermoadaptive Growth.

The salt-tolerant yeast Zygosaccharomyces rouxii is a typical aroma-producing yeast used in food brewing, but its mechanism of high temperature tolerance is still unclear. In this study, the response mechanism of Z. rouxii to glucose under high temperature stress at 40 °C was explored, based on the total synthetic lowest-nutrient medium. The results of the growth curves and scanning electron microscopy showed that high glucose was necessary for Z. rouxii to restore growth under high temperature stress, with the biomass at 300 g/L of glucose (OD600, 120h = 2.44 ± 0.26) being 8.71 times higher than that at 20 g/L (OD600, 120h = 0.28 ± 0.08). The results of the transcriptome analysis, combined with RT-qPCR, showed that the KEGG analysis of differentially expressed genes was enriched in pathways related to glucose metabolism, and high glucose (300 g/L) could effectively stimulate the gene expression of glucose transporters, trehalose synthesis pathways, and xylitol synthesis pathways under a high temperature, especially the expression of the glucose receptor gene RGT2 (up-regulated 193.7 times at 12 h). The corresponding metabolic characteristics showed that the contents of intracellular metabolites, such as glucose (Cmax, 6h = 6.50 ± 0.12 mg/g DCW), trehalose (Cmax, 8h = 369.00 ± 17.82 µg/g DCW), xylitol (Cmax, 8h = 1.79 ± 0.27 mg/g DCW), and glycerol (Cmax, 8h = 268.10 ± 44.49 µg/g DCW), also increased with time. The accumulation of acetic acid, as the main product of overflow metabolism under high temperature stress (intracellular Cmax, 2h = 126.30 ± 10.96 µg/g DCW; extracellular Cmax, 12h = 499.63 ± 27.16 mg/L), indicated that the downstream glycolysis pathway was active. Compared with the normal physiological concentration of glucose, a high glucose concentration can effectively stimulate the gene expression and metabolism of salt-tolerant Z. rouxii under high-temperature conditions to restore growth. This study helps to deepen the current understanding of the thermoadaptive growth mechanism of salt-tolerant Z. rouxii.

Microstructure and Properties of Aluminum-Graphene-SiC Matrix Composites after Friction Stir Processing.

Enhancing the mechanical properties of conventional ceramic particles-reinforced aluminum (Al 1060) metal matrix composites (AMCs) with lower detrimental phases is difficult. In this research work, AMCs are reinforced with graphene nanosheet (GNS) and hybrid reinforcement (GNS combined with 20% SiC, synthesized by shift-speed ball milling (SSBM), and further fabricated by two-pass friction stir processing (FSP). The effect of GNS content and the addition of SiC on the microstructure and mechanical properties of AMCs are studied. The microstructure, elemental, and phase composition of the developed composite are examined using SEM, EDS, and XRD techniques, respectively. Mechanical properties such as hardness, wear, and tensile strength are analyzed. The experimental results show that the GNS and the SiC are fairly distributed in the Al matrix via SSBM, which is beneficial for the mechanical properties of the composites. The maximum tensile strength of the composites is approximately 171.3 MPa in AMCs reinforced by hybrid reinforcements. The tensile strength of the GNS/Al composites increases when the GNS content increases from 0 to 1%, but then reduces with the further increase in GNS content. The hardness increases by 2.3%, 24.9%, 28.9%, and 41.8% when the Al 1060 is reinforced with 0.5, 1, 2% GNS, and a hybrid of SiC and GNS, respectively. The SiC provides further enhancement of the hardness of AMCs reinforced by GNS. The coefficient of friction decreases by about 7%, 13%, and 17% with the reinforcement of 0.5, 1, and 2% GNS, respectively. Hybrid reinforcement has the lowest friction coefficient (0.41). The decreasing friction coefficient contributes to the self-lubrication of GNSs, the reduction in the contact area with the substrate, and the load-bearing ability of ceramic particles. According to this study, the strengthening mechanisms of the composites may be due to thermal mismatch, grain refinement, and Orowan looping. In summary, such hybrid reinforcements effectively improve the mechanical and tribological properties of the composites.

Real-Time Observation of Conformational Changes and Translocation of Endogenous Cytochrome c within Intact Mitochondria.

Cytochrome c (cyt c) is a multifunctional protein with varying conformations. However, the conformation of cyt c in its native environment, mitochondria, is still unclear. Here, we applied NMR spectroscopy to investigate the conformation and location of endogenous cyt c within intact mitochondria at natural isotopic abundance, mainly using widespread methyl groups as probes. By monitoring time-dependent chemical shift perturbations, we observed that most cyt c is located in the inner mitochondrial membrane and partially unfolded, which is distinct from its native conformation in solution. When suffering oxidative stress, cyt c underwent oxidative modifications due to increasing reactive oxygen species (ROS), weakening electrostatic interactions with the membrane, and gradually translocating into the inner membrane spaces of mitochondria. Meanwhile, the lethality of oxidatively modified cyt c to cells was reduced compared with normal cyt c. Our findings significantly improve the understanding of the molecular mechanisms underlying the regulation of ROS by cyt c in mitochondria. Moreover, it highlights the potential of NMR to monitor high-concentration molecules at a natural isotopic abundance within intact cells or organelles.

Change analysis for intermediate disease markers in nutritional epidemiology: a causal inference perspective.

BACKGROUND: Several approaches are commonly used to estimate the effect of diet on changes of various intermediate disease markers in prospective studies, including "change-score analysis", "concurrent change-change analysis" and "lagged change-change analysis". Although empirical evidence suggests that concurrent change-change analysis is most robust, consistent, and biologically plausible, in-depth dissection and comparison of these approaches from a causal inference perspective is lacking. We intend to explicitly elucidate and compare the underlying causal model, causal estimand and interpretation of these approaches, intuitively illustrate it with directed acyclic graph (DAG), and further clarify strengths and limitations of the recommended concurrent change-change analysis through simulations. METHODS: Causal model and DAG are deployed to clarify the causal estimand and interpretation of each approach theoretically. Monte Carlo simulation is used to explore the performance of distinct approaches under different extents of time-invariant heterogeneity and the performance of concurrent change-change analysis when its causal identification assumptions are violated. RESULTS: Concurrent change-change analysis targets the contemporaneous effect of exposure on outcome (measured at the same survey wave), which is more relevant and plausible in studying the associations of diet and intermediate biomarkers in prospective studies, while change-score analysis and lagged change-change analysis target the effect of exposure on outcome after one-period timespan (typically several years). Concurrent change-change analysis always yields unbiased estimates even with severe unobserved time-invariant confounding, while the other two approaches are always biased even without time-invariant heterogeneity. However, concurrent change-change analysis produces almost linearly increasing estimation bias with violation of its causal identification assumptions becoming more serious. CONCLUSIONS: Concurrent change-change analysis might be the most superior method in studying the diet and intermediate biomarkers in prospective studies, which targets the most plausible estimand and circumvents the bias from unobserved individual heterogeneity. Importantly, careful examination of the vital identification assumptions behind it should be underscored before applying this promising method.

Expression of Interleukin-13 Receptor Alpha 2 in Brainstem Gliomas.

The objective of this study was to investigate IL13Ra2 expression in brainstem glioma (BSG) and its correlation with key markers, functions, and prognostic implications, evaluating its therapeutic potential. A total of 80 tumor samples from BSG patients were analyzed. Multiplex immunofluorescence was used to examine six markers-IL13Ra2, H3.3K27M, CD133, Ki67, HLA-1, and CD4-establishing relationships between IL13Ra2 and these markers. Survival analysis, employing Kaplan-Meier and Cox proportional hazard regression models, encompassed 66 patients with complete follow-up. RNA-Seq data from a previously published study involving 98 patients were analyzed using the DESeq2 library to determine differential gene expression between groups. Gene Ontology (GO) enrichment and single-sample gene set enrichment analysis (ssGSEA) via the clusterProfiler library were used to delineate the gene functions of differentially expressed genes (DEGs). Nearly all the BSG patients displayed varying IL13Ra2 expression, with 45.0% (36/80) exhibiting over a 20% increase. Elevated IL13Ra2 levels were notably observed in pontine gliomas, diffuse intrinsic pontine gliomas (DIPGs), H3F3A-mutant gliomas, and WHO IV gliomas. IL13Ra2 expression was strongly correlated with H3.3K27M mutant protein, Ki67, and CD133. Patients with IL13Ra2 expression >20% showed shorter overall survival compared to those with ≤20% IL13Ra2 expression. The Cox proportional hazard regression model identified H3F3A mutations, rather than IL13Ra2 expression, as an independent prognostic factor. Analysis of RNA-Seq data from our prior cohort confirmed IL13Ra2's correlation with H3.3, CD133, and Ki67 levels. Widespread IL13Ra2 expression in BSG, particularly elevated in the H3F3A mutant group, was strongly correlated with H3F3A mutations, increased proliferation, and heightened tumor stemness. IL13Ra2 represents a promising therapeutic target for BSGs, potentially benefiting patients with H3K27M mutations, DIPGs, WHO Grade IV, and pontine location-specific BSGs, particularly those with H3K27M mutations.

Colorectal cancer and its attributable risk factors in East Asia, 1990-2030.

BACKGROUND: The disease burden of colorectal cancer in East Asia has been at a high level. However, the epidemiological characteristics of the disease burden in this region have not been systematically studied. METHOD: Data were obtained from the Global Burden of Disease 2019 program. Joinpoint analysis was used to identify long-term trends in mortality of colorectal cancer. Independent effects of age, period, and cohort were detected by the age-period-cohort model. The Bayesian age-period-cohort model was performed to predict the burden of colorectal cancer across East Asia by 2030. RESULTS: From 1990 to 2019, the average annual percentage change (AAPC) showed upward trends in mainland China (1.05 [95% confidence interval (CI)], 0.82, 1.28) as well as Taiwan Province of China (1.81 [95% CI], 1.51, 2.10) but downward in Japan (-0.60 [95% CI], -0.70, -0.49) (P < 0.05). Attributable risk factors for colorectal cancer in East Asia remained stable over 30 years, while the risk of metabolic factors is noteworthy in the future. In the next decade, the age-standardized death rate (ASDR) of colorectal cancer in China was predicted to surpass that of Japan and South Korea in expectation. CONCLUSION: The mortality of colorectal cancer is escalating in developing countries, while it is gradually declining in high-income countries across East Asia. Nonetheless, the disease burden of colorectal cancer in high-income countries remains substantial level.

The Protein Response of Salt-Tolerant Zygosaccharomyces rouxii to High-Temperature Stress during the Lag Phase.

Zygosaccharomyces rouxii used in soy sauce brewing is an osmotolerant and halotolerant yeast, but it is not tolerant to high temperatures and the underlying mechanisms remain poorly understood. Using a synthetic medium containing only Pro as a nitrogen source, the response of Z. rouxii in protein level to high-temperature stress (40 °C, HTS) during the lag phase was investigated. Within the first two h, the total intracellular protein concentration was significantly decreased from 220.99 ± 6.58 µg/mg DCW to 152.63 ± 10.49 µg/mg DCW. The analysis of the amino acid composition of the total protein through vacuum proteolysis technology and HPLC showed that new amino acids (Thr, Tyr, Ser, and His) were added to newborn protein over time during the lag phase under HTS. The nutritional conditions used in this study determined that the main source of amino acid supply for protein synthesis was through amino acid biosynthesis and ubiquitination-mediated protein degradation. Differential expression analysis of the amino acid biosynthesis-related genes in the transcriptome showed that most genes were upregulated under HTS, excluding ARO8, which was consistently repressed during the lag phase. RT-qPCR results showed that high-temperature stress significantly increased the upregulation of proteolysis genes, especially PSH1 (E3 ubiquitin ligase) by 13.23 ± 1.44 fold (p < 0.0001) within 4 h. Overall, these results indicated that Z. rouxii adapt to prolonged high temperatures stress by altering its basal protein composition. This protein renewal was related to the regulation of proteolysis and the biosynthesis of amino acids.

A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management: a single-institution experience of 57 cases.

OBJECTIVE: Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decision-making and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up. METHODS: Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed. RESULTS: The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0-12.8 years); the largest tumor volume (median 31.9 cm3, IQR 17.2-42.6 cm3); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50-70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image-guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8-33 years); tumor volume (median 13.9 cm3, IQR 9.5-20.5 cm3); a good preoperative KPS score (median 80, IQR 70-80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm3, IQR 5.1-17.4 cm3 and median 11.84 cm3, IQR 5.7-18.3 cm3, respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches. CONCLUSIONS: A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.