Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review).

Several studies have indicated that the gut microbiome and tumor microbiota may affect tumors. Emerging metabolomics research illustrates the need to examine the variations in microbial metabolite composition between patients with cancer and healthy individuals. Microbial metabolites can impact the progression of tumors and the immune response by influencing a number of mechanisms, including modulation of the immune system, cancer or immune­related signaling pathways, epigenetic modification of proteins and DNA damage. Microbial metabolites can also alleviate side effects and drug resistance during chemotherapy and immunotherapy, while effectively activating the immune system to exert tumor immunotherapy. Nevertheless, the impact of microbial metabolites on tumor immunity can be both beneficial and harmful, potentially influenced by the concentration of the metabolites or the specific cancer type. The present review summarizes the roles of various microbial metabolites in different solid tumors, alongside their influence on tumor immunity and treatment. Additionally, clinical trials evaluating the therapeutic effects of microbial metabolites or related microbes on patients with cancer have been listed. In summary, studying microbial metabolites, which play a crucial role in the interaction between the microbiota and tumors, could lead to the identification of new supplementary treatments for cancer. This has the potential to improve the effectiveness of cancer treatment and enhance patient prognosis.

Soft-tissue sound-speed-aware ultrasound-CT registration method for computer-assisted orthopedic surgery.

Ultrasound (US) has been introduced to computer-assisted orthopedic surgery for bone registration owing to its advantages of nonionizing radiation, low cost, and noninvasiveness. However, the registration accuracy is limited by US image distortion caused by variations in the acoustic properties of soft tissues. This paper proposes a soft-tissue sound-speed-aware registration method to overcome the above challenge. First, the feature enhancement strategy of multi-channel overlay is proposed for U2-net to improve bone segmentation performance. Secondly, the sound speed of soft tissue is estimated by simulating the bone surface distance map for the update of US-derived points. Finally, an iterative registration strategy is adopted to optimize the registration result. A phantom experiment was conducted using different registration methods for the femur and tibia/fibula. The fiducial registration error (femur, 0.98 ± 0.08 mm (mean ± SD); tibia/fibula, 1.29 ± 0.19 mm) and the target registration error (less than 2.11 mm) showed the high accuracy of the proposed method. The experimental results suggest that the proposed method can be integrated into navigation systems that provide surgeons with accurate 3D navigation information.

TPP-Based Microfluidic Chip Design and Fabrication Method for Optimized Nerve Cells Directed Growth.

Microfluidic chips offer high customizability and excellent biocompatibility, holding important promise for the precise control of biological growth at the microscale. However, the microfluidic chips employed in the studies of regulating cell growth are typically fabricated through 2D photolithography. This approach partially restricts the diversity of cell growth platform designs and manufacturing efficiency. This paper presents a method for designing and manufacturing neural cell culture microfluidic chips (NCMC) using two-photon polymerization (TPP), where the discrete and directional cell growth is optimized through studying the associated geometric parameters of on-chip microchannels. This study involves simulations and discussions regarding the effects of different hatching distances on the mold surface topography and printing time in the Describe print preview module, which determines the appropriate printing accuracy corresponding to the desired mold structure. With the assistance of the 3D maskless lithography system, micron-level rapid printing of target molds with different dimensions were achieved. For NCMC with different geometric parameters, COMSOL software was used to simulate the local flow velocity and shear stress characteristics within the microchannels. SH-SY5Y cells were selected for directional differentiation experiments on NCMC with different geometric parameters. The results demonstrate that the TPP-based manufacturing method efficiently constructs neural microfluidic chips with high precision, optimizing the discrete and directional cell growth. We anticipate that our method for designing and manufacturing NCMC will hold great promise in construction and application of microscale 3D drug models.

Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer's disease.

The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-ß deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.

Digital exclusion and cognitive impairment in older people: findings from five longitudinal studies.

OBJECTIVES: Older people are more likely to have digital exclusion, which is associated with poor health. This study investigated the relationship between digital exclusion and cognitive impairment in older adults from 23 countries across five longitudinal surveys. DESIGN AND MEASUREMENTS: Digital exclusion is defined as self-reported non-use of the Internet. We assessed cognitive impairment on three dimensions: orientation, memory, and executive function. We used generalized estimation equations fitting binary logistic regression with exchangeable correlations to study the relationship between digital exclusion and cognitive impairment, and apply the minimum sufficiently adjusted set of causally directed acyclic graphs as the adjusted variable. SETTING AND PARTICIPANTS: We pooled a nationally representative sample of older adults from five longitudinal studies, including the China Health and Retirement Longitudinal study (CHARLS), the English Longitudinal Study of Ageing (ELSA), the Health and Retirement Study (HRS), the Mexican Health and Ageing Study (MHAS) and the Survey of Health, Ageing and Retirement in European (SHARE). RESULTS: We included 62,413 participants from five longitudinal studies. Digital exclusion varied by country, ranging from 21.69% (SHARE) in Denmark to 97.15% (CHARLS) in China. In the original model, digital exclusion was significantly associated with cognitive impairment in all five studies. In the adjusted model, these associations remained statistically significant: CHARLS (Odds ratio [OR] = 2.81, 95% confidence interval [CI] 1.84-4.28, ELSA (1.92 [1.70-2.18]), HRS(2.48[2.28-2.71), MHAS (1.92 [1.74-2.12]), and SHARE (2.60 [2.34-2.88]). CONCLUSION: Our research shows that a significant proportion of older people suffer from digital exclusion, especially in China. Digital exclusion was positively correlated with cognitive impairment. These findings suggest that digital inclusion could be an important strategy to improve cognitive function and reduce the risk of cognitive impairment in older adults.

Clinical Implementation of Total-Body PET in China.

Total-body (TB) PET/CT is a groundbreaking tool that has brought about a revolution in both clinical application and scientific research. The transformative impact of TB PET/CT in the realms of clinical practice and scientific exploration has been steadily unfolding since its introduction in 2018, with implications for its implementation within the health care landscape of China. TB PET/CT's exceptional sensitivity enables the acquisition of high-quality images in significantly reduced time frames. Clinical applications have underscored its effectiveness across various scenarios, emphasizing the capacity to personalize dosage, scan duration, and image quality to optimize patient outcomes. TB PET/CT's ability to perform dynamic scans with high temporal and spatial resolution and to perform parametric imaging facilitates the exploration of radiotracer biodistribution and kinetic parameters throughout the body. The comprehensive TB coverage offers opportunities to study interconnections among organs, enhancing our understanding of human physiology and pathology. These insights have the potential to benefit applications requiring holistic TB assessments. The standard topics outlined in The Journal of Nuclear Medicine were used to categorized the reviewed articles into 3 sections: current clinical applications, scan protocol design, and advanced topics. This article delves into the bottleneck that impedes the full use of TB PET in China, accompanied by suggested solutions.

Comparative profiling of serum, urine, and feces bile acids in humans, rats, and mice.

Bile acids (BAs) play important pathophysiological roles in both humans and mammalian animals. Laboratory rats and mice are widely used animal models for assessing pharmacological effects and their underlying molecular mechanisms. However, substantial physiological differences exist in BA composition between humans and murine rodents. Here, we comprehensively compare BA profiles, including primary and secondary BAs, along with their amino acid conjugates, and sulfated metabolites in serum, urine, and feces between humans and two murine rodents. We further analyze the capabilities in gut microbial transform BAs among three species and compare sex-dependent variations within each species. As a result, BAs undergo amidation predominately with glycine in humans and taurine in mice but are primarily unamidated in rats. BA sulfation is a unique characteristic in humans, whereas rats and mice primarily perform multiple hydroxylations during BA synthesis and metabolism. For gut microbial transformed BA capabilities, humans are comparable to those of rats, stronger than those of mice in deconjugation and 7α-dehydroxylation, while humans are weak than those of rats or mice in oxidation and epimerization. Such differences enhance our understanding of the divergent experimental outcomes observed in humans and murine rodents, necessitating caution when translating findings from these rodent species to humans.

General reversal of N-decomposition relationship during long-term decomposition in boreal and temperate forests.

Decomposition of dead organic matter is fundamental to carbon (C) and nutrient cycling in terrestrial ecosystems, influencing C fluxes from the biosphere to the atmosphere. Theory predicts and evidence strongly supports that the availability of nitrogen (N) limits litter decomposition. Positive relationships between substrate N concentrations and decomposition have been embedded into ecosystem models. This decomposition paradigm, however, relies on data mostly from short-term studies analyzing controls on early-stage decomposition. We present evidence from three independent long-term decomposition investigations demonstrating that the positive N-decomposition relationship is reversed and becomes negative during later stages of decomposition. First, in a 10-y decomposition experiment across 62 woody species in a temperate forest, leaf litter with higher N concentrations exhibited faster initial decomposition rates but ended up a larger recalcitrant fraction decomposing at a near-zero rate. Second, in a 5-y N-enrichment experiment of two tree species, leaves with experimentally enriched N concentrations had faster decomposition initial rates but ultimately accumulated large slowly decomposing fractions. Measures of amino sugars on harvested litter in two experiments indicated that greater accumulation of microbial residues in N-rich substrates likely contributed to larger slowly decomposing fractions. Finally, a database of 437 measurements from 120 species in 45 boreal and temperate forest sites confirmed that higher N concentrations were associated with a larger slowly decomposing fraction. These results challenge the current treatment of interactions between N and decomposition in many ecosystems and Earth system models and suggest that even the best-supported short-term controls of biogeochemical processes might not predict long-term controls.

Westerlies-driven transboundary transport of atmospheric mercury to the north-central Tibetan Plateau.

The transboundary mercury (Hg) pollution has caused adverse effects on fragile ecosystems of the Tibetan Plateau (TP). Yet, knowledge of transport paths and source regions of atmospheric Hg on the inland TP remains poor. Continuous measurements of atmospheric total gaseous mercury (TGM) were conducted in the central TP (Tanggula station, 5100 m a.s.l., June-October). Atmospheric TGM level at Tanggula station (1.90 ± 0.30 ng m-3) was higher than the background level in the Northern Hemisphere. The identified high-potential source regions of atmospheric TGM were primarily located in the northern South Asia region. TGM concentrations were lower during the Indian summer monsoon (ISM)-dominant period (1.81 ± 0.25 ng m-3) than those of the westerly-receding period (2.18 ± 0.40 ng m-3) and westerly-intensifying period (1.91 ± 0.26 ng m-3), contrary to the seasonal pattern in southern TP. The distinct TGM minima during the ISM-dominant period indicated lesser importance of ISM-transported Hg to Tanggula station located in the northern boundary of ISM intrusion, compared to stations in proximity to South and Southeast Asia source regions. Instead, from the ISM-dominant period to the westerly-intensifying period, TGM concentrations showed an increasing trend as westerlies intensified, indicating the key role of westerlies in transboundary transport of atmospheric Hg to the inland TP.

Association of social health with all-cause mortality and cause-specific mortality: A population-based cohort study.

BACKGROUND: Previous studies only focused on the individual social factors, without considering the overall social health patterns. The present study aimed to develop an integrated social health score (SHS) and investigate its associations with all-cause, cardiovascular disease (CVD), cancer mortality. METHODS: A total of 330,716 participants (mean age 56.3 years; 52.4 % female) from UK Biobank was included between 2006 and 2010, and thereafter followed up to 2021. SHS was calculated by using information on social connections, social engagement and social support. Cox proportional hazards models was used to estimate the hazard ratios and 95 % confidence intervals (CIs) of the association between SHS and all-cause and cause-specific mortality and the 4-way decomposition was used to quantify the mediating effect of lifestyle factors. RESULTS: During a median follow-up period of 12.4 years, 37,897 death cases were recorded, including 4347 CVD and 10,380 cancer cases. The SHS was inversely associated with the risks of all-cause, CVD and cancer mortality in a dose-dependent manner (P for trend <0.001). The association between SHS with all-cause mortality was mediated by lifestyle factors including diet score, smoking status and alcohol consumption. CONCLUSION: Integrated SHS was inversely associated with risks of all-cause, CVD and cancer mortality, and the associations were partially mediated by lifestyle factors. Our study highlights the importance of maintaining high levels of social health by jointly enhancing social involvement, expanding social networks, and cultivating enduring intimate relationships across the life course.

Achieving net zero energy heating by integrating the building envelope as a thermal battery.

Photovoltaic (PV) heating is a promising technology for achieving fossil fuel-free heating and carbon neutrality in the building sector. Cost-effective energy storage plays a critical role in PV heating to solve the temporal mismatch between supply and demand. Herein, we propose the concept of using a building envelope as an active energy-storage device for a PV heating system, thus transforming the building envelope into a thermal battery. Experimental results show that the energy storage capacity of 142 kW h/m2, which is higher than that of conventional thermal storage systems. We developed a top-down macro performance assessment model to quantify the contribution of a PV heating system using a building envelope as energy storage. By our estimation, the envelope-embedded system can reduce heating-related CO2 emissions by 7435.7 tons annually in northern China. Our study provides insights into innovative energy-saving building energy storage systems that can help achieve global carbon neutrality and sustainability.

Application of poly(L-lactic acid)-based films for equilibrium modified atmosphere packaging of "Kyoho" grapes and its favorable protection for anthocyanins.

Grapes were packaged by different Poly (L-lactic acid)-based packaging films (PLTL-PLEL) and stored at 5 °C for 35 days to investigate the effects of equilibrium modified atmosphere packaging on the quality of "Kyoho" grapes during storage. Changes in physiochemical quality, antioxidant content and senescence of grapes were studied. Furthermore, UPLC-Q-TOF-MS/MS was used to observe and identify key factors influencing the variation of grape anthocyanins under different atmosphere conditions. Alterations in gas components and enzyme activities significantly impacted anthocyanin levels, highlighting oxygen concentration as the primary influence on total anthocyanin levels. The PLTL-PLEL50 packaging resulted in an approximate 5.7% lower weight loss and increased soluble solids by approximately 14.4%, vitamin C, total phenols and flavonoids reaching 60.2 mg/100 g, 8.4 mg/100 g and 7.2 mg/100 g, respectively. This packaging also preserved higher anthocyanin levels, with malvidin-3-glucoside and peonidin-3-glucoside at 0.55 µg/mL and 1.62 µg/mL, respectively, on the 35th day of storage.

MSC microvesicles loaded G-quadruplex-enhanced circular single-stranded DNA-9 inhibits tumor growth by targeting MDSCs.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) promote tumor growth, metastasis, and lead to immunotherapy resistance. Studies revealed that miRNAs are also expressed in MDSCs and promote the immunosuppressive function of MDSCs. Currently, few studies have been reported on inducible cellular microvesicle delivery of nucleic acid drugs targeting miRNA in MDSCs for the treatment of malignant tumors. RESULTS AND CONCLUSION: In this study, we designed an artificial DNA named G-quadruplex-enhanced circular single-stranded DNA-9 (G4-CSSD9), that specifically adsorbs the miR-9 sequence. Its advanced DNA folding structure, rich in tandem repeat guanine (G-quadruplex), also provides good stability. Mesenchymal stem cells (MSCs) were prepared into nanostructured vesicles by membrane extrusion. The MSC microvesicles-encapsulated G4-CSSD9 (MVs@G4-CSSD9) was delivered into MDSCs, which affected the downstream transcription and translation process, and reduced the immunosuppressive function of MDSCs, so as to achieve the purpose of treating melanoma. In particular, it provides an idea for the malignant tumor treatment.

The value of dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting EGFR mutations.

OBJECTIVES: 18F-fluorodeoxyglucose (FDG) PET/CT has been widely used for the differential diagnosis of cancer. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may make it difficult to differentiate between benign and malignant lesions. It is crucial to find reliable quantitative metabolic parameters to further support the diagnosis. This study aims to evaluate the value of the quantitative metabolic parameters derived from dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting epidermal growth factor receptor (EGFR) mutation status. METHODS: We included 147 patients with lung lesions to perform FDG PET/CT dynamic plus static imaging with informed consent. Based on the results of the postoperative pathology, the patients were divided into benign/malignant groups, adenocarcinoma (AC)/squamous carcinoma (SCC) groups, and EGFR-positive (EGFR+)/EGFR-negative (EGFR-) groups. Quantitative parameters including K1, k2, k3, and Ki of each lesion were obtained by applying the irreversible two-tissue compartmental modeling using an in-house Matlab software. The SUV analysis was performed based on conventional static scan data. Differences in each metabolic parameter among the group were analyzed. Wilcoxon rank-sum test, independent-samples T-test, and receiver-operating characteristic (ROC) analysis were performed to compare the diagnostic effects among the differentiated groups. P < 0.05 were considered statistically significant for all statistical tests. RESULTS: In the malignant group (N = 124), the SUVmax, k2, k3, and Ki were higher than the benign group (N = 23), and all had-better performance in the differential diagnosis (P < 0.05, respectively). In the AC group (N = 88), the SUVmax, k3, and Ki were lower than in the SCC group, and such differences were statistically significant (P < 0.05, respectively). For ROC analysis, Ki with cut-off value of 0.0250 ml/g/min has better diagnostic specificity than SUVmax (AUC = 0.999 vs. 0.70). In AC group, 48 patients further underwent EGFR testing. In the EGFR (+) group (N = 31), the average Ki (0.0279 ± 0.0153 ml/g/min) was lower than EGFR (-) group (N = 17, 0.0405 ± 0.0199 ml/g/min), and the difference was significant (P < 0.05). However, SUVmax and k3 did not show such a difference between EGFR (+) and EGFR (-) groups (P>0.05, respectively). For ROC analysis, the Ki had a cut-off value of 0.0350 ml/g/min when predicting EGFR status, with a sensitivity of 0.710, a specificity of 0.588, and an AUC of 0.674 [0.523-0.802]. CONCLUSION: Although both techniques were specific, Ki had a greater specificity than SUVmax when the cut-off value was set at 0.0250 ml/g/min for the differential diagnosis of lung cancer. At a cut-off value of 0.0350 ml/g/min, there was a 0.710 sensitivity for EGFR status prediction. If EGFR testing is not available for a patient, dynamic imaging could be a valuable non-invasive screening method.

Hydrological response of drought impacts across catchments worldwide.

Drought will inevitably affect linkages between different water components, which have previously been investigated across different spatiotemporal scales. Elucidating drought-induced precipitation (P) partition effects remain uncertain because they involve drought propagation, even inducing streamflow (Q) non-stationarity. This study collected data on 1069 catchments worldwide to investigate Q and evapotranspiration (ET) impacts from P deficit-derived reductions in drought propagation. Results show that P deficits trigger soil moisture drought, subsequently inducing negative Q and ET anomalies that vary under different climate regimes. Generally, drought-induced hydrological legacies indicate that breaks in hydrological linkages cause a relatively rapid Q response (i.e., negative Q anomaly), amplified by drought strength and duration. Compared with the Q response, the ET response to drought stress involves a more complex, associative vegetation response and an associative evaporative state controlled by water and energy, which lags behind the Q response and can also intensify with increasing drought severity and duration. This is confirmed by the ET response under different climate regimes. Namely, in drier climates, a positive ET anomaly can be detected in its early stages, this is unusual in wetter climate. Additionally, Q and ET sensitivity to drought strength can be mechanistically explained by the water and energy status. This implies that ET is mainly controlled by water and energy, resulting in higher and lower drought sensitivity within water- and energy-limited regions, respectively. Understanding the impacts of drought on Q and ET response is essential for identifying key linkages in drought propagation across different climate regimes. Our findings will also be useful for developing early warning and adaptation systems that support both human and ecosystem requirements.

The association among thriving in life, quality of life, and suicidal ideation in Chinese urban older adults: the moderating effects of attitude toward own aging.

BACKGROUND: As the global trend of population aging intensifies, the health and well-being of the older population has gradually become a focus of attention for the global community. This study assessed the status of thriving in life among Chinese urban older adults and identified its relationship with attitude toward own aging and quality of life (QoL). It also tested whether attitude toward own aging moderates the association between thriving in life and Qol or between thriving in life and suicidal ideation. METHODS: Primary data were collected through a cross-sectional survey among urban older adults from three provinces in China. They were invited to complete an anonymous survey using face-to-face interviews from December 2019 to January 2020. Data from 764 older adults were analyzed. RESULTS: Approximately 44.39% of participants reported positive responses toward the four domains of thriving in life. Thriving in life and attitude toward own aging had a significant association with QoL. Thriving in life was a protective factor for suicidal ideation for older adults. Moreover, attitude toward own aging moderated the association between thriving in life and QoL and that between thriving in life and suicidal ideation. CONCLUSIONS: Chinese urban older adults were reportedly thriving in life, which contributed to increased QoL and reduced suicidal ideation. Notably, the study revealed that more positive attitudes towards own aging were associated with higher levels of thriving in life, better QoL, and reduced suicidal ideation. Targeted interventions for older adults should be devised to promote thriving in life and prevent negative attitudes of older people towards their own aging, further raising QoL and reducing suicidal ideation.

Effects of nitrogen forms on Cd uptake and tolerance in wheat seedlings.

Hydroponic experiment was conducted to explore the effects of two nitrogen (N) levels with five nitrate nitrogen (NO3--N) and ammonium nitrogen (NH4+-N) ratios on the growth status and Cd migration patterns of wheat seedlings under Cd5 and Cd30 level. Results showed that higher Cd were detrimental to the growth, absorption of K and Ca, expression of genes mediating NO3--N and NH4+-N transport, which also increased the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in shoots and roots of wheat seedlings. Higher N treatment alleviated the inhibitory effects of Cd stress on the biomass, root development, photosynthesis and increased the tolerance index of wheat seedlings. The ratio of NO3--N and NH4+-N was the main factor driving Cd accumulation in wheat seedlings, the combined application of NH4+-N and NO3--N was more conducive for the growth, nitrogen assimilation and Cd tolerance to the Cd stressed wheat seedlings. Increased NO3--N application rates significantly up-regulated the expression levels of TaNPF2.12, TaNRT2.2, increased NH4+-N application rates significantly up-regulated the expression levels of TaAMT1.1. The high proportion of NO3--N promoted the absorption of K, Ca and Cd in the shoots and roots of wheat seedlings, while NH4+-N was the opposite. Under low Cd conditions, the NO3--N to NH4+-N ratio of 1:1 was more conducive to the growth of wheat seedlings, under high Cd stress, the optimal of NO3--N to NH4+-N was 1:2 for inhibiting the accumulation of Cd in wheat seedlings. The results indicated that increasing NH4+-N ratio appropriately could inhibit wheat Cd uptake by increasing NH4+, K+ and Ca2+ for K and Ca channels, and promote wheat growth by promoting N assimilation process.

Time Is Ripe for Targeting Per- and Polyfluoroalkyl Substances-Induced Hormesis: Global Aquatic Hotspots and Implications for Ecological Risk Assessment.

Globally implemented ecological risk assessment (ERA) guidelines marginalize hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition. The present study illuminated the promise of hormesis as a scientific dose-response model for ERA of per- and polyfluoroalkyl substances (PFAS) represented by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). A total of 266 hormetic dose-response relationships were recompiled from 1237 observations, covering 30 species from nine representative taxonomic groups. The standardized hormetic amplitudes followed the log-normal probability distribution, being subject to the limits of biological plasticity but independent of stress inducers. The SHapley Additive exPlanations algorithm revealed that the target endpoint was the most important variable explaining the hormetic amplitudes. Subsequently, quantitative frameworks were established to incorporate hormesis into the predicted no-effect concentration levels, with a lower induction dose and a zero-equivalent point but a broader hormetic zone for PFOS. Realistically, 10,117 observed concentrations of PFOA and PFOS were gathered worldwide, 4% of which fell within hormetic zones, highlighting the environmental relevance of hormesis. Additionally, the hormesis induction potential was identified in other legacy and emerging PFAS as well as their alternatives and mixtures. Collectively, it is time to incorporate the hormesis concept into PFAS studies to facilitate more realistic risk characterizations.

AKIMLpred: An interpretable machine learning model for predicting acute kidney injury within seven days in critically ill patients based on a prospective cohort study.

BACKGROUND: Early recognition and timely intervention for AKI in critically ill patients were crucial to reduce morbidity and mortality. This study aimed to use biomarkers to construct a optimal machine learning model for early prediction of AKI in critically ill patients within seven days. METHODS: The prospective cohort study enrolled 929 patients altogether who were admitted in ICU including 680 patients in training set (Jiefang Campus) and 249 patients in external testing set (Binjiang Campus). After performing strict inclusion and exclusion criteria, 421 patients were selected in training set for constructing predictive model and 167 patients were selected in external testing for evaluating the predictive performance of resulting model. Urine and blood samples were collected for kidney injury associated biomarkers detection. Baseline clinical information and laboratory data of the study participants were collected. We determined the average prediction efficiency of six machine learning models through 10-fold cross validation. RESULTS: In total, 78 variables were collected when admission in ICU and 43 variables were statistically significant between AKI and non-AKI cohort. Then, 35 variables were selected as independent features for AKI by univariate logistic regression. Spearman correlation analysis was used to remove two highly correlated variables. Three ranking methods were used to explore the influence of 33 variables for further determining the best combination of variables. The gini importance ranking method was found to be applicable for variables filtering. The predictive performance of AKIMLpred which constructed by the XGBoost algorithm was the best among six machine learning models. When the AKIMLpred included the nine features (NGAL, IGFBP7, sCysC, CAF22, KIM-1, NT-proBNP, IL-6, IL-18 and L-FABP) with the highest influence ranking, its model had the best prediction performance, with an AUC of 0.881 and an accuracy of 0.815 in training set, similarly, with an AUC of 0.889 and an accuracy of 0.846 in validation set. Moreover, the performace was slightly outperformed in testing set with an AUC of 0.902 and an accuracy of 0.846. The SHAP algorithm was used to interpret the prediction results of AKIMLpred. The web-calculator of AKIMLpred was shown for predicting AKI with more convenient(https://www.xsmartanalysis.com/model/list/predict/model/html?mid=8065&symbol=11gk693982SU6AE1ms21). AKIMLpred was better than the optimal model built with only routine tests for predicting AKI in critically ill patients within 7 days. CONCLUSION: The model AKIMLpred constructed by the XGBoost algorithm with selecting the nine most influential biomarkers in the gini importance ranking method had the best performance in predicting AKI in critically ill patients within 7 days. This data-driven predictive model will help clinicians to make quick and accurate diagnosis.

IL-37 ameliorates myocardial fibrosis by regulating mtDNA-enriched vesicle release in diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.