UFObow: A single-wavelength excitable Brainbow for simultaneous multicolor ex-vivo and in-vivo imaging of mammalian cells.

Brainbow is a genetic cell-labeling technique that allows random colorization of multiple cells and real-time visualization of cell fate within a tissue, providing valuable insights into understanding complex biological processes. However, fluorescent proteins (FPs) in Brainbow have distinct excitation spectra with peak difference greater than 35 nm, which requires sequential imaging under multiple excitations and thus leads to long acquisition times. In addition, they are not easily used together with other fluorophores due to severe spectral bleed-through. Here, we report the development of a single-wavelength excitable Brainbow, UFObow, incorporating three newly developed blue-excitable FPs. We have demonstrated that UFObow enables not only tracking the growth dynamics of tumor cells in vivo but also mapping spatial distribution of immune cells within a sub-cubic centimeter tissue, revealing cell heterogeneity. This provides a powerful means to explore complex biology in a simultaneous imaging manner at a single-cell resolution in organs or in vivo.

Metabolic dysfunction-associated fatty liver disease and nonalcoholic fatty liver disease from clinical to pathological characteristics: a multi-center cross-sectional study in real world.

BACKGROUND: The evaluation of patients with fatty liver as defined by metabolic dysfunction-associated fatty liver disease (MAFLD) in the real world remains poorly researched. This study aimed to analyse the clinical and histological features of patients with MAFLD and nonalcoholic fatty liver disease (NAFLD) and to characterize each metabolic subgroup of MAFLD. METHODS: A total of 2563 patients with fatty liver confirmed by ultrasonography and/or magnetic resonance tomography and/or liver biopsy-proven from three hospitals in China were included in the study. Patients were divided into different groups according to diagnostic criteria for MAFLD and NAFLD, and MAFLD into different subgroups. RESULTS: There were 2337 (91.2%) patients fitting the MAFLD criteria, and 2095 (81.7%) fitting the NAFLD criteria. Compared to patients with NAFLD, those with MAFLD were more likely to be male, had more metabolic traits, higher liver enzyme levels, and noninvasive fibrosis scores. Among the patients with liver biopsy, the extent of advanced fibrosis in cases with MAFLD was significantly higher than those with NAFLD, 31.8% versus 5.2% (P < .001); there was no significant difference in advanced fibrosis between obese cases and lean individuals in MAFLD (P > .05); MAFLD complicated with diabetes had significantly higher advanced fibrosis than those without diabetes (43.3% and 17.2%, respectively; P < .001). CONCLUSIONS: Patients with MAFLD have a higher degree of liver fibrosis than NAFLD patients. In addition, diabetic patients should be screened for fatty liver and liver fibrosis degree.

Impact of a dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta-analysis.

AIMS: To evaluate the impact of a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide (TZP), and its potential dose-response effect, on heart rate. METHODS: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP-1 receptor agonists [GLP-1RAs], insulin, placebo). The GLP-1RA and non-GLP-1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta-analyses and network meta-analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). RESULTS: Eight articles were included in this systematic review and meta-analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta-analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP-1RAs and non-GLP-1RAs (GLP-1 RAs: MD 2.29, 95% CI 1.00, 3.59; non-GLP-1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD -0.97, 95% CI -1.79, -0.14; TZP 15 mg: MD -2.57, 95% CI -3.79, -1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD -1.5, 95% CI -2.38, -0.82). Network meta-analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP-1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). CONCLUSIONS: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP-1RA and non-GLP-1RA groups, but also that the 15-mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose-response impact on heart rate. Further research on the effects of TZP treatment-related increases in heart rate is required.

Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator (CFTR) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction.

FBXO38 regulates macrophage polarization to control the development of cancer and colitis.

Macrophages are highly plastic cells that differentially regulate multiple pathological conditions, including cancer and autoimmune diseases. In response to various stimuli, macrophages activate different intrinsic signaling pathways and polarize into distinct macrophage subsets. We aimed to identify key new effectors that could control macrophage polarization and impact the development of cancer or colitis. Following treatment with the supernatants of tumor cells, macrophages showed an upregulation in Fbxo38 expression. Subsequently, we further identified that FBXO38 promotes macrophage immunosuppressive function by upregulating the expression of M2-like genes via MAPK and IRF4 signaling without affecting M1-like macrophage polarization. Deletion of Fbxo38 in macrophages was found to block tumor development and protect against DSS-induced colitis. Considering the distinct regulation of tumor development by FBXO38 in T cells and macrophages, we suggest that a comprehensive understanding of FBXO38 function in different cell types is critical for its further translational usage.

A novel natural killer-related signature to effectively predict prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent tumor that poses a significant threat to human health, with 80% of cases being primary HCC. At present, Early diagnosis and predict prognosis of HCC is challenging and the it is characterized by a high degree of invasiveness, both of which negatively impact patient prognosis. Natural killer cells (NK) play an important role in the development, diagnosis and prognosis of malignant tumors. The potential of NK cell-related genes for evaluating the prognosis of patients with hepatocellular carcinoma remains unexplored. This study aims to address this gap by investigating the association between NK cell-related genes and the prognosis of HCC patients, with the goal of developing a reliable model that can provide novel insights into evaluating the immunotherapy response and prognosis of these patients. This work has the potential to significantly advance our understanding of the complex interplay between immune cells and tumors, and may ultimately lead to improved clinical outcomes for HCC patients. METHODS: For this study, we employed transcriptome expression data from the hepatocellular carcinoma cancer genome map (TCGA-LIHC) to develop a model consisting of NK cell-related genes. To construct the NK cell-related signature (NKRLSig), we utilized a combination of univariate COX regression, Area Under Curve (AUC) LASSO COX regression, and multivariate COX regression. To validate the model, we conducted external validation using the GSE14520 cohort. RESULTS: We developed a prognostic model based on 5-NKRLSig (IL18RAP, CHP1, VAMP2, PIC3R1, PRKCD), which divided patients into high- and low-risk groups based on their risk score. The high-risk group was associated with a poor prognosis, and the risk score had good predictive ability across all clinical subgroups. The risk score and stage were found to be independent prognostic indicators for HCC patients when clinical factors were taken into account. We further created a nomogram incorporating the 5-NKRLSig and clinicopathological characteristics, which revealed that patients in the low-risk group had a better prognosis. Moreover, our analysis of immunotherapy and chemotherapy response indicated that patients in the low-risk group were more responsive to immunotherapy. CONCLUSION: The model that we developed not only sheds light on the regulatory mechanism of NK cell-related genes in HCC, but also has the potential to advance our understanding of immunotherapy for HCC. With its strong predictive capacity, our model may prove useful in evaluating the prognosis of patients and guiding clinical decision-making for HCC patients.

Plasma Methylated SEPT9 as a Novel Biomarker for Predicting Liver Metastasis in Colorectal Cancer.

This study aimed to explore the role of plasma methylated SEPT9 (mSEPT9) in predicting liver metastasis (LM) in colorectal cancer (CRC) patients. The clinicopathological information of 115 consecutive CRC patients were collected. The differences of clinical characteristics and several biomarkers between CRC patients with LM and those with non-liver metastasis (NM) were analyzed. Multivariate logistic regression analysis was used to identify the risk factors for predicting LM in CRC patients. Receiver operating characteristic curve (ROC) analysis was applied to investigate the sensitivity and specificity of potential biomarkers in indicating the presence of LM in CRC. Compared with the CRC without LM, the levels of plasma mSEPT9 and carcinoembryonic antigen (CEA) were significantly increased in CRC with LM. Multivariate logistic regression analysis showed that plasma mSEPT9 was an independent risk factor for predicting LM in CRC. ROC curves showed that mSEPT9 and CEA could efficiently distinguish LM from NM in CRC. The area under the curve (AUC) of mSEPT9 was 0.850, which was slightly higher than that of CEA (0.842). The optimal cut-off value of mSEPT9 was 35.09 with a sensitivity of 81.82% and a specificity of 73.33%, both similar with that of CEA (sensitivity 87.27% and specificity 75.00%). In addition, the combination of mSEPT9 and CEA had a higher specificity than CEA alone (81.70% Vs 75.00%). Our findings suggest, for the first time, that plasma mSEPT9 might serve as a potential biomarker to predict LM in CRC, which deserves further in-depth study.

Mealybug salivary microbes inhibit induced plant defenses.

BACKGROUND: Phenacoccus solenopsis is a polyphagous invasive mealybug that caused serious damage to crops worldwide. Phloem-sucking hemipterans are known to carry symbiotic microbes in their saliva. However, the role of salivary bacteria of P. solenopsis in modulating plant defenses remains limited. Exploring the impact of salivary bacteria on plant defense responses will contribute to the development of new targets for efficient control of invasive mealybugs. RESULTS: Salivary bacteria of the invasive mealybug P. solenopsis can suppress herbivore-induced plant defenses and thus enhance mealybug fitness. Mealybugs treated with an antibiotic showed decreased weight gain, fecundity and survival. Untreated mealybugs suppressed jasmonic acid (JA)-regulated defenses but activated salicylic acid (SA)-regulated defenses in cotton plants. In contrast, antibiotic-treated mealybugs triggered JA-responsive gene expression and JA accumulation, and showed shortened phloem ingestion. Reinoculating antibiotic-treated mealybugs with Enterobacteriaceae or Stenotrophomonas cultivated from mealybug saliva promoted phloem ingestion and fecundity, and restored the ability of mealybugs to suppress plant defenses. Fluorescence in situ hybridization visualization revealed that Enterobacteriaceae and Stenotrophomonas colonize salivary glands and are secreted into the mesophyll cells and phloem vessels. Exogenous application of the bacterial isolates to plant leaves inhibited JA-responsive gene expression and activated SA-responsive gene expression. CONCLUSION: Our findings imply that symbiotic bacteria in the saliva of the mealybug play an important role in manipulating herbivore-induced plant defenses, enabling this important pest to evade induced plant defenses and promoting its performance and destructive effects on crops. © 2023 Society of Chemical Industry.

Calenduloside e modulates macrophage polarization via KLF2-regulated glycolysis, contributing to attenuates atherosclerosis.

Glycolysis-mediated macrophage polarization plays a crucial role in atherosclerosis. Although it is known that calenduloside E (CE) exerts anti-inflammatory and lipid-lowering effects in atherosclerosis, the underlying mechanism of action is not clearly understood. We hypothesized that CE functions by inhibiting M1 macrophage polarization via regulation of glycolysis. To verify this hypothesis, we determined the effects of CE in apolipoprotein E deficient (ApoE-/-) mice and on macrophage polarization in oxidized low-density lipoprotein (ox-LDL)-induced RAW 264.7 macrophages and peritoneal macrophages. We also determined whether these effects are linked to regulation of glycolysis both in vivo and in vitro. The plaque size was reduced, and serum cytokine levels were decreased in the ApoE-/- +CE group compared with that in the model group. CE decreased lipid droplet formation, inflammatory factor levels, and mRNA levels of M1 macrophage markers in ox-ldl-induced macrophages. CE suppressed ox-ldl-induced glycolysis, lactate levels, and glucose uptake. The relationship between glycolysis and M1 macrophage polarization was demonstrated using the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one. CE substantially upregulated ox-ldl-induced Kruppel-like transcription factor (KLF2) expression, and the effects of CE on ox-ldl-induced glycolysis and inflammatory factor levels disappeared after KLF2 knockdown. Together, our findings suggest that CE alleviates atherosclerosis by inhibiting glycolysis-mediated M1 macrophage polarization through upregulation of KLF2 expression, providing a new strategy for the treatment of atherosclerosis.

Single-cell transcriptome sequencing of macrophages in common cardiovascular diseases.

Macrophages are strategically located throughout the body at key sites in the immune system. A key feature in atherosclerosis is the uptake and accumulation of lipoproteins by arterial macrophages, leading to the formation of foam cells. After myocardial infarction, macrophages derived from monocytes infiltrate the infarcted heart. Macrophages are also closely related to adverse remodeling after heart failure. An in-depth understanding of the functions and characteristics of macrophages is required to study heart health and pathophysiological processes; however, the heterogeneity and plasticity explained by the classic M1/M2 macrophage paradigm are too limited. Single-cell sequencing is a high-throughput sequencing technique that enables the sequencing of the genome or transcriptome of a single cell. It effectively complements the heterogeneity of gene expression in a single cell that is ignored by conventional sequencing and can give valuable insights into the development of complex diseases. In the present review, we summarize the available research on the application of single-cell transcriptome sequencing to study the changes in macrophages during common cardiovascular diseases, such as atherosclerosis, myocardial infarction, and heart failure. This article also discusses the contribution of this knowledge to understanding the pathogenesis, development, diagnosis, and treatment of heart diseases.

Estimates and trends of the global burden of NASH-related liver cancer attributable to high fasting plasma glucose in 1990-2019: analysis of data from the 2019 Global Burden of Disease Study.

BACKGROUND: Experimental and epidemiological studies have indicated an association between diabetes exposure and an increased risk of liver cancer due to nonalcoholic steatohepatitis (NASH). However, to date, no systematic study has specifically investigated the burden of NASH-related liver cancer due to exposure to high fasting plasma glucose (HFPG) levels worldwide. METHODS: The number and rate of deaths and disability-adjusted life years (DALYs) from HFPG-induced NASH-related liver cancer were estimated based on the results of the 2019 Global Burden of Disease Study. The estimated annual percentage changes (EAPCs) for age-standardized death or DALYs rates were calculated using a generalized linear model with a Gaussian distribution to quantify the temporal trends in the global burden of NASH-related liver cancer attributable to HFPG. The strength and direction of the association between the sociodemographic index (SDI) and death or DALY rate were measured using Spearman's rank-order correlation. RESULTS: Globally, approximately 7.59% of all DALY and 8.76% of all mortalities of NASH-related liver cancer in 2019 were due to HFPG. The age-standardized death and DALY rates of NASH-related liver cancer attributable to HFPG increased from 1990 to 2019. The corresponding EAPCs were 0.69 (95% UI 0.48-0.89), and 0.30 (95% UI 0.05-0.56), respectively. This increasing pattern was most obvious in the high- and low-SDI regions. The age-standardized mortality and DALYs rate of NASH-related liver cancer attributable to HFPG varies considerably worldwide, with the middle SDI region having the highest death and DALY rates in 2019 (DALY 0.96 [95% UI 0.23-2.18]; death 0.05 [95% UI 0.01-0.11]). CONCLUSION: The burden of NASH-related liver cancer attributable to HFPG has increased over the past three decades, particularly in regions with high and low SDI.

Stable Fluorescent Nanoparticles Based on Co-assembly of Acifluorfen and Poly(salicylic acid) for Enhancing Herbicidal Activity and Reducing Environmental Risks.

Herbicides are widely used in modern agricultural production for their advantages of high efficiency, convenience, and speed. However, there have been many problems caused by herbicide formulations, such as volatilization, leaching, and rain-washing loss in the process of agricultural application. Self-assembled nanotechnology is a promising strategy to solve these existing problems due to the environmentally friendly preparation process and high delivery efficiency. In this study, the stable fluorescent nanoparticles (AP NPs) based on co-assembly of acifluorfen (ACI) and poly(salicylic acid) (PSA) are constructed by using non-covalent bond interactions. The results indicate that the obtained nanoparticles with a stable fluorescence characteristic show improved physiochemical properties, such as uniform morphology, good thermal stability, low surface tension, and high retention on plants. The co-assembly can produce singlet oxygen to enhance the herbicidal activity under irradiation of light and reduce the leaching property of ACI to minimize the adverse impact on the aquatic environment. The safety evaluation of soybean seedlings indicates that AP NPs have no damage to non-target plants. In summary, the co-assembled herbicidal nano-formulation composed of ACI and PSA has high bioactivity and low environmental risks, which can be widely used in agricultural production.

Ascorbate oxidase-like nanozyme with high specificity for inhibition of cancer cell proliferation and online electrochemical DOPAC monitoring.

Despite the extensive investigation of the nanozymes exhibit their favorable performance compared to natural enzymes, nevertheless, the highly specific nanozyme still needs to be developed so that it can meet the requirements of exploring the mechanism as well as administration of related diseases and selective monitoring in biological system. In this study, self-assembled glutathione-Cu/Cu2O nanoparticles (GSH-Cu/Cu2O NPs) that exhibits specific ascorbic acid (AA) oxidase-like catalytic activity were constructed for AA-activated and H2O2-reinforced cancer cell proliferation inhibition and selective neurochemical monitoring. Cu/Cu2O NPs demonstrates effective AA oxidase-like activity and no common characteristics of other redox mimic enzymes often present in nanozyme. In particular, we found that the AA oxidase-like activity of GSH-Cu/Cu2O nanozyme was significantly improved by about 40% by improving the activation ability toward oxygen. The synthesized nanozyme can induce the generation of active oxygen by accelerating the oxidation of AA, which effectively suppresses the proliferation of cancer cells. We constructed an online electrochemical system (OECS) though loading nanozyme with enhanced ascorbate oxidase activity into a microreactor and setting it in the upstream of the detector. This GSH-Cu/Cu2O NPs-integrated microreactor can completely eliminate AA interference of the physical level toward 3,4-dihydroxy phenylacetic acid (DOPAC) electrochemical measurement, and the nanozyme-based OECS is able to continuously capture DOPAC alteration in rat brain acidosis model. Our findings may inspire rational design of nanozymes with high specificity as well as nanozyme-based selectivity solution for in vivo detection and show promising opportunities for their involvement in neurochemistry investigation.

[Comprehensive evaluation of Pinellia ternata germplasm resources based on phenotypic trait classification].

The evaluation of germplasm resources is the prerequisite for the development, utilization, and conservation of Chinese medicinal resources. The selection of excellent germplasm is the key to the breeding and orderly production of Pinellia ternata. In this study, 21 germplasm materials of P. ternata from major production areas in China were collected and analyzed for population diversity after phenotypic preliminary screening. The results have revealed that the P. ternata population has abundant phenotypic variation, and the phenotypic changes could be divided into five phenotypes in terms of organ trait variation. Further analysis of variation in 20 quantitative traits of the population revealed that the coefficient of variation for adenosine content(339.05%) was the largest, while the coefficient of variation for the underground plant height(16.35%) was the smallest. Correlation analysis showed that there was a strong correlation among various traits, with 52 pairs of traits showing highly significant correlation(P<0.01) and 19 pairs of traits showing a significant correlation(P<0.05). The 21 germplasms in the test could be classified into three major clusters by cluster analysis, with Cluster Ⅱ having the highest number and content of nucleosides, making it suitable for the selection and breeding of P. ternata varieties with high content of nucleosides. The yield in Cluster Ⅲ was higher than that in other groups, making it suitable for the selection and breeding of P. ternata varieties with a high yield. All trait indicators could be simplified into five principal component factors through principal component analysis, and the cumulative contribution rate was up to 86.04%. Further, comprehensive analysis using membership function and stepwise regression analysis identified nine traits, such as plant height, main leaf length, and underground plant height as characteristic indicators for the comprehensive evaluation of germplasm resources of P. ternata. BX007, BX008, and BX005 were identified as germplasms with both high yield and high uridine content, with BX007 having the highest uridine content of 479.51 µg·g~(-1). It belonged to the germplasm of P. ternata with double bulbils and could be cultivated as a potential good variety. Based on the phenotypic classification of P. ternata, systematic resource evaluation was carried out in this study, which could lay a foundation for the excavation of genetic resources and the breeding of new varieties of P. ternata.

Occupational and domestic physical activity and diabetes risk in adults: Results from a long-term follow-up cohort.

Background: Physical activity (PA) has been associated with decreased incidence of diabetes. However, few studies have evaluated the influence of occupational and domestic PA on the risk of diabetes with a long-term follow-up. We aimed to examine the association between occupational and domestic PA and the risk of diabetes in a long-term prospective cohort of Chinese adults. Methods: A total of 10,343 adults who were followed up in the China Health and Nutrition Survey from 1997 to 2015 were included in our analysis. Occupational and domestical PA were collected with detailed seven-day data and were converted into metabolic equivalents values. Total PA included occupational, domestic, transportation, and leisure time PA. Diabetes cases were identified by self-reported doctor/health professional diagnosis of diabetes, fasting blood glucose ≥7.0 mmol/L, and glycosylated hemoglobin (HbA1c) ≥6.5%. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results: During up to 18 years of follow-up (median 10 years), there were 575 diabetes cases documented. Occupational PA accounted for the majority of total PA (68%) in Chinese population, followed by domestic PA (25%). With adjustments for possible covariates, the highest quartiles of total PA (HR, 0.728 [95% CI, 0.570-0.929]) and occupational PA (HR, 0.765 [95% CI, 0.596-0.982]) were significantly associated with a lower risk of diabetes compared with lowest quartiles. The association between domestic PA and the risk of diabetes was insignificant (P >0.05). Conclusion: Higher levels of occupational PA were associated with a decreased risk of diabetes risk in the Chinese population. Domestic PA was not associated with the incidence of diabetes.

Mesoscale visualization of three-dimensional microvascular architecture and immunocyte distribution in intact mouse liver lobes.

Rational: The complex vascular architecture and diverse immune cells of the liver are critical for maintaining liver homeostasis. However, quantification of the network of liver vasculature and immunocytes at different scales from a single hepatic lobule to an intact liver lobe remains challenging. Methods: Here, we developed a fast and fluorescence-preserving transparency method, denoted liver-CUBIC, for systematic and integrated analysis of the microcirculation and the three-dimensional distribution of dendritic cells (DCs)/macrophages in intact liver lobes. Results: Whole-mount imaging at mesoscale revealed that the hepatic classical lobule preferred the oblate ellipsoid morphology in the mouse liver and exhibited hepatic sinusoids with heterogeneous arrangement and intricate loop structure. Liver fibrosis not only induces sinusoidal density increase but also promotes sinusoidal arrangement with increased sinusoidal branch and loop structure. Meanwhile, we found that CD11c+ DCs followed a lognormal distribution in the hepatic lobules, skewing toward lobular boundary in steady state. CCl4-induced chronic liver injury promoted CD11c+ DC rearrangement at the lobular border before the formation of liver fibrosis. Furthermore, through whole-mount imaging of tumor-immune cell-vascular crosstalk in intact lobes based on liver-CUBIC, we characterized an accumulation of CX3CR1+CCR2+F4/80+ macrophages at metastatic foci in early colorectal liver metastases. Importantly, colorectal cells secrete CCL2 to mobilize CX3CR1+CCR2+F4/80+ macrophages to accumulate at liver micrometastases, and the interruption of CCL2-induced macrophage accumulation inhibits early colonization of metastasis in the liver. Conclusions: Our investigation of the sinusoidal network and DC/macrophage arrangements through the liver-CUBIC approach and whole-mount imaging provide a powerful platform for understanding hepatic circulatory properties and immune surveillance in the liver.

Au nanoflower film-based stretchable biosensors for in situ monitoring of superoxide anion release in cell mechanotransduction.

Cell mechanotransduction plays an important role in vascular regulation and disease development. Excessive accumulation of ROS, especially superoxide anion radicals (O2˙-), is closely related to cardiovascular diseases. Lately, NADPH oxidases, which are the major source of O2˙- production in vascular tissues, have been demonstrated to be involved in cardiovascular diseases. Therefore, in situ and real-time monitoring of superoxide anions (O2˙-) is essential for exploring the mechanisms of mechanotransduction associated with NADPH oxidase function in living cells. Here we report a rationally designed ultrasonication-assisted approach for growing Au nanoflower films on a flexible surface, which serves as the desired interface for cysteine and superoxide dismutase (SOD) anchoring to form a flexible and stretchable electrode (SOD/Cys/Au SE). The SOD/Cys/Au SE shows good stretchability, fast electron-transfer rates, and high selectivity to measure O2˙- released from cells during the stretching states. Our strategy provides a basis for developing more sophisticated stretchable biosensing tools to induce and monitor transient biochemical signals during cell mechanotransduction.

The prevalence of hypophosphatemia and refeeding-related hypophosphatemia in hospitalized patients requiring parental nutrition: a retrospective study.

OBJECTIVE: Hypophosphatemia might cause respiratory and heart failure and even death. We aimed to evaluate risk factors for hypophosphatemia and refeeding-related hypophosphatemia in patients requiring parental nutrition (PN). METHODS: This was a single-center, retrospective study. Clinical parameters were obtained from medical records. Serum phosphate (inorganic phosphorus) was measured by photometric analysis. Hypophosphatemia was confirmed when serum phosphate level was less than 0.8 mmol/L (≈2.5 mg/dl). Refeeding related hypophosphatemia was confirmed if serum phosphate level had a decrease of 0.16 mmol/L or more from baseline and if the final assessment was below 0.65 mmol/L. RESULTS: A total number of 655 (426 men and 229 women, aged 62.8 ± 14.8 years) hospitalized patients requiring PN were included in the study, and 60.6% of them were patients with cancer. The average body mass index (BMI) was 21.1 ± 4.1 kg/m2 and the median of serum phosphate was 0.9 mmol/L (quartile range: 0.68 mmol/L, 1.11 mmol/L). The prevalence of hypophosphatemia was 37.6% (246/655). Older age (≥ 65 years vs. < 65 years), lower serum level of pre-albumin (< 160 mg/L vs. ≥ 160 mg/L), calcium (< 2.11 mmol/L vs. ≥ 2.11 mmol/L), and magnesium (< 0.75 mmol/L vs. ≥ 0.75 mmol/L) were associated with high risk of hypophosphatemia by multivariate logistic regression (OR ranged from 1.43 to 3.06, all p < 0.05). Refeeding related hypophosphatemia was 9.5% (16/168). Serum level of calcium at baseline was significantly lower in participants with refeeding related hypophosphatemia than those without it. Total calorie and nitrogen delivered during first week of PN period showed no obvious difference between patients with and without refeeding related hypophosphatemia. CONCLUSIONS: Hypophosphatemia is common (37.6%) in hospitalized patients requiring PN. Monitoring of serum level of phosphorus is necessary to facilitate early treatment of hypophosphatemia.

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

Importance: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial. Objective: To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations. Data Sources: MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions. Study Selection: Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non-GLP-1 RA drugs in adults. Data Extraction and Synthesis: Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Main Outcomes and Measures: The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021. Results: A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction). Conclusions and Relevance: This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss. Trial Registration: PROSPERO Identifier: CRD42021271599.