The c-di-GMP signalling component YfiR regulates multiple bacterial phenotypes and virulence in Pseudomonas plecoglossicida.

AIMS: Pseudomonas plecoglossicida (P. plecoglossicida) is the causative agent of visceral granulomas disease in large yellow croaker (Larimichthys crocea) and it causes severe economic loss to its industry. Biofilm formation, related to intracellular cyclic bis (3'-5') diguanylic acid (c-di-GMP) levels, is essential for the lifestyle of P. plecoglossicida. This research aims to investigate the role of YfiR-a key regulator of the diguanylate cyclase YfiN to regulate c-di-GMP levels and reveal its regulatory function of bacterial virulence expression in P. plecoglossicida. METHODS AND RESULTS: A genetic analysis was carried out to identify the yfiBNR operon for c-di-GMP regulation in P. plecoglossicida. Then, we constructed a yfiR mutant and observed increased c-di-GMP levels, enhanced biofilm formation, increased exopolysaccharides, and diminished swimming and swarming motility in this strain. Moreover, through establishing a yolk sac microinjection infection model in zebrafish larvae, an attenuated phenotype of yfiR mutant that manifested as restored survival and lower bacterial colonization was found. CONCLUSIONS: YfiR is the key regulator of virulence in P. plecoglossicida, which contributes to c-di-GMP level, biofilm formation, exopolysaccharides production, swimming, swarming motility, and bacterial colonization in zebrafish model.

Intermittent fasting induces rapid hepatocyte proliferation to restore the hepatostat in the mouse liver.

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary changes influence liver homeostasis. Here, we show that a switch from ad libitum feeding to intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF-induced hepatocyte proliferation is driven by the combined action of systemic FGF15 and localized WNT signaling. Hepatocyte proliferation during periods of fasting and re-feeding re-establishes a constant liver-to-body mass ratio, thus maintaining the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and challenges the widely held view that liver tissue is mostly quiescent unless chemically or mechanically injured.

AI support for accurate and fast radiological diagnosis of COVID-19: an international multicenter, multivendor CT study.

OBJECTIVES: Differentiation between COVID-19 and community-acquired pneumonia (CAP) in computed tomography (CT) is a task that can be performed by human radiologists and artificial intelligence (AI). The present study aims to (1) develop an AI algorithm for differentiating COVID-19 from CAP and (2) evaluate its performance. (3) Evaluate the benefit of using the AI result as assistance for radiological diagnosis and the impact on relevant parameters such as accuracy of the diagnosis, diagnostic time, and confidence. METHODS: We included n = 1591 multicenter, multivendor chest CT scans and divided them into AI training and validation datasets to develop an AI algorithm (n = 991 CT scans; n = 462 COVID-19, and n = 529 CAP) from three centers in China. An independent Chinese and German test dataset of n = 600 CT scans from six centers (COVID-19 / CAP; n = 300 each) was used to test the performance of eight blinded radiologists and the AI algorithm. A subtest dataset (180 CT scans; n = 90 each) was used to evaluate the radiologists' performance without and with AI assistance to quantify changes in diagnostic accuracy, reporting time, and diagnostic confidence. RESULTS: The diagnostic accuracy of the AI algorithm in the Chinese-German test dataset was 76.5%. Without AI assistance, the eight radiologists' diagnostic accuracy was 79.1% and increased with AI assistance to 81.5%, going along with significantly shorter decision times and higher confidence scores. CONCLUSION: This large multicenter study demonstrates that AI assistance in CT-based differentiation of COVID-19 and CAP increases radiological performance with higher accuracy and specificity, faster diagnostic time, and improved diagnostic confidence. KEY POINTS: • AI can help radiologists to get higher diagnostic accuracy, make faster decisions, and improve diagnostic confidence. • The China-German multicenter study demonstrates the advantages of a human-machine interaction using AI in clinical radiology for diagnostic differentiation between COVID-19 and CAP in CT scans.

Assessment of Hepatocyte Ploidy by Flow Cytometry.

Polyploidy is a common and dynamic feature of mature rodent and human hepatocytes. While polyploidization occurs naturally during growth, alterations in the distribution of diploid and polyploid cells in the liver can be indicative of tissue stress or a pathologic state. Here, we describe a method for flow cytometric quantification of ploidy distribution by staining with propidium iodide. We first outline a hepatocyte isolation procedure from mouse liver through a two-step perfusion system for analysis of cellular ploidy. In an alternative approach, we employ a nuclei isolation protocol to assess nuclear ploidy. Finally, we describe how the use of fluorescent cell markers is compatible with these methods and helps retain information on cellular position within the tissue.

EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and ß-oxidation.

EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Assembly of Poly(ethylene glycol)ylated Oleanolic Acid on a Linear Polymer as a Pseudomucin for Influenza Virus Inhibition and Adsorption.

Biomimicry of the mucin barrier function is an efficient strategy to counteract influenza. We report the simple aminolyzation of poly(methyl vinyl ether-alt-maleic anhydride) (PM) using amine-terminated poly(ethylene glycol)ylated oleanolic acid (OAPEG) to mimic the mucin structure and its adsorption of the influenza virus. Direct interactions between influenza hemagglutinin (HA) and the prepared macromolecule evaluated by surface plasmon resonance and isothermal titration calorimetry demonstrated that the multivalent presentation of OAPEG on PM enhanced the binding affinity to HA with a decrease in KD of approximately three orders of magnitude compared with monomeric OAPEG. Moreover, hemagglutination inhibition assay, viral growth inhibition assay, and cytopathic effect reduction assay indicated that the nonglycosylated polymer could mimic natural heavily glycosylated mucin and thus promote the attachment of the virus in a subnanomolar range. Further investigation of the antiviral effects via time-of-addition assay, dynamic light scattering experiments, and transmission electron microscopy photographs indicated that the pseudomucin could adsorb the virion particles and synergistically inhibit the early attachment and final release steps of the influenza infection cycle. These findings demonstrate the effectiveness of the macromolecule in the physical sequestration and prevention of viral infection. Notably, due to its structural similarities with mucin, the biomacropolymer also has the potential for the rational design of antiviral drugs, influenza adsorbents, or filtration materials and the construction of model systems to explore protection against other pathogenic viruses.

Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade.

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/ß-catenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of E2f7 and E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.

An intelligent T1-T2 switchable MRI contrast agent for the non-invasive identification of vulnerable atherosclerotic plaques.

Unlike stable atherosclerotic plaques, vulnerable plaques are very likely to cause serious cardio-cerebrovascular diseases. Meanwhile, how to non-invasively identify vulnerable plaques at early stages has been an urgent but challenging problem in clinical practices. Here, we propose a macrophage-targeted and in situ stimuli-triggered T1-T2 switchable magnetic resonance imaging (MRI) nanoprobe for the non-invasive diagnosis of vulnerable plaques. Precisely, single-dispersed iron oxide nanoparticles (IONPs) modified with hyaluronic acid (HA), denoted as IONP-HP, show macrophage targetability and T1 MRI enhancement (r2/r1 = 3.415). Triggered by the low pH environment of macrophage lysosomes, the single-dispersed IONP-HP transforms into a cluster analogue, which exhibits T2 MRI enhancement (r2/r1 = 13.326). Furthermore, an in vivo switch of T1-T2 enhancement modes shows that the vulnerable plaques exhibit strong T1 enhancement after intravenous administration of the nanoprobe, followed by a switch to T2 enhancement after 9 h. In contrast, stable plaques show only slight T1 enhancement but without T2 enhancement. It is therefore imperative that the intelligent and novel nanoplatform proposed in this study achieves a substantial non-invasive diagnosis of vulnerable plaques by means of a facile but effective T1-T2 switchable process, which will significantly contribute to the application of materials science in solving clinical problems.

Isolated Metastasis to Spleen-Stomach Space From Follicular Thyroid Cancer Combined With a Benign Subcutaneous Nodule on 18F-FDG PET/CT and 131I Scintigraphy.

ABSTRACT: A 40-year-old woman with follicular thyroid cancer underwent a systemic PET/CT evaluation before operation and then received total thyroidectomy and radioactive 131I ablation therapy. Posttreatment imaging of 131I whole-body scan with SPECT/CT showed that metastasis on the spleen-stomach space coexists with mimicking subcutaneous metastasis, considering their level of 131I accumulation and morphological changes on PET/CT. However, histopathology confirmed the subcutaneous lesion of fibrous hyperplasia by fine-needle aspiration. This case demonstrates a vital role of SPECT/CT in the diagnosis of metastatic thyroid cancer and mimicking metastasis.

Guanidinothiosialoside-Human Serum Albumin Conjugate Mimics mucin Barrier to Restrict Influenza Infection.

A guanidinothiosialoside-human serum albumin conjugate as mucin mimic was prepared via a copper-free click reaction. Matrix-Assisted Laser Desorption/Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) indicated that three sialoside groups were grafted onto the protein backbone. The synthetic glycoconjugate exhibited strong influenza virion capture and trapping capability. Further mechanistic studies showed that this neomucin bound tightly to neuraminidase on the surface of influenza virus with a dissociation constant (KD) in the nanomolar range and had potent antiviral activity against a broad spectrum of virus strains. Most notably, the glycoconjugate acted as a biobarrier was able to protect Madin-Darby canine kidney (MDCK) cells from influenza viral infection with 50% effective concentrations (EC50) in the nanomolar range and showed no cytotoxicity towards Human Umbilical Vein Endothelial Cells (HUVEC) at high concentrations. This research establishes an attractive strategy for the development of new multivalent antiviral agents based on mucin structure. Moreover, the method for the functionalization of the natural biological macromolecular scaffold with bioactive small molecules also lays the experimental foundation for potential biomedical and biomaterial applications.

Clinical features of COVID-19 convalescent patients with re-positive nucleic acid detection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic that has rapidly spread worldwide. Increasingly, confirmed patients being discharged according to the current diagnosis and treatment protocols, follow-up of convalescent patients is important to knowing about the outcome. METHODS: A retrospective study was performed among 98 convalescent patients with COVID-19 in a single medical center. The clinical features of patients during their hospitalization and 2-week postdischarge quarantine were collected. RESULTS: Among the 98 COVID-19 convalescent patients, 17 (17.3%) were detected positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid during 2-week postdischarge quarantine. The median time from discharge to SARS-CoV-2 nucleic acid re-positive was 4 days (IQR, 3-8.5).The median time from symptoms onset to final respiratory SARS-CoV-2 detection of negative result was significantly longer in re-positive group (34 days [IQR, 29.5-42.5]) than in non-re-positive group (19 days [IQR, 16-26]). On the other hand, the levels of CD3-CD56 + NK cells during hospitalization and 2-week postdischarge were higher in re-positive group than in non-re-positive group (repeated measures ANOVA, P = .018). However, only one case in re-positive group showed exudative lesion recurrence in pulmonary computed tomography (CT) with recurred symptoms. CONCLUSION: It is still possible for convalescent patients to show positive for SARS-CoV-2 nucleic acid detection, but most of the re-positive patients showed no deterioration in pulmonary CT findings. Continuous quarantine and close follow-up for convalescent patients are necessary to prevent possible relapse and spread of the disease to some extent.

Differential Diagnosis of Benign and Malignant Thyroid Nodules Using Deep Learning Radiomics of Thyroid Ultrasound Images.

PURPOSE: We aimed to propose a highly automatic and objective model named deep learning Radiomics of thyroid (DLRT) for the differential diagnosis of benign and malignant thyroid nodules from ultrasound (US) images. METHODS: We retrospectively enrolled and finally include US images and fine-needle aspiration biopsies from 1734 patients with 1750 thyroid nodules. A basic convolutional neural network (CNN) model, a transfer learning (TL) model, and a newly designed model named deep learning Radiomics of thyroid (DLRT) were used for the investigation. Their diagnostic accuracy was further compared with human observers (one senior and one junior US radiologist). Moreover, the robustness of DLRT over different US instruments was also validated. Analysis of receiver operating characteristic (ROC) curves were performed to calculate optimal area under it (AUC) for benign and malignant nodules. One observer helped to delineate the nodules. RESULTS: AUCs of DLRT were 0.96 (95% confidence interval [CI]: 0.94-0.98), 0.95 (95% confidence interval [CI]: 0.93-0.97) and 0.97 (95% confidence interval [CI]: 0.95-0.99) in the training, internal and external validation cohort, respectively, which were significantly better than other deep learning models (P < 0.01) and human observers (P < 0.001). No significant difference was found when applying DLRT on thyroid US images acquired from different US instruments. CONCLUSIONS: DLRT shows the best overall performance comparing with other deep learning models and human observers. It holds great promise for improving the differential diagnosis of benign and malignant thyroid nodules.

Effect of elasticity on the phagocytosis of micro/nanoparticles.

A broad range of investigation methods and frameworks are currently used to throughly study the elasticity of various types of micro/nanoparticles (MNPs) with different properties and to explore the effect of such properties on their interactions with biological species. Specifically, the elasticity of MNPs serves as a key influencing factor with respect to important aspects of phagocytosis, such as the clathrin-mediated phagocytosis, caveolae-mediated phagocytosis, macropinocytosis, and cell membrane fusion. Achieving a clear understanding of the relationships that exist between the elasticity of MNPs and their phagocytic processes is essential to improve their performance in drug delivery, which is related to aspects such as circulation lifetime in blood, accumulation time in tissues, and resistance to metabolism. Resolving such aspects is very challenging, and related efforts require using the right tools/methods, which are not always easy to identify. This review aims to facilitate this by summarizing and comparing different cell phagocytosis pathways, while considering various MNPs exhibiting different elastic properties, shape change capabilities, and their effect on cellular uptake. We conduct an overview of the advantages exhibited by different MNPs with respect to both in vitro and in vivo delivery, taking computational simulation analysis and experimental results into account. This study will provide a guide for how to investigate various types of MNPs in terms of their elastic properties, together with their biomedical effects that rely on phagocytosis.

The relationship among occupational irradiation, DNA methylation status, and oxidative damage in interventional physicians.

Ionizing radiation can induce deoxyribonucleic acid (DNA) methylation pattern change, and ionizing radiation-induced oxidative damage may also affect DNA methylation status. However, the influence of low-dose ionizing radiation, such as occupational radiation exposure, on DNA methylation is still controversial.By investigating the relationship between occupational radiation exposure and DNA methylation changes, we evaluated whether radiation-induced oxidative damage was related to DNA methylation alterations and then determined the relationship among occupational radiation level, DNA methylation status, and oxidative damage in interventional physicians.The study population included 117 interventional physicians and 117 controls. We measured global methylation levels of peripheral blood leukocyte DNA and expression level of DNA methyltransferase (Dnmts) and homocysteine (Hcy) in serum to assess the DNA methylation status of the body. We measured 8-hydroxy-2'-deoxyguanosine (8-OHDG) and 4-hydroxynonenal (4-HNE) levels as indices of oxidative damage. Relevance analysis between multiple indices can reflect the relationship among occupational radiation exposure, DNA methylation changes, and oxidative damage in interventional physicians.The expression levels of Dnmts, 4-HNE, and 8-OHDG in interventional physicians were higher than those in controls, while there was no statistical difference in total DNA methylation rate and expression of Hcy between interventional physicians and controls. Total cumulative personal dose equivalent in interventional physicians was positively correlated with the expression levels of Dnmts, 8-OHDG, and 4-HNE. The expression levels of 8-OHDG in interventional physicians were negatively correlated with global DNA methylation levels and positively correlated with the expression levels of Hcy.Occupational radiation exposure of interventional physicians has a certain effect on the expression of related enzymes in the process of DNA methylation, while ionizing radiation-induced oxidative damage also has a certain effect on DNA methylation. However, there was no evidence that dose burden of occupational exposure was associated to changes of DNA methylation status of interventional physicians, since it is rather unclear which differences are observed among the effects produced by radiation exposure and oxidative damage.

Computed Tomography Radiomic Nomogram for Preoperative Prediction of Extrathyroidal Extension in Papillary Thyroid Carcinoma.

Objectives: Determining the presence of extrathyroidal extension (ETE) is important for patients with papillary thyroid carcinoma (PTC) in selecting the proper surgical approaches. This study aimed to explore a radiomic model for preoperative prediction of ETE in patients with PTC. Methods: The study included 624 PTC patients (without ETE, n = 448; with minimal ETE, n = 52; with gross ETE, n = 124) whom were divided randomly into training (n = 437) and validation (n = 187) cohorts; all data were gathered between January 2016 and November 2017. Radiomic features were extracted from computed tomography (CT) images of PTCs. Key radiomic features were identified and incorporated into a radiomic signature. Combining the radiomic signature with clinical risk factors, a radiomic nomogram was constructed using multivariable logistic regression. Delong test was used to compare different receiver operating characteristic curves. Results: Five key radiomic features were incorporated into the radiomic signature, which were significantly associated with ETE (p < 0.001 for both cohorts) and slightly better than clinical model integrating significant clinical risk factors in the training cohort (area under the receiver operating characteristic curve (AUC), 0.791 vs. 0.778; F1 score, 0.729 vs. 0.714) and validation cohort (AUC, 0.772 vs. 0.756; F1 score, 0.710 vs. 0.692). The radiomic nomogram significantly improved predictive value in the training cohort (AUC, 0.837, p < 0.001; F1 score, 0.766) and validation cohort (AUC, 0.812, p = 0.024; F1 score, 0.732). Conclusions: The radiomic nomogram significantly improved the preoperative prediction of ETE in PTC patients. It indicated that radiomics could be a valuable method in PTC research.

Radiomic analysis for preoperative prediction of cervical lymph node metastasis in patients with papillary thyroid carcinoma.

PURPOSE: Cervical lymph node (LN) metastasis of papillary thyroid carcinoma (PTC) is critical for treatment and prognosis. We explored the feasibility of using radiomics to preoperatively predict cervical LN metastasis in PTC patients. METHOD: Total 221 PTC patients (training cohort: n = 154; validation cohort: n = 67; divided randomly at the ratio of 7:3) were enrolled and divided into 2 groups based on LN pathologic diagnosis (N0: n = 118; N1a and N1b: n = 88 and 15, respectively). We extracted 546 radiomic features from non-contrast and venous contrast-enhanced computed tomography (CT) images. We selected 8 groups of candidate feature sets by minimum redundancy maximum relevance (mRMR), and obtained 8 radiomic sub-signatures by support vector machine (SVM) to construct the radiomic signature. Incorporating the radiomic signature, CT-reported cervical LN status and clinical risk factors, a nomogram was constructed using multivariable logistic regression. The nomogram's calibration, discrimination, and clinical utility were assessed. RESULTS: The radiomic signature was associated significantly with cervical LN status (p < 0.01 for both training and validation cohorts). The radiomic signature showed better predictive performance than any radiomic sub-signatures devised by SVM. Addition of radiomic signature to the nomogram improved the predictive value (area under the curve (AUC), 0.807 to 0.867) in the training cohort; this was confirmed in an independent validation cohort (AUC, 0.795 to 0.822). Good agreement was observed using calibration curves in both cohorts. Decision curve analysis demonstrated the radiomic nomogram was worthy of clinical application. CONCLUSIONS: Our radiomic nomogram improved the preoperative prediction of cervical LN metastasis in PTC patients.

Synergistic triple-combination therapy with hyaluronic acid-shelled PPy/CPT nanoparticles results in tumor regression and prevents tumor recurrence and metastasis in 4T1 breast cancer.

Breast cancer is characterized by high aggression, poor prognosis, and high recurrence rate. Early detection and specific targeted treatment with less toxicity are the ultimate goals for breast cancer therapy. To improve antitumor therapeutic effects, we developed a novel polypyrrole nanoparticle using the near infrared dye IRDye800CW with camptothecin (CPT)-conjugated hyaluronic acid (HA) shell (PPy@CPT-HA-IRDye800CW) and performed a photothermal therapy (PTT), along with chemotherapy, guided by fluorescence and photoacoustic dual-modality imaging, in combination with immunotherapy. Irradiation with near infrared (NIR) light offered a strong PTT effect and promoted CPT drug release in tumors. Moreover, we found that chemo-photothermal therapy with PPy@CPT-HA-IRDye800CW NPs, in combination with immune checkpoint inhibitor anti-PD-L1 immunotherapy, synergistically enhanced the anti-tumor immune response, thereby eliminating primary breast cancer and preventing tumor metastases and recurrences in 4T1 tumor-bearing mice. This approach may provide important clues for the clinical management of breast cancer and other malignant tumors.

Effect of Copper Foil Crystal Orientation on Graphene Quality Synthesized by Chemical Vapor Deposition.

Line defects such as wrinkles are believed to change the electrical properties of graphene. However, they are often observed in graphene grown via chemical vapor deposition; hence, it is important to study the impact of the substrate condition on graphene quality. In this work, graphene was synthesized on various copper domains with different crystal orientations and surface morphologies. During the synthesis process, three typical crystal orientations were obtained Cu(001), Cu(101), and Cu(111) showing different surface morphologies with various densities of wrinkles. Graphene wrinkles along with copper wrinkles were studied using atomic force microscopy and Kelvin probe force microscopy. The quality of graphene on different crystal orientations and morphologies was evaluated as well. It was found that different crystallographic orientations lead to different degrees of wrinkle and roughness. In addition, these wrinkle defects exhibited characteristic surface potential variations and the density of substrate wrinkles was closely associated with the uniformity of graphene and led to a disordered structure and low crystallinity.

Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/ß-Catenin Signaling.

In the liver, Wnt/ß-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of ß-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/ß-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.

Manganese-Zeolitic Imidazolate Frameworks-90 with High Blood Circulation Stability for MRI-Guided Tumor Therapy.

Zeolitic imidazolate frameworks (ZIFs) as smart drug delivery systems with microenvironment-triggered release have attracted much attention for tumor therapy. However, the exploration of ZIFs in biomedicine still encounters many issues, such as inconvenient surface modification, fast drug release during blood circulation, undesired damage to major organs, and severe in vivo toxicity. To address the above issues, we developed an Mn-ZIF-90 nanosystem functionalized with an originally designed active-targeting and pH-responsive magnetic resonance imaging (MRI) Y1 receptor ligand [Asn28, Pro30, Trp32]-NPY (25-36) for imaging-guided tumor therapy. After Y1 receptor ligand modification, the Mn-ZIF-90 nanosystem exhibited high drug loading, better blood circulation stability, and dual breast cancer cell membrane and mitochondria targetability, further favoring specific microenvironment-triggered tumor therapy. Meanwhile, this nanosystem showed promising T1-weighted magnetic resonance imaging contrast in vivo in the tumor sites. Especially, this nanosystem with fast clean-up had almost no obvious toxicity and no damage occurred to the major organs in mice. Therefore, this nanosystem shows potential for use in imaging-guided tumor therapy.