Preliminary study on diagnosis of gallbladder neoplastic polyps based on contrast-enhanced ultrasound and grey scale ultrasound radiomics.

Objective: Neoplastic gallbladder polyps (GPs), including adenomas and adenocarcinomas, are considered absolute indications for surgery; however, the distinction of neoplastic from non-neoplastic GPs on imaging is often challenging. This study thereby aimed to develop a CEUS radiomics nomogram, and evaluate the role of a combined grey-scale ultrasound and CEUS model for the prediction and diagnosis of neoplastic GPs. Methods: Patients with GPs of ≥ 1 cm who underwent CEUS between January 2017 and May 2022 were retrospectively enrolled. Grey-scale ultrasound and arterial phase CEUS images of the largest section of the GPs were used for radiomics feature extraction. Features with good reproducibility in terms of intraclass correlation coefficient were selected. Grey-scale ultrasound and CEUS Rad-score models were first constructed using the Mann-Whitney U and LASSO regression test, and were subsequently included in the multivariable logistic regression analysis as independent factors for construction of the combined model. Results: A total of 229 patients were included in our study. Among them, 118 cholesterol polyps, 68 adenomas, 33 adenocarcinomas, 6 adenomyomatoses, and 4 inflammatory polyps were recorded. A total of 851 features were extracted from each patient. Following screening, 21 and 15 features were retained in the grey-scale and CEUS models, respectively. The combined model demonstrated AUCs of 0.88 (95% CI: 0.83 - 0.93) and 0.84 (95% CI: 0.74 - 0.93) in the training and testing set, respectively. When applied to the whole dataset, the combined model detected 111 of the 128 non-neoplastic GPs, decreasing the resection rate of non-neoplastic GPs to 13.3%. Conclusion: Our proposed combined model based on grey-scale ultrasound and CEUS radiomics features carries the potential as a non-invasive, radiation-free, and reproducible tool for the prediction and identification of neoplastic GPs. Our model may not only guide the treatment selection for GPs, but may also reduce the surgical burden of such patients.

The comparison of contrast-enhanced ultrasound and gadoxetate disodium-enhanced MRI LI-RADS for nodules ≤2 cm in patients at high risk for HCC: a prospective study.

Objectives: To investigate the consistency of LI-RADS of CEUS and EOB-MRI in the categorization of liver nodules ≤2cm in patients at high risk for HCC. Methods: Patients at high risk for HCC with nodules ≤2cm who underwent CEUS and EOB-MRI in our hospital were prospectively enrolled. The CEUS images and EOB-MRI imaging of each liver nodule were observed to evaluate inter-observer consistency and category according to CEUS LI-RADS V2017 and CT/MRI LI-RADS V2017 criteria double blinded. Pathology and/or follow-up were used as reference standard. Results: A total of 127 nodules in 119 patients met the inclusion criteria. The inter-observer agreement was good on CEUS and EOB-MRI LI-RADS (kappa = 0.76, 0.76 p < 0.001). The inter-modality agreement was fair (kappa=0.21, p < 0.001). There was no statistical difference in PPV and specificity between CEUS and EOB-MRI LR-5 for HCC, while the difference in AUC was statistically significant. We used new criteria (CEUS LR-5 and EOB-MRI LR-4/5 or CEUS LR-4/5 and EOB-MRI LR-5) to diagnose HCC. The sensitivity, specificity, and AUC of this criteria was 63.4%, 95.6%, and 0.80. Conclusions: CEUS and EOB-MRI showed fair inter-modality agreement in LI-RADS categorization of nodules ≤2 cm. The inter-observer agreement of CEUS and EOB-MRI LI-RADS were substantial. CEUS and EOB-MRI LR-5 have equally good positive predictive value and specificity for HCC ≤ 2cm, and combining these two modalities may better diagnose HCC ≤ 2 cm. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04212286.

Turning Ultra-Low Coercivity and Ultra-High Temperature Stability Within 897 K via Continuous Crystal Ordering Fluctuations.

High-performance soft magnetic materials are important for energy conservation and emission reduction. One challenge is achieving a combination of reliable temperature stability, high resistivity, high Curie temperature, and high saturation magnetization in a single material, which often comes at the expense of intrinsic coercivity-a typical trade-off in the family of soft magnetic materials with homogeneous microstructures. Herein, a nanostructured FeCoNiSiAl complex concentrated alloy is developed through a hierarchical structure strategy. This alloy exhibits superior soft magnetic properties up to 897 K, maintaining an ultra-low intrinsic coercivity (13.6 A m-1 at 297 K) over a wide temperature range, a high resistivity (138.08 µΩ cm-1 at 297 K) and the saturation magnetization with only a 16.7% attenuation at 897 K. These unusual property combinations are attributed to the dual-magnetic-state nature with exchange softening due to continuous crystal ordering fluctuations at the atomic scale. By deliberately controlling the microstructure, the comprehensive performance of the alloy can be tuned and controlled. The research provides valuable guidance for the development of soft magnetic materials for high-temperature applications and expands the potential applications of related functional materials in the field of sustainable energy.

Novel artemisinin derivative P31 inhibits VEGF-induced corneal neovascularization through AKT and ERK1/2 pathways.

Corneal neovascularization (CoNV)is a major cause of blindness in many ocular diseases. Substantial evidence indicates that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of corneal neovascularization. Previous evidence showed that artemisinin may inhibit angiogenesis through down regulation of the VEGF receptors. We designed and synthesized artemisinin derivatives, and validated their inhibitory effect on neovascularization in cell and animal models, and explored the mechanisms by which they exert an inhibitory effect on CoNV. Among these derivatives, P31 demonstrated significant anti-angiogenic effects in vivo and in vitro. Besides, P31 inhibited VEGF-induced HUVECs angiogenesis and neovascularization in rabbit model via AKT and ERK pathways. Moreover, P31 alleviated angiogenic and inflammatory responses in suture rabbit cornea. In conclusion, as a novel artemisinin derivative, P31 attenuates corneal neovascularization and has a promising application in ocular diseases.

Bile acid-microbiota crosstalk in hepatitis B virus infection.

Hepatitis B virus (HBV) is a hepatotropic non-cytopathic virus characterized by liver-specific gene expression. HBV infection highjacks bile acid metabolism, notably impairing bile acid uptake via sodium taurocholate cotransporting polypeptide (NTCP), which is a functional receptor for HBV entry. Concurrently, HBV infection induces changes in bile acid synthesis and the size of the bile acid pool. Conversely, bile acid facilitates HBV replication and expression through the signaling molecule farnesoid X receptor (FXR), a nuclear receptor activated by bile acid. However, in HepaRG cells and primary hepatocytes, FXR agonists suppress HBV RNA expression and the synthesis and secretion of DNA. In the gut, the size and composition of the bile acid pool significantly influence the gut microbiota. In turn, the gut microbiota impacts bile acid metabolism and innate immunity, potentially promoting HBV clearance. Thus, the bile acid-gut microbiota axis represents a complex and evolving relationship in the context of HBV infection. This review explores the interplay between bile acid and gut microbiota in HBV infection and discusses the development of HBV entry inhibitors targeting NTCP.

Dynamic Contrast-Enhanced Ultrasonography Combined With LR-M Classification Criteria for Differentiating Malignant Liver Nodules at High Risk for Hepatocellular Carcinoma.

OBJECTIVE: We aimed to investigate the value of quantitative parameters derived from dynamic contrast-enhanced ultrasonography (DCE-US) and a combination of these quantitative parameters with the LR-M classification criteria in distinguishing hepatocellular carcinoma (HCC) nodules and non-HCC malignancies. METHODS: HCC and non-HCC malignant nodules were grouped using pathologic results, and each nodule was classified using CEUS LI-RADS 2017. Quantitative CEUS analysis of each nodule was performed using VueBox, and quantitative parameters were compared between the HCC and non-HCC groups. The diagnostic efficacy of the LR-5 category for HCC was analyzed using the LR-M classification criteria along with time-related quantitative parameters. RESULTS: Of the 190 malignant liver nodules, 137 and 53 were HCCs and non-HCC malignancies, respectively. The median values of quantitative parameters RT (rise time), TTP (time to peak), mTTl (mean transit time local), and FT (fall time) in the non-HCC malignant group were lower than those in the HCC group, with p < 0.05. There was a statistically significant difference in WiAUC (wash-in area under the curve), WoAUC (wash-out area under the curve), WiWoAUC (wash-in and wash-out area under the curve), and WoR (wash-out rate) values between HCC and non-HCC malignant groups, with p < 0.05. Using LR-M washout time <60 s and FT ≤21.2 s as the new diagnostic standard, the LR-5 category showed a sensitivity of 83.9%, specificity of 96.2%, and positive predictive value of 98.3% for HCC diagnosis. CONCLUSION: DCE-US can facilitate the distinction of HCCs and non-HCC malignancies. Non-HCC malignancies present with earlier peak enhancement and more rapid and marked washout than HCC nodules. The combination of the LR-M classification criteria and FT ≤21.2 s can significantly improve the diagnostic sensitivity of the LR-5 category for HCC.

Harnessing instability for work hardening in multi-principal element alloys.

The strength-ductility trade-off has long been a Gordian knot in conventional metallic structural materials and it is no exception in multi-principal element alloys. In particular, at ultrahigh yield strengths, plastic instability, that is, necking, happens prematurely, because of which ductility almost entirely disappears. This is due to the growing difficulty in the production and accumulation of dislocations from the very beginning of tensile deformation that renders the conventional dislocation hardening insufficient. Here we propose that premature necking can be harnessed for work hardening in a VCoNi multi-principal element alloy. Lüders banding as an initial tensile response induces the ongoing localized necking at the band front to produce both triaxial stress and strain gradient, which enables the rapid multiplication of dislocations. This leads to forest dislocation hardening, plus extra work hardening due to the interaction of dislocations with the local-chemical-order regions. The dual work hardening combines to restrain and stabilize the premature necking in reverse as well as to facilitate uniform deformation. Consequently, a superior strength-and-ductility synergy is achieved with a ductility of ~20% and yield strength of 2 GPa during room-temperature and cryogenic deformation. These findings offer an instability-control paradigm for synergistic work hardening to conquer the strength-ductility paradox at ultrahigh yield strengths.

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Lanosterol regulates abnormal amyloid accumulation in LECs through the mediation of cholesterol pathway metabolism.

Age-related cataract (ARC) is the predominant cause of global blindness, linked to the progressive aging of the lens, oxidative stress, perturbed calcium homeostasis, hydration irregularities, and modifications in crystallin proteins. Currently, surgical intervention remains the sole efficacious remedy, albeit carrying inherent risks of complications that may culminate in irreversible blindness. It is urgent to explore alternative, cost-effective, and uncomplicated treatment modalities for cataracts. Lanosterol has been widely reported to reverse cataracts, but the mechanism of action is not yet clear. In this study, we elucidated the mechanism through which lanosterol operates in the context of cataract reversal. Through the targeted suppression of sterol regulatory element-binding protein 2 (SREBP2) followed by lanosterol treatment, we observed the restoration of lipid metabolism disorders induced by SREBP2 knockdown in lens epithelial cells (LECs). Notably, lanosterol exhibited the ability to effectively counteract amyloid accumulation and cellular apoptosis triggered by lipid metabolism disorders. In summary, our findings suggest that lanosterol, a pivotal intermediate in lipid metabolism, may exert its therapeutic effects on cataracts by influencing lipid metabolism. This study shed light on the treatment and pharmaceutical development targeting Age-related Cataracts (ARC).

Establishment of the molecular subtypes and a risk model for stomach adenocarcinoma based on genes related to reactive oxygen species.

Background: Oxidative stress promotes the development of stomach adenocarcinoma (STAD) and resistance of STAD patients to chemotherapy. This study developed a risk classification and prognostic model for STAD based on genes related to oxidative stress. Methods: Univariate Cox regression and least absolute shrinkage and selection operator (Lasso) regression analysis were performed using transcriptome data of STAD from The Cancer Genome Atlas (TCGA) and reactive oxygen species (ROS)-related genes from Gene Set Enrichment Analysis (GSEA) website to develop a risk model. Genetic landscape, pathway characteristics and immune characteristics between the two risk groups were assessed to evaluate patients' response to anti-tumor therapy. Further, a nomogram was created to evaluate the clinical outcomes of STAD patients. The mRNA levels of genes were detected by reverse transcription quantitative PCR (RT-qPCR). Results: Two ROS-related molecular subtypes (subtype C1 and C2) were classified, with subtype C2 having unfavorable prognosis, higher immune score, and greater infiltration of macrophages, myeloid-derived suppressor cells (MDSCs), mast cells, regulatory T cells, and C-C chemokine receptor (CCR). Five ROS-related genes (ASCL2, COMP, NOX1, PEG10, and VPREB3) were screened to develop a prognostic model, the robustness of which was validated in TCGA and external cohorts. RT-qPCR analysis showed that ASCL2, COMP, NOX1, and PEG10 were upregulated, while the mRNA level of VPREB3 was downregulated in gastric cancer cells. The risk score showed a negative relation to tumor mutation burden (TMB). Low-risk patients exhibited higher mutation frequencies of TTN, SYNE1, and ARID1A, higher response rate to immunotherapy and were more sensitive to 32 traditional chemotherapeutic drugs, while high-risk patients were sensitive to 13 drugs. Calibration curve and DCA confirmed the accuracy and reliability of the nomogram. Conclusion: These findings provided novel understanding on the mechanism of ROS in STAD. The current study developed a ROS-related signature to help predict the prognosis of patients suffering from STAD and to guide personalized treatment.

Malignancy diagnosis of liver lesion in contrast enhanced ultrasound using an end-to-end method based on deep learning.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) is considered as an efficient tool for focal liver lesion characterization, given it allows real-time scanning and provides dynamic tissue perfusion information. An accurate diagnosis of liver lesions with CEUS requires a precise interpretation of CEUS images. However,it is a highly experience dependent task which requires amount of training and practice. To help improve the constrains, this study aims to develop an end-to-end method based on deep learning to make malignancy diagnosis of liver lesions using CEUS. METHODS: A total of 420 focal liver lesions with 136 benign cases and 284 malignant cases were included. A deep learning model based on a two-dimensional convolution neural network, a long short-term memory (LSTM), and a linear classifier (with sigmoid) was developed to analyze the CEUS loops from different contrast imaging phases. For comparison, a 3D-CNN based method and a machine-learning (ML)-based time-intensity curve (TIC) method were also implemented for performance evaluation. RESULTS: Results of the 4-fold validation demonstrate that the mean AUC is 0.91, 0.88, and 0.78 for the proposed method, the 3D-CNN based method, and the ML-based TIC method, respectively. CONCLUSIONS: The proposed CNN-LSTM method is promising in making malignancy diagnosis of liver lesions in CEUS without any additional manual features selection.

Occurrence and dissemination of antibiotic resistance genes in the Yellow River basin: focused on family farms.

As an emerging contaminant, antibiotic resistance genes (ARGs) have attracted growing attention, owing to their widespread dissemination and potential risk in the farming environment. However, ARG pollution from family livestock farms in the Yellow River basin, one of the main irrigation water sources in the North China Plain, remains unclear. Herein, we targeted 21 typical family farms to assess the occurrence patterns of ARGs in livestock waste and its influence on ARGs in receiving environment by real-time quantitative PCR (qPCR). Results showed that common ARGs were highly prevalent in family livestock waste, and tet-ARGs and sul-ARGs were the most abundant in these family farms. Most ARG levels in fresh feces of different animals varied, as the trend of chicken farms (broilers > laying hens) > swine farms (piglets > fattening pigs > boars and sows) > cattle farms (dairy cattle > beef cattle). The effect of natural composting on removing ARGs for chicken manure was better than that for cattle manure, while lagoon storage was not effective in removing ARGs from family livestock wastewater. More troublesomely, considerable amounts of ARGs were discharged with manure application, further leading to the ARG increase in farmland soil (up to 58-119 times), which would exert adverse impacts on human health and ecological safety.

Boosting Sono-immunotherapy of Prostate Carcinoma through Amplifying Domino-Effect of Mitochondrial Oxidative Stress Using Biodegradable Cascade-Targeting Nanocomposites.

Sono-immunotherapy faces challenges from poor immunogenicity and low response rate due to complex biological barriers. Herein, we prepared MCTH nanocomposites (NCs) consisting of disulfide bonds (S-S) doped mesoporous organosilica (MONs), Cu-modified protoporphyrin (CuPpIX), mitochondria-targeting triphenylphosphine (TPP), and CD44-targeting hyaluronic acid (HA). MCTH NCs efficiently accumulate at the tumor site due to the overexpressed CD44 receptors on the membrane of the cancer cells. Under the function of HAase and glutathione (GSH), MCTH degrades and exposes TPP to deliver CuPpIX to the mitochondrial site and induce a reactive oxygen species (ROS) burst in situ under ultrasound irradiations, thereby causing severe mitochondria dysfunction. This cascade-targeting ability of MCTH NCs not only reinforces oxidative stress in cancer cells but also amplifies immunogenic cell death (ICD) to stimulate the body's immune response and alleviate the tumor immunosuppressive microenvironment. These NCs significantly enhance the infiltration of immune cells into the tumor, particularly CD8+ T cells, for a powerful antitumor sono-immunotherapy. The proposed cascade-targeting strategy holds promise for strengthening sono-immunotherapy for prostate cancer treatment and overcoming the limitations of traditional immunotherapy.

Interpretable Predicting Creep Rupture Life of Superalloys: Enhanced by Domain-Specific Knowledge.

Evaluating and understanding the effect of manufacturing processes on the creep performance in superalloys poses a significant challenge due to the intricate composition involved. This study presents a machine-learning strategy capable of evaluating the effect of the heat treatment process on the creep performance of superalloys and predicting creep rupture life with high accuracy. This approach integrates classification and regression models with domain-specific knowledge. The physical constraints lead to significantly enhanced prediction accuracy of the classification and regression models. Moreover, the heat treatment process is evaluated as the most important descriptor by integrating machine learning with superalloy creep theory. The heat treatment design of Waspaloy alloy is used as the experimental validation. The improved heat treatment leads to a significant enhancement in creep performance (5.5 times higher than the previous study). The research provides novel insights for enhancing the precision of predicting creep rupture life in superalloys, with the potential to broaden its applicability to the study of the effects of heat treatment processes on other properties. Furthermore, it offers auxiliary support for the utilization of machine learning in the design of heat treatment processes of superalloys.

The TICE Pathway: Mechanisms and Potential Clinical Applications.

PURPOSE OF REVIEW: Transintestinal cholesterol excretion (TICE) is a non-biliary pathway that excretes excess cholesterol from the body through feces. This article focuses on the research progress of the TICE pathway in the last few years, including the discovery process of the TICE pathway, its molecular mechanism, and potential clinical applications. RECENT FINDINGS: Cholesterol homeostasis is vital for cardiovascular diseases, stroke, and neurodegenerative diseases. Beyond the cholesterol excretion via hepatobiliary pathway, TICE contributes significantly to reverse cholesterol transport ex vivo and in vivo. Nuclear receptors are ligand-activated transcription factors that regulate cholesterol metabolism. The farnesoid X receptor (FXR) and liver X receptor (LXR) activated, respectively, by oxysterols and bile acids promote intestinal cholesterol secretion through ABCG5/G8. Nutrient regulators and intestinal flora also modulate cholesterol secretion through the TICE pathway. TICE allows direct elimination of plasma cholesterol, which may provide an attractive therapeutic targets. TICE pathway may provide a potential target to stimulate cholesterol elimination and reduce the risk of cardiovascular diseases.

Case Report: Successful treatment of advanced hepatocarcinoma with the PD-1 inhibitor Camrelizumab.

Primary liver cancer is characterized by closely related with chronic liver inflammation, thereby reversing hypoxic immunosuppressive microenvironment of tumor cell growth by immunotherapy drug is a potentially effective strategy. Camrelizumab is an anti-PD-1 antibody being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. We reported a case of an adult critical Chinese patient with primary hepatocellular carcinoma and lung metastasis completely responding to Camrelizumab, most of the lesions were stable and no new lesions occurred after 1-year treatment, which provides us to reconsider the therapeutic effect of Camrelizumab on such patients. Camrelizumab had a safety profile for the patient in our case report, except for the occurrence of RCCEP. This case provides the evidence of the effective antitumor activity and manageable toxicities of Camrelizumab for patients with advanced hepatocellular carcinoma, which was the first application as far as we know.

Regulating Relative Nitrogen Locations of Diazine Functionalized Covalent Organic Frameworks for Overall H2 O2 Photosynthesis.

Nitrogen-heterocycle-based covalent organic frameworks (COFs) are considered promising candidates for the overall photosynthesis of hydrogen peroxide (H2 O2 ). However, the effects of the relative nitrogen locations remain obscured and photocatalytic performances of COFs need to be further improved. Herein, a collection of COFs functionalized by various diazines including pyridazine, pyrimidine, and pyrazine have been judiciously designed and synthesized for photogeneration of H2 O2 without sacrificial agents. Compared with pyrimidine and pyrazine, pyridazine embedded in TpDz tends to stabilize endoperoxide intermediate species, leading toward the more efficient direct 2e- oxygen reduction reaction (ORR) pathway. Benefiting from the effective electron-hole separation, low charge transfer resistance, and high-efficiency ORR pathway, an excellent production rate of 7327 µmol g-1 h-1 and a solar-to-chemical conversion (SCC) value of 0.62 % has been achieved by TpDz, which ranks one of the best COF-based photocatalysts. This work might shed fresh light on the rational design of functional COFs targeting photocatalysts in H2 O2 production.

Dual enzyme-mimicking carbon dots for enhanced antibacterial activity.

Carbon dot (CD)-based nanozymes have great potential in antibacterial applications. In order to achieve enhanced broad-spectrum antibacterial capacity, we synthesized Co-doped drug-based CDs (Co-Lvx-CDs) using levofloxacin and vitamin B12 as precursors by mimicking the catalysis of antibacterial activity of natural enzymes. The Co-Lvx-CDs retained not only the effective functional groups of the traditional antibiotic levofloxacin but also achieved oxidase-like and peroxidase-like activities to generate reactive oxygen species (ROS) through Co doping. Additionally, the Co-Lvx-CDs had superb fluorescence properties and could be applied in information encryption. The CDs were validated to have a broad-spectrum bactericidal effect against Gram-positive and -negative bacteria, compensating for the limitations of levofloxacin while also having enhanced sterilization ability. Importantly, the proposed Co-Lvx-CDs provide a new idea for the design of multifunctional CD-based nanozymes with preconceived outcomes.

Pharmacokinetics of Sirolimus Eye Drops Following Topical Ocular Administration in Rabbits.

Purpose: To evaluate the pharmacokinetics of sirolimus eye drops following topical instillation in rabbits. Methods: The study included 2 experiments. In single-dose pharmacokinetic study, rabbits received a single bilateral instillation of 0.05% sirolimus eye drops (0.5 mg/mL, 50 µL/eye). In repeat-dose pharmacokinetic study, 0.05% sirolimus eye drops (0.5 mg/mL, 50 µL/eye/time) were instilled into both eyes of rabbits four times a day for 6 consecutive days and one time on day 7. Whole blood, tears, aqueous humor, cornea, and conjunctiva samples were collected. Sirolimus concentration was determined by a validated liquid chromatography-tandem mass spectrometry. Results: Sirolimus was hardly detected in plasma or aqueous humor after either single or repeated dosing. The Cmax of sirolimus in tears, cornea, and conjunctiva after a single instillation was 163.34 ± 69.30 µg/g, 150.56 ± 84.98 ng/g, and 113.22 ± 49.82 ng/g, respectively. As the number of instillation elevated, the Cmax of sirolimus was increased to 486.18 ± 297.93 µg/g, 418.63 ± 41.07 ng/g, and 314.25 ± 63.74 ng/g, respectively. In repeat-dose administration, the steady state of sirolimus concentration was achieved on the third day. Ocular exposure to sirolimus after single and repeated dosing, based on AUC0-t, was highest in tears, followed by cornea and conjunctiva. Compared with single administration, a significant increase in sirolimus exposure as measured by AUC0-t was observed in tears, cornea, and conjunctiva following repeated administration. Conclusions: Topical administration of sirolimus eye drops results in extensive distribution of sirolimus in tears, cornea, and conjunctiva, while aqueous humor and systemic exposure were negligible. Repeat-dose administration increases sirolimus exposure in tears, cornea, and conjunctiva.

Anisotropic Black Phosphorene Structural Modulation for Thermal Storage and Solar-Thermal Conversion.

Exploiting novel strategies for simultaneously harvesting ubiquitous, renewable, and easily accessible solar energy based on the photothermal effect, and efficiently storing the acquired thermal energy plays a vital role in revolutionizing the current fossil fuel-dominating energy structure. Developing black phosphorene-based phase-change composites with optimized photothermal conversion efficiencyand high latent heat is the most promising way to achieve efficient solar energy harvesting and rapid thermal energy storage. However, exfoliating high-quality black phosphorene nanosheets  remains challenging, Furthermore, an efficient strategy that can construct the aligned black phosphorene frameworks to maximize thermal conductivity enhancement is still lacking. Herein, high-quality black phosphorene nanosheets are prepared by an optimized exfoliating strategy. Meanwhile, by regulating the temperature gradient during freeze-casting, the framework consisting of shipshape aligned black phosphorene at long-range is successfully fabricated, improving the thermal conductivity of the poly(ethylene glycol) matrix up to 1.81 W m-1  K-1 at 20 vol% black phosphorene loading. The framework also endows the composite with excellent phase-change material encapsulation capacity and  high latent heat of 103.91 J g-1 . It is envisioned that the work advances the paradigm of contrasting frameworks with nanosheets toward controllable structure thermal enhancement of the composites.