Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome ...this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.
A poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with the “do not eat me” CD47 signal via reactive oxygen species‐responsive bond and blood‐brain barrier penetrating peptide CRTIGPSVC is developed for microglia‐targeted Nec‐1s delivery. This nanoparticle shows increased brain distribution and microglial delivery of drug via conditionally releasable CD47 and can modulate pathological microglia to a beneficial state in Alzheimer's disease treatment.
C-lignin is a homo-biopolymer, being made up of caffeyl alcohol exclusively. There is significant interest in developing efficient and selective catalyst for depolymerization of C-lignin, as it ...represents an ideal feedstock for producing catechol derivatives. Here we report an atomically dispersed Ru catalyst, which can serve as an efficient catalyst for the hydrogenolysis of C-lignin via the cleavage of C-O bonds in benzodioxane linkages, giving catechols in high yields with TONs up to 345. A unique selectivity to propenylcatechol (77%) is obtained, which is otherwise hard to achieve, because this catalyst is capable of hydrogenolysis rather than hydrogenation. This catalyst also demonstrates good reusability in C-lignin depolymerization. Detailed investigations by model compounds concluded that the pathways involving dehydration and/or dehydrogenation reactions are incompatible routes; we deduced that caffeyl alcohol generated via concurrent C-O bonds cleavage of benzodioxane unit may act as an intermediate in the C-lignin hydrogenolysis. Current demonstration validates that atomically dispersed metals can not only catalyze small molecules reactions, but also drive the transformation of abundant and renewable biopolymer.
Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, ...particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti‐fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl4‐induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl4‐ and TGF‐β1‐induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF‐β1/Smad signaling, which were consistent with its protection against CCl4‐induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF‐β1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.
The yeast Saccharomyces cerevisiae has been an essential component of human civilization because of its long global history of use in food and beverage fermentation. However, the diversity and ...evolutionary history of the domesticated populations of the yeast remain elusive. We show here that China/Far East Asia is likely the center of origin of the domesticated populations of the species. The domesticated populations form two major groups associated with solid- and liquid-state fermentation and appear to have originated from heterozygous ancestors, which were likely formed by outcrossing between diverse wild isolates primitively for adaptation to maltose-rich niches. We found consistent gene expansion and contraction in the whole domesticated population, as well as lineage-specific genome variations leading to adaptation to different environments. We show a nearly panoramic view of the diversity and life history of S. cerevisiae and provide new insights into the origin and evolution of the species.
Background and Aims
The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3–5‐cm HCC over time.
Approach and Results
From ...2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008–2019 (n = 335 in each group) and 2014–2019 (n = 257 in each group) cohorts, respectively. For cohort 2008–2019, during a median follow‐up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65–1.19, p = 0.420), and MWA was inferior to LLR regarding disease‐free survival (DFS) (HR 1.36, 95% CI 1.05–1.75, p = 0.017). For cohort 2014–2019, there was comparable OS (HR 0.85, 95% CI 0.56–1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98–1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1–4.0‐cm HCCs (HR 0.88, 95% CI 0.53–1.47, p = 0.630) and 4.1–5.0‐cm HCCs (HR 0.77, 95% CI 0.37–1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p > 0.05), shorter hospitalization, and lower cost to LLR (all p < 0.001).
Conclusions
MWA might be a first‐line alternative to LLR for solitary 3–5‐cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.
The construction of a novel nanocarrier that can break the redox balance in tumor cell is a promising anti‐tumor strategy. Herein, a tumor microenvironment (TME)‐responsive nanocarrier VC@Lipo is ...rationally designed by embedding ultrasmall VOx nanozyme and photosensitizer chlorin e6 (Ce6) into liposomes. The size of VC@Lipo nanocarrier is ≈35 nm and can be degraded in the weakly acidic environment of TME. The VOx nanozyme exhibits peroxidase‐like activity and generates highly toxic hydroxyl radical ∙OH through Fenton‐like reaction and 1O2 in the presence of H2O2 independent of light, and more 1O2 can be generated by the photodynamic effect of Ce6. In addition, the VOx nanozyme can effectively deplete intracellular overexpressed glutathione (GSH) through redox reactions. In vivo experiments demonstrate that the nanocarrier shows excellent biocompatibility, presents the largest enrichment at the tumor site after 6 h of intravenous injection into mice with the highest tumor inhibition rate of 54.18% after laser irradiation. Compared with the single treatment mode, VC@Lipo shows the best synergistic effect of chemodynamic‐photodynamic therapy. This work provides a new paradigm for nanocatalytic therapy of cancer and is expected to provide new ideas for precision medicine in cancer.
A novel strategy of constructing nanocatalytic medicine for disturbing redox homeostasis in the tumor microenvironment is presented through co‐loading vanadium‐based VOx nanozyme and photosensitizer chlorin e6 ( Ce6) into the liposome. This study provides an ideal tumor microenvironment‐responsive nanocarrier, which can effectively improve reactive oxygen level and reduce glutathione content to amplify oxidative stress for enchancing chemodynamic‐mediated therapy of cancer.
Upconversion nanoparticles (UCNPs) doped with lanthanide ions that possess ladder‐like energy levels can give out multiple emissions at specific ultra‐violet or visible wavelengths irrespective of ...excitation light. However, precisely controlling energy migration processes between different energy levels of the same lanthanide ion to generate switchable emissions remains elusive. Herein, a novel dumbbell‐shaped UCNP is reported with upconverted red emission switched to green emission when excitation wavelength changed from 980 to 808 nm. The sensitizer Yb ions are doped with activator Er ions and energy modulator Mn ions in NaYF4 core nanocrystal coated with an inner NaYF4:Yb shell to generate red emission after harvesting 980 nm excitation light, while an outer NaNdF4:Yb shell is coated to form a dumbbell shape to generate green emission upon 808 nm excitation. Such specially designed UCNPs with switchable green and red emissions are further explored for imaging of latent fingerprint and detection of explosive residues in the fingerprint simultaneously. This work suggests a novel research interest in fine‐tuning of upconversion emissions through precisely controlling energy migration processes of the same lanthanide activator ion. Furthermore, use of these nanoparticles in other applications such as simultaneous dual‐color imaging or orthogonal bidirectional photoactivation can be explored.
Energy migration of a single lanthanide activator ion in a novel dumbbell‐shaped upconversion nanoparticle is navigated along the favored electronic transitions pathway at specific excitation wavelengths, resulting in orthogonal emission properties. Such specially designed nanoparticles are further explored for simultaneous imaging of latent fingerprints and analysis of trace amounts of explosive residues in fingerprints.
Fascin-1 is a cytoskeletal protein and it can specifically bind to F-actin, it can be abnormally expressed in a variety of solid tumors. Fascin-1 was identified as a factor for poor prognosis in ...non-small cell lung cancer (NSCLC). However, the relevant molecular mechanisms are not yet fully understood. In this study, the fascin-1 knockdown cells were produced by lentivirus infection, and then cell proliferation, invasion and cell migration assay were used to investigate the role of fascin-1 in NSCLC cells. The MAPK pathway related proteins were determined by western blot. In the current study, lentivirus-mediated fascin-1 knockdown significantly decreased the proliferation of NSCLC cells. Furthermore, fascin-1 silencing partly inhibited cell invasion and migration. Inhibition of fascin-1 decreased the activity of the MAPK pathway. Therefore, targeting fascin-1 may inhibit the growth and metastasis of NSCLC cells, which is a potentially effective therapeutic strategy for treating NSCLC.
•The fascin-1 promotes NSCLC cells proliferation.•The fascin-1 promotes NSCLC cells invasion and migration.•The fascin-1 promotes the malignant phenotype by targeting MAPK signal pathway in NSCLC cells.
In the electronics industry environment, rapid recognition of objects to be grasped from digital images is essential for visual guidance of intelligent robots. However, electronic components have a ...small size, are difficult to distinguish, and are in motion on a conveyor belt, making target detection more difficult. For this reason, the YOLOv4-tiny method is used to detect electronic components and is improved. Then, different network structures are built for the adaptive integration of middle- and high-level features to address the phenomenon in which the original algorithm integrates all feature information indiscriminately. The method is deployed on an electronic component dataset for validation. Experimental results show that the accuracy of the original algorithm is improved from 93.74 to 98.6%. Compared with other current mainstream algorithms, such as Faster RCNN, SSD, RefineDet, EfficientDet, and YOLOv4, the method can maintain high detection accuracy at the fastest speed. The method can provide a technical reference for the development of manufacturing robots in the electronics industry.
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