Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate ...neuropathic pain. Inflammation/immune response at the site of complete Freund's adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1β (IL-1β), in inflammatory pain remains unknown.
Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes.
The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1β in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-κB p65 translocation from the cytosol to the nucleus in activated macrophages (CD68
and CX3CR1
) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPKα shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1β and NF-κB activation in inflamed skin tissues.
Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-κB activation and reducing the expression of IL-1β in inflammatory pain.
Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the ...biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ).
The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2
) and activated microglia (CD68
IBA1
) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (
) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined.
MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (
) and Optineurin (
), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage.
Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.
Background
Dual‐phenotype hepatocellular carcinoma (DPHCC) is highly aggressive and difficult to distinguish from hepatocellular carcinoma (HCC).
Purpose
To develop and validate clinical and ...radiomics models based on contrast‐enhanced MRI for the preoperative diagnosis of DPHCC.
Study type
Retrospective.
Population
A total of 87 patients with DPHCC and 92 patients with non‐DPHCC randomly divided into a training cohort (n = 125: 64 non‐DPHCC; 61 DPHCC) and a validation cohort (n = 54: 28 non‐DPHCC; 26 DPHCC).
Field Strength/Sequence
A 3.0 T; dynamic contrast‐enhanced MRI with time‐resolved T1‐weighted imaging sequence.
Assessment
In the clinical model, the maximum tumor diameter and hepatitis B virus (HBV) were independent risk factors of DPHCC. In the radiomics model, a total of 1781 radiomics features were extracted from tumor volumes of interest (VOIs) in the arterial phase (AP) and portal venous phase (PP) images. For feature reduction and selection, Pearson correlation coefficient (PCC) and recursive feature elimination (RFE) were used. Clinical, AP, PP, and combined radiomics models were established using machine learning algorithms (support vector machine SVM, logistic regression LR, and logistic regression‐least absolute shrinkage and selection operator LR‐LASSO) and their discriminatory efficacy assessed and compared.
Statistical Tests
The independent sample t test, Mann–Whitney U test, Chi‐square test, regression analysis, receiver operating characteristic curve (ROC) analysis, Pearson correlation analysis, the Delong test. A P value < 0.05 was considered statistically significant.
Results
In the validation cohort, the combined radiomics model (area under the curve AUC = 0.908, 95% confidence interval CI: 0.831–0.985) showed the highest diagnostic performance. The AUCs of the PP (AUC = 0.879, 95% CI: 0.779–0.979) and combined radiomics models were significantly higher than that of clinical model (AUC = 0.685, 95% CI: 0.526–0.844). There were no significant differences in AUC between AP or PP radiomics model and combined radiomics model (P = 0.286, 0.180 and 0.543).
Conclusion
MRI radiomics models may be useful for discriminating DPHCC from non‐DPHCC before surgery.
Evidence Level
4
Technical Efficacy
Stage 2
aquatic product, known as one of the good resources for white meat, has been widely accepted by the consumers due to its high protein, low fat, especially low cholesterol. With the fast development ...of living standards around the world, the consumer demands for high quality, nutrition, safety and freshness of ifshery food are increasing. Thus, high efifcient preservation technologies for aquatic products become particularly important. Superchilling is one of the controlled-temperature preservation technologies for seafood. Aquatic products can be kept in better quality under superchilling conditions. This review introduced the principle and development of superchilling process, mainly focusing on research progresses and technical dififculties of superchilling. The growth mechanism of ice crystals and the feasibility of application of computational lfuid dynamics in analyzing the temperatures variation and ice crystals during superchilling progress were also discussed, which will provide theoretical foundation for its improvement and application.
Cancer incidence is rising, and the efficacy of current available anticancer agents is limited by severe dose‐limiting toxicities and drug resistance problems. Nanoparticles are heralded as the next ...frontier in cancer treatment. Here, a pure physical method is used to efficiently fabricate very small silver particles even approaching the Ångstrom (Ång) dimension. Fructose is used as a dispersant and stabilizer to coat the Ång‐scale silver particles (AgÅPs). Functional and mechanistic studies demonstrate that fructose‐coated AgÅPs (F‐AgÅPs) can enter and accumulate in multiple cultured cancer cell lines to induce apoptotic death, whereas most normal cells are resistant to the efficacious dose of F‐AgÅPs; in vivo, intravenous administration of F‐AgÅPs potently inhibits the growth of pancreatic and lung cancer xenografts in nude mice, without inducing notable toxic effects on the healthy tissues. The results suggest the promising potential of F‐AgÅPs as a potent, safe, and broad‐spectrum agent for the cancer treatment.
Physical method‐fabricated fructose‐coated Ångstrom‐scale silver particles (F‐AgÅPs) have the ability to enter multiple cancer cells to induce apoptosis. Intravenous injection of F‐AgÅPs potently inhibits the growth of cancer xenograft models, without inducing notable toxic effects on healthy tissues. These results suggest that F‐AgÅPs have a great potential to be used as a potent, safe, and broad‐spectrum agent for cancer treatment.
Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a ...pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as optn
-
/ -
mice. Importantly, restoring Optn by transplanting wild-type MSCs to optn
-
/ -
mice or infecting optn
-
/ -
mice with Optn-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of Optn
K193R
failed to reestablish a bone-fat balance. We further identified FABP3 (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. FABP3 promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of FABP3 alleviated bone loss in optn
-
/ -
mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of FABP3 degradation via selective autophagy. FABP3 accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting FABP3 would open a new avenue to treat senile OP.
Abbreviations: ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; NBR1: NBR1, autophagy cargo receptor; OP: osteoporosis; OPTN: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-GLB1: senescence-associated (SA)-GLB1 (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; μCT: micro computed tomography.
Circular RNAs (circRNAs) are aberrantly expressed in various tumors and are associated with tumorigenesis. The present study aimed to determine the role of circRNA_001275 in cisplatin‑resistant ...esophageal cancer. Three pairs of cisplatin‑resistant tissues and corresponding adjacent tissues were collected and subjected to circRNA chip analysis. Additionally, the effect of circRNA_001275 on cisplatin‑resistant cells was investigated. The relationship between circRNA_001275, microRNAs (miRs) and target genes were analyzed using luciferase assays, and validated via reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. The results showed that circRNA_001275 was significantly upregulated in cisplatin‑resistant esophageal cancer tissues and cells (P<0.05). Overexpression of circRNA_001275 promoted the proliferation and invasion, and decreased the apoptosis of cisplatin‑resistant cells. On the other hand, circRNA_001275 silencing inhibited cell proliferation and invasion, and promoted cell apoptosis (P<0.05). Dual‑luciferase reporter assays revealed that circRNA_001275 directly binds to miR‑370‑3p, and that Wnt family member 7A (Wnt7a) is targeted by miR‑370‑3p. RT‑qPCR and western blotting further demonstrated that circRNA_001275 serves as an miR‑370‑3p sponge to upregulate Wnt7a expression. In conclusion, the present study revealed that circRNA_001275 was upregulated in cisplatin‑resistant esophageal cancer and promoted cisplatin resistance by sponging miR‑370‑3p to upregulate Wnt7a expression. Therefore, circRNA_001275 may serve as a potential diagnostic biomarker and therapeutic target for patients with cisplatin‑resistant esophageal cancer.
Purpose
Ultrasound (US) imaging has been widely used in breast tumor diagnosis and treatment intervention. Automatic delineation of the tumor is a crucial first step, especially for the ...computer‐aided diagnosis (CAD) and US‐guided breast procedure. However, the intrinsic properties of US images such as low contrast and blurry boundaries pose challenges to the automatic segmentation of the breast tumor. Therefore, the purpose of this study is to propose a segmentation algorithm that can contour the breast tumor in US images.
Methods
To utilize the neighbor information of each pixel, a Hausdorff distance based fuzzy c‐means (FCM) method was adopted. The size of the neighbor region was adaptively updated by comparing the mutual information between them. The objective function of the clustering process was updated by a combination of Euclid distance and the adaptively calculated Hausdorff distance. Segmentation results were evaluated by comparing with three experts’ manual segmentations. The results were also compared with a kernel‐induced distance based FCM with spatial constraints, the method without adaptive region selection, and conventional FCM.
Results
Results from segmenting 30 patient images showed the adaptive method had a value of sensitivity, specificity, Jaccard similarity, and Dice coefficient of 93.60 ± 5.33%, 97.83 ± 2.17%, 86.38 ± 5.80%, and 92.58 ± 3.68%, respectively. The region‐based metrics of average symmetric surface distance (ASSD), root mean square symmetric distance (RMSD), and maximum symmetric surface distance (MSSD) were 0.03 ± 0.04 mm, 0.04 ± 0.03 mm, and 1.18 ± 1.01 mm, respectively. All the metrics except sensitivity were better than that of the non‐adaptive algorithm and the conventional FCM. Only three region‐based metrics were better than that of the kernel‐induced distance based FCM with spatial constraints.
Conclusion
Inclusion of the pixel neighbor information adaptively in segmenting US images improved the segmentation performance. The results demonstrate the potential application of the method in breast tumor CAD and other US‐guided procedures.
Flexible and lightweight high-performance electromagnetic interference shielding materials with minimal thickness, excellent mechanical properties, and outstanding reliability are highly desired in ...the field of fifth-generation (5G) communication, yet remain extremely challenging to manufacture. Herein, we prepared an ultrathin densified carbon nanotube (CNT) film with superior mechanical properties and ultrahigh shielding effectiveness. Upon complete removal of impurities in pristine CNT film, charge separation in individual CNTs induced by polar molecules leads to strong CNT–CNT attraction and film densification, which significantly improve the electrical conductivity, shielding performance, and mechanical strength. The tensile strength is up to 822 ± 21 MPa, meanwhile the electrical conductivity is as high as 902,712 S/m, and the density is only 1.39 g cm–3. Notably, the shielding effectiveness is over 51 dB with a thickness of merely 1.85 μm in the broad frequency range of 4–18 GHz, and it reaches to ∼82 dB at 6.36 μm and ∼101 dB at 14.7 μm, respectively. Further, such CNT film exhibits excellent reliability after an extended period in strong acid/alkali, high temperature, and high humidity. It demonstrates the best overall performance among representative shielding materials by far, representing a critical breakthrough in the preparation of shielding film toward applications in wearable electronics and 5G communication.
Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes ...of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.
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•Six high-quality ixodid tick genomes and 678 re-sequenced tick specimens•Insights into the genetic basis of tick hematophagy and related phenotypes•Population structure and genetic diversity of six tick species•Tick-borne pathogen composition and distribution by metagenome analyses
The high-quality genomes of six ixodid tick species and resequencing of 678 tick specimens are a resource to understand the genetic diversity, population structure, and pathogen distribution of ticks with implications for control of ticks and tick-borne diseases.
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