Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of ...reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.
Objectives
This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its ...prognostic value.
Methods
For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients.
Results
The radiomics signature comprised eight LN-status–related features and showed significant association with LN metastasis in both cohorts (
p
< 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both
p
< 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival.
Conclusions
Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making.
Key Points
• The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup.
• Prognosis of high-risk patients remains dismal after curative-intent resection.
• The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.
High‐spin conjugated radicals have great potential in magnetic materials and organic spintronics. However, to obtain high‐spin conjugated radicals is still quite challenging due to their poor ...stability. We report the successful synthesis and isolation of a stable triplet conjugated diradical, 10,12‐diaryldiindeno1,2‐b:2′,1′‐epyrazine (m‐DIP). With the m‐xylylene analogue skeleton containing electron‐deficient sp2‐nitrogen atoms, m‐DIP displays significant aromatic character within its pyrazine ring and its spin density mainly delocalizes on the meta‐pyrazine unit, making it a triplet ground state conjugated diradical. Our work provides an effective “spin density tuning” strategy for stable high‐spin conjugated radicals.
A stable triplet‐ground‐state conjugated diradical with pyrazine as a linker group was synthesized with a half‐life time of about 22 days under ambient conditions. The electron‐deficient pyrazine unit impedes spin delocalization to the peripheral phenyl rings, which increases the spin density distribution on the central meta‐pyrazine unit, leading to a large ΔES‐T.
Low n‐doping efficiency and inferior stability restrict the thermoelectric performance of n‐type conjugated polymers, making their performance lag far behind of their p‐type counterparts. Reported ...here are two rigid coplanar poly(p‐phenylene vinylene) (PPV) derivatives, LPPV‐1 and LPPV‐2, which show nearly torsion‐free backbones. The fused electron‐deficient rigid structures endow the derivatives with less conformational disorder and low‐lying lowest unoccupied molecular orbital (LUMO) levels, down to −4.49 eV. After doping, two polymers exhibited high n‐doping efficiency and significantly improved air stability. LPPV‐1 exhibited a high conductivity of up to 1.1 S cm−1 and a power factor as high as 1.96 μW m−1 K−2. Importantly, the power factor of the doped LPPV‐1 thick film degraded only 2 % after 7 day exposure to air. This work demonstrates a new strategy for designing conjugated polymers, with planar backbones and low LUMO levels, towards high‐performance and potentially air‐stable n‐type polymer thermoelectrics.
Stability: A new rigid coplanar poly(p‐phenylene vinylene) (PPV) derivative, LPPV‐1, is synthesized with a rigid planar backbone and low‐lying LUMO, which lead to reduced conformational disorder and high n‐type doping efficiency. The conductivity of LPPV‐1 is up to 1.1 S cm−1, and the power factor is only 2 % after a 7 day exposure to air. This work represents an effective strategy towards high‐performance and potentially air‐stable n‐type polymer thermoelectrics.
Transdermal drug delivery (TDD) systems with feedback control have attracted extensive research and clinical interest owing to their unique advantages of convenience, self‐administration, and safety. ...Here, a self‐powered wearable iontophoretic TDD system that can be driven and regulated by the energy harvested from biomechanical motions is proposed for closed‐loop motion detection and therapy. A wearable triboelectric nanogenerator (TENG) is used as the motion sensor and energy harvester that can convert biomechanical motions into electricity for iontophoresis without stored‐energy power sources, while a hydrogel‐based soft patch with side‐by‐side electrodes is designed to enable noninvasive iontophoretic TDD. Proof‐of‐concept experiments on pig skin with dyes as model drugs successfully demonstrate the feasibility of the proposed system. This work not only extends the application of TENG in the biomedical field, but may also provide a cost‐effective solution for noninvasive, electrically assisted TDD with closed‐loop sensing and treatment.
A self‐powered wearable iontophoretic transdermal drug delivery system that can be driven and regulated by the energy harvested from biomechanical motions is proposed for closed‐loop motion detection and therapy. It consists of a wearable triboelectric nanogenerator and a hydrogel‐based iontophoretic patch. The feasibility of the proposed system is demonstrated by proof‐of‐concept experiments on pig skin with dyes as model drugs.
Background and Aims
Apolipoprotein A‐1 (ApoA‐1), the major apolipoprotein of high‐density lipoprotein, plays anti‐atherogenic role in cardiovascular diseases and exerts anti‐inflammation effect in ...various inflammatory and infectious diseases. However, the role and mechanism of ApoA‐1 in hepatic ischaemia–reperfusion (I/R) injury is unknown.
Methods
In this study, we measured ApoA‐1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA‐1 knockout mice, ApoA‐1 mimetic peptide D‐4F treatment mice and corresponding control mice to examine the effect of ApoA‐1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study.
Results
The results showed that ApoA‐1 expression was down‐regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA‐1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA‐1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA‐1 deficiency. Furthermore, the up‐regulated pyroptosis process was testified to be mediated by ApoA‐1 through TLR4–NF‐κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D‐4F ameliorated hepatic I/R injury.
Conclusions
Our study has identified the protective role of ApoA‐1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4–NF‐κB pathway. The effect of ApoA‐1 may provide a novel therapeutic approach for hepatic I/R injury.
The charge carrier mobility of p-type and ambipolar polymer field-effect transistors (FETs) has been improved substantially. Nonetheless, high-mobility n-type polymers are rare, and few can be ...operated under ambient conditions. This situation is mainly caused by the scarcity of strong electron-deficient building blocks. Herein, we present two novel electron-deficient building blocks, FBDOPV-1 and FBDOPV-2, with low LUMO levels down to −4.38 eV. On the basis of both building blocks, we develop two poly(p-phenylene vinylene) derivatives (PPVs), FBDPPV-1 and FBDPPV-2, for high-performance n-type polymer FETs. The introduction of the fluorine atoms effectively lowers the LUMO levels of both polymers, leading to LUMO levels as low as −4.30 eV. Fluorination endows both polymers with not only lower LUMO levels, but also more ordered thin-film packing, smaller π–π stacking distance, stronger interchain interaction and locked conformation of polymer backbones. All these factors provide FBDPPV-1 with high electron mobilities up to 1.70 cm2 V–1 s–1 and good stability under ambient conditions. Furthermore, when polymers have different fluorination positions, their backbone conformations in solid state differ, eventually leading to different device performance.
Current approaches to fabrication of nSC composites for bone tissue engineering (BTE) have limited capacity to achieve uniform surface functionalization while replicating the complex architecture and ...bioactivity of native bone, compromising application of these nanocomposites for in situ bone regeneration. A robust biosilicification strategy is reported to impart a uniform and stable osteoinductive surface to porous collagen scaffolds. The resultant nSC composites possess a native‐bone‐like porous structure and a nanosilica coating. The osteoinductivity of the nSC scaffolds is strongly dependent on the surface roughness and silicon content in the silica coating. Notably, without the use of exogenous cells and growth factors (GFs), the nSC scaffolds induce successful repair of a critical‐sized calvarium defect in a rabbit model. It is revealed that topographic and chemical cues presented by nSC scaffolds could synergistically activate multiple signaling pathways related to mesenchymal stem cell recruitment and bone regeneration. Thus, this facile surface biosilicification approach could be valuable by enabling production of BTE scaffolds with large sizes, complex porous structures, and varied osteoinductivity. The nanosilica‐functionalized scaffolds can be implanted via a cell/GF‐free, one‐step surgery for in situ bone regeneration, thus demonstrating high potential for clinical translation in treatment of massive bone defects.
A biosilicification strategy is developed to provide a uniform and robust osteoinductive surface on porous natural collagen scaffolds. The resultant nanosilica–collagen (nSC) scaffolds possess topographical and chemical cues for superior in situ bone defect repair, without the use of exogenous cells or growth factors. This novel preparation of biomimetic bone scaffolds shows promising clinical applications in the treatment of bone defects.
Planar backbone, locked conformation, and low lowest unoccupied molecular orbital level provide polymer F4BDOPV‐2T with ultrahigh electron mobilities of up to 14.9 cm2 V−1 s−1 and good air stability. ...It is found that the nonlinear transfer curves can be tuned to near‐ideal ones by changing fabrication conditions, indicating that film morphology largely contributes to the nonlinear transfer curves in high‐mobility conjugated polymers.
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