Inhibition of MFN1 restores tamoxifen-induced apoptosis in resistant cells by disrupting aberrant mitochondrial fusion dynamics.

Tamoxifen (TAM) resistance presents a major clinical obstacle in the management of estrogen-sensitive breast cancer, highlighting the need to understand the underlying mechanisms and potential therapeutic approaches. We showed that dysregulated mitochondrial dynamics were involved in TAM resistance by protecting against mitochondrial apoptosis. The dysregulated mitochondrial dynamics were associated with increased mitochondrial fusion and decreased fission, thus preventing the release of mitochondrial cytochrome c to the cytoplasm following TAM treatment. Dynamin-related GTPase protein mitofusin 1 (MFN1), which promotes fusion, was upregulated in TAM-resistant cells, and high MFN1 expression indicated a poor prognosis in TAM-treated patients. Mitochondrial translocation of MFN1 and interaction between MFN1 and mitofusin 2 (MFN2) were enhanced to promote mitochondrial outer membrane fusion. The interaction of MFN1 and cristae-shaping protein optic atrophy 1 (OPA1) and OPA1 oligomerization were reduced due to augmented OPA1 proteolytic cleavage, and their apoptosis-promoting function was reduced due to cristae remodeling. Furthermore, the interaction of MFN1 and BAK were increased, which restrained BAK activation following TAM treatment. Knockdown or pharmacological inhibition of MFN1 blocked mitochondrial fusion, restored BAK oligomerization and cytochrome c release, and amplified activation of caspase-3/9, thus sensitizing resistant cells to apoptosis and facilitating the therapeutic effects of TAM both in vivo and in vitro. Conversely, overexpression of MFN1 alleviated TAM-induced mitochondrial apoptosis and promoted TAM resistance in sensitive cells. These results revealed that dysregulated mitochondrial dynamics contributes to the development of TAM resistance, suggesting that targeting MFN1-mediated mitochondrial fusion is a promising strategy to circumvent TAM resistance.

Wireless Bioelectronics for In Vivo Pressure Monitoring with Mechanically-Compliant Hydrogel Biointerfaces.

Recent electronics-tissues biointefacing technology has offered unprecedented opportunities for long-term disease diagnosis and treatment. It remains a grand challenge to robustly anchor the pressure sensing bioelectronics onto specific organs, since the periodically-varying stress generated by normal biological processes may pose high risk of interfacial failures. Here, a general yet reliable approach is reported to achieve the robust hydrogel interface between wireless pressure sensor and biological tissues/organs, featuring highly desirable mechanical compliance and swelling resistance, despite the direct contact with biofluids and dynamic conditions. The sensor is operated wirelessly through inductive coupling, characterizing minimal hysteresis, fast response times, excellent stability, and robustness, thus allowing for easy handling and eliminating the necessity for surgical extraction after a functional period. The operation of the wireless sensor has been demonstrated with a custom-made pressure sensing model and in vivo intracranial pressure monitoring in rats. This technology may be advantageous in real-time post-operative monitoring of various biological inner pressures after the reconstructive surgery, thus guaranteeing the timely treatment of lethal diseases.

Mechanically-Compliant Bioelectronic Interfaces through Fatigue-Resistant Conducting Polymer Hydrogel Coating.

Because of their distinct electrochemical and mechanical properties, conducting polymer hydrogels have been widely exploited as soft, wet, and conducting coatings for conventional metallic electrodes, providing mechanically compliant interfaces and mitigating foreign body responses. However, the long-term viability of these hydrogel coatings is hindered by concerns regarding fatigue crack propagation and/or delamination caused by repetitive volumetric expansion/shrinkage during long-term electrical interfacing. This study reports a general yet reliable approach to achieving a fatigue-resistant conducting polymer hydrogel coating on conventional metallic bioelectrodes by engineering nanocrystalline domains at the interface between the hydrogel and metallic substrates. It demonstrates the efficacy of this robust, biocompatible, and fatigue-resistant conducting hydrogel coating in cardiac pacing, showcasing its ability to effectively reduce the pacing threshold voltage and enhance the long-term reliability of electric stimulation. This study findings highlight the potential of its approach as a promising design and fabrication strategy for the next generation of seamless bioelectronic interfaces.

Engineering Electrodes with Robust Conducting Hydrogel Coating for Neural Recording and Modulation.

Coating conventional metallic electrodes with conducting polymers has enabled the essential characteristics required for bioelectronics, such as biocompatibility, electrical conductivity, mechanical compliance, and the capacity for structural and chemical functionalization of the bioelectrodes. However, the fragile interface between the conducting polymer and the electrode in wet physiological environment greatly limits their utility and reliability. Here, a general yet reliable strategy to seamlessly interface conventional electrodes with conducting hydrogel coatings is established, featuring tissue-like modulus, highly-desirable electrochemical properties, robust interface, and long-term reliability. Numerical modeling reveals the role of toughening mechanism, synergy of covalent anchorage of long-chain polymers, and chemical cross-linking, in improving the long-term robustness of the interface. Through in vivo implantation in freely-moving mouse models, it is shown that stable electrophysiological recording can be achieved, while the conducting hydrogel-electrode interface remains robust during the long-term low-voltage electrical stimulation. This simple yet versatile design strategy addresses the long-standing technical challenges in functional bioelectrode engineering, and opens up new avenues for the next-generation diagnostic brain-machine interfaces.

Impact-Resistant Hydrogels by Harnessing 2D Hierarchical Structures.

With the strengthening capacity through harnessing multi-length-scale structural hierarchy, synthetic hydrogels hold tremendous promise as a low-cost and abundant material for applications demanding unprecedented mechanical robustness. However, integrating high impact resistance and high water content, yet superior softness, in a single hydrogel material still remains a grand challenge. Here, a simple, yet effective, strategy involving bidirectional freeze-casting and compression-annealing is reported, leading to a hierarchically structured hydrogel material. Rational engineering of the distinct 2D lamellar structures, well-defined nanocrystalline domains and robust interfacial interaction among the lamellae, synergistically contributes to a record-high ballistic energy absorption capability (i.e., 2.1 kJ m-1 ), without sacrificing their high water content (i.e., 85 wt%) and superior softness. Together with its low-cost and extraordinary energy dissipation capacity, the hydrogel materials present a durable alternative to conventional hydrogel materials for armor-like protection circumstances.

Integrated 3D printing of flexible electroluminescent devices and soft robots.

Flexible and stretchable light emitting devices are driving innovation in myriad applications, such as wearable and functional electronics, displays and soft robotics. However, the development of flexible electroluminescent devices via conventional techniques remains laborious and cost-prohibitive. Here, we report a facile and easily-accessible route for fabricating a class of flexible electroluminescent devices and soft robotics via direct ink writing-based 3D printing. 3D printable ion conducting, electroluminescent and insulating dielectric inks were developed, enabling facile and on-demand creation of flexible and stretchable electroluminescent devices with good fidelity. Robust interfacial adhesion with the multilayer electroluminescent devices endowed the 3D printed devices with attractive electroluminescent performance. Integrated our 3D printed electroluminescent devices with a soft quadrupedal robot and sensing units, an artificial camouflage that can instantly self-adapt to the environment by displaying matching color was fabricated, laying an efficient framework for the next generation soft camouflages.

Machine Learning Analysis of MicroRNA Expression Data Reveals Novel Diagnostic Biomarker for Ischemic Stroke.

OBJECTIVES: Ischemic stroke (IS) is one of the leading causes of morbidity and mortality worldwide. Circulating microRNAs have a potential as minimally invasive biomarkers for disease prediction, diagnosis, and prognosis. In this study, we sought to use different machine learning algorithms to identify an optimal model of microRNA by integrating the expression data of pre-selected microRNAs for discriminating patients with IS from controls. METHODS: The expression level of microRNAs in the peripheral blood of 50 patients with IS and 50 matched controls were assessed through real-time polymerase chain reaction (qRT-PCR). Machine learning algorithms, including artificial neural network, random forest, extreme gradient boosting, and support vector machine (SVM) were employed via R 3.6.3 software to establish diagnostic models for IS. RESULTS: The IS group had significantly increased expression levels of miR-19a (P < 0.001), miR-148a (P < 0.001), miR-320d (P = 0.003), and miR-342-3p (P < 0.001) compared with the control group. MiR-148a, miR-342-3p, miR-19a, and miR-320d yielded areas under the receiver operating characteristic curve (AUC) of 0.872, 0.844, 0.721, and 0.673, respectively, with 0.740, 0.940, 0.740, and 0.840 sensitivity and 0.920, 0.640, 0.600, and 0.440 specificity, respectively. Model miR-148a + miR-342-3p + miR-19a had the best predictive value when analyzed via SVM algorithm with AUC, sensitivity, and specificity values of 0.958, 0.937, and 0.889, respectively. CONCLUSION: The diagnostic value of the combination of miR-148a, miR-342-3p, and miR-19a through SVM algorithm has the potential to serve as a feasible approach to promote the diagnosis of IS.

A 3' Untranslated Region Polymorphism of CTNNB1 (Rs2953) Alters MiR-3161 Binding and Affects the Risk of Ischemic Stroke and Coronary Artery Disease in Chinese Han Population.

BACKGROUND: CTNNB1 is reported to be related to the pathological process of ischemic stroke (IS) and coronary artery disease (CAD). Polymorphism located in the 3' untranslated region (3'UTR) of a gene might affect gene expression by modifying binding sites for microRNAs (miRNAs). This study aimed to analyze the association between polymorphism rs2953, which locates in the 3'UTR of CTNNB1, and the risk of IS and CAD. METHODS: The CTNNB1 messenger RNA (mRNA) expression level in peripheral venous blood was measured. In total, 533 patients with IS, 500 patients with CAD, and 531 healthy individuals were genotyped by Sequenom Mass-Array technology. The binding of miR-3161 to CTNNB1 was determined by dual-luciferase reporter assay. RESULTS: The CTNNB1 mRNA expression level for the IS group was significantly lower than that for the control group. Rs2953 was significantly associated with both IS risk and CAD risk. Significant association was also found between polymorphism rs2953 and many conventional factors, such as serum lipid level, blood coagulation markers, blood glucose level, and homocysteine level in patients. Rs2953 T allele introduced a binding site to miRNA-3161 and thus decreased luciferase activity. CONCLUSION: Polymorphism rs2953 is associated with the risk of both IS and CAD. Moreover, polymorphism rs2953 (T) introduces a binding site to miRNA-3161 and thus decreases luciferase activity in cell lines.

Tumor localization of oncolytic adenovirus assisted by pH-degradable microgels with JQ1-mediated boosting replication and PD-L1 suppression for enhanced cancer therapy.

Oncolytic therapy is a fast-developing cancer treatment field based on the promising clinical performance from the selective tumor cell killing and induction of systemic antitumor immunity. The virotherapy efficacy, however, is strongly hindered by the limited virus propagation and negative immune regulation in the tumor microenvironments. To enhance the antitumor activity, we developed injectable pH-degradable PVA microgels encapsulated with oncolytic adenovirus (OA) by microfluidics for localized OA delivery and cancer treatments. PVA microgels were tailored with an OA encapsulation efficiency of 68% and exhibited a pH-dependent OA release as the microgel degradation at mildly acidic conditions. PVA microgels mediated fast viral release and increased replication in HEK293T and A549 cells at a lower pH, and the replication efficiency could be further reinforced by co-loading with one BET bromodomain inhibitor JQ1, inducing significant cytotoxicity against A549 cells. An in vivo study revealed that OA release was highly located at the tumor tissue assisted by PVA microgels, and the OA infection was also enhanced with the addition of JQ1 treatment, meanwhile greatly inhibiting the PD-L1 expression to overcome the immune suppression. OA/JQ1 co-encapsulated injectable microgels exhibited a superior in vivo antitumor activity on the A549 lung tumor-bearing mice by the combination of inhibited proliferation, amplified oncolysis, and potential immune regulation.

Tumor-Adhesive and pH-Degradable Microgels by Microfluidics and Photo-Cross-Linking for Efficient Antiangiogenesis and Enhanced Cancer Chemotherapy.

Tumor angiogenesis with the vascular network formation provides nutrition and oxygen for cancer cells, promoting the proliferation and metastasis of malignant tumors. Bevacizumab (Bev) as an efficient antiangiogenic antibody is able to normalize the tumor vasculature with better blood flow and reduced interstitial fluid pressure, allowing drugs with more uniform distribution and deeper penetration into the tumor; however, it is highly difficult to realize the simultaneous delivery of Bev and anticancer drugs localized at the tumor tissue. Here, we prepared tumor-adhesive and pH-degradable poly(vinyl alcohol) (PVA) microgels for tumor-localized delivery of Bev and docetaxel (DTX), to achieve efficient antiangiogenesis and enhanced cancer chemotherapy. PVA microgels (∼200 µm) decorated with tissue-adhesive dopamine (DA) moieties were fabricated by a combination of high-throughput microfluidics technology and photo-cross-linking chemistry with a considerable coencapsulation efficiency for Bev and DTX. PVA microgels exhibited sustained drug release at the tumoral acidic conditions as the microgel degradation, and DA moieties on the microgels facilitated Bev with long retention at the tumor tissue, highly blocking the vascular endothelial growth factor (VEGF) and inhibiting tumor angiogenesis, as compared to free Bev or no DA-decorated microgels. In addition, the antitumor activity on the 4T1-Luc breast tumor mouse model treated with Bev/DTX-coloaded microgels showed obviously superior tumor growth inhibition than the other treatment groups, in which the combinational therapy efficacy of Bev and DTX mediated by the tumor-adhesive microgels was further confirmed by the immunohistochemistry (IHC) analysis. These PVA microgels with efficient antiangiogenesis and enhanced cancer chemotherapy provide a highly potential platform to treat different malignant tumors as well as the recurrent and metastatic tumors.

Machine learning-based prediction of toxicity of organic compounds towards fathead minnow.

Predicting the acute toxicity of a large dataset of diverse chemicals against fathead minnows (Pimephales promelas) is challenging. In this paper, 963 organic compounds with acute toxicity towards fathead minnows were split into a training set (482 compounds) and a test set (481 compounds) with an approximate ratio of 1 : 1. Only six molecular descriptors were used to establish the quantitative structure-activity/toxicity relationship (QSAR/QSTR) model for 96 hour pLC50 through a support vector machine (SVM) along with genetic algorithm. The optimal SVM model (R 2 = 0.756) was verified using both internal (leave-one-out cross-validation) and external validations. The validation results (q int 2 = 0.699 and q ext 2 = 0.744) were satisfactory in predicting acute toxicity in fathead minnows compared with other models reported in the literature, although our SVM model has only six molecular descriptors and a large data set for the test set consisting of 481 compounds.

Folated pH-degradable nanogels for the simultaneous delivery of docetaxel and an IDO1-inhibitor in enhancing cancer chemo-immunotherapy.

Combining chemotherapy and immunotherapy has been considered as an attractive approach to improve cancer therapy. Here we prepared folated PVA-based nanogels for the simultaneous delivery of docetaxel (DTX) and the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919 (N9) for enhancing cancer chemo-immunotherapy. FDA-approved poly(vinyl alcohol) (PVA) with good biocompatibility was modified with vinyl ether acrylate (VEA) groups for UV-crosslinking and acidic degradation. Carboxyl groups were introduced via modification with succinic anhydride for improved drug loading and folic acid (FA) ligands were incorporated for tumor targeting. UV-crosslinked folated PVA nanogels were efficiently taken up by tumor cells followed by endo/lysosomal pH-triggered intracellular drug release, which induced significant cytotoxicity towards 4T1 breast cancer cells in vitro. DTX and N9 co-loaded PVA nanogels exhibited a much higher antitumor efficiency in 4T1 mouse breast cancer models in vivo as compared to the free drug controls. The drug-laden nanogels not only directly killed the tumor cells by DTX, but also induced immunogenic cell death (ICD) promoting intratumoral accumulation of cytotoxic T lymphocytes, and further combining with N9 elevated the intratumoral infiltration of CD8+ T cells and NK cells and inhibited the infiltration of MDSCs, downregulating IDO1-mediated immunosuppression.