DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.

BACKGROUND: Breast cancer (BC) poses a global threat, with HER2-positive BC being a particularly hazardous subtype. Despite the promise shown by neoadjuvant therapy (NAT) in improving prognosis, resistance in HER2-positive BC persists despite emerging targeted therapies. The objective of this study is to identify markers that promote therapeutic sensitivity and unravel the underlying mechanisms. METHODS: We conducted an analysis of 86 HER2-positive BC biopsy samples pre-NAT using RNA-seq. Validation was carried out using TCGA, Kaplan‒Meier Plotter, and Oncomine databases. Phenotype verification utilized IC50 assays, and prognostic validation involved IHC on tissue microarrays. RNA-seq was performed on wild-type/DUSP4-KO cells, while RT‒qPCR assessed ROS pathway regulation. Mechanistic insights were obtained through IP and MS assays. RESULTS: Our findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC. Moreover, DUSP4 hinders G6PD activity via ALDOB dephosphorylation, with a noteworthy association with heightened ROS levels. CONCLUSIONS: In summary, our study unveils a metabolic reprogramming paradigm in BC, highlighting DUSP4's role in enhancing therapeutic sensitivity in HER2-positive BC cells. DUSP4 interacts with ALDOB, inhibiting G6PD activity and the ROS pathway, establishing it as an independent prognostic predictor for HER2-positive BC patients.

The Application of 2d Mxene Nanosheet -Based Thermosensitive Gel Delivery System Loaded with Cisplatin and Imiquimod for Lung Cancer.

Introduction: Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Methods: Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. Results: The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. Conclusion: MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.

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The endoplasmic reticulum is a key site for protein production and quality control. More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum. However, during protein folding, unfolded and/or misfolded proteins are prone to occur, which may lead to endoplasmic reticulum stress. Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control (ERQC) and endoplasmic reticulum-associated degradation (ERAD), which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins. The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored. Therefore, this paper reviews the process and function of protein folding and ERAD in mammalian cells, in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.

Mechanical Properties of Lattice Structures with a Central Cube: Experiments and Simulations.

In this study, a new structure is proposed based on the body-centered cubic (BCC) lattice structure by adding a cubic truss in the center of the BCC structure and denoting it TLC (truss-lattice-cube). The different dimensions of the central cube can notably affect the mechanical properties of the lattice structure. With a fixed length (15 mm) of a unit cell, the optimal size for the central cube is determined to be 5 mm. Quasi-static compressive tests are performed on specimens made of polylactic acid (PLA) using additive manufacturing technology. The deformation characteristics of the new structure are analyzed in detail by experiments and numerical simulations. Compared to the BCC structure, the mechanical properties of the TLC structure were significantly improved. The initial flow stress of the TLC increased by 122% at a strain of 0.1; the specific strength enhanced by 293% at a strain of 0.5; and the specific energy absorption improved by 312% at a strain of 0.6. Printing defects in the lattice structure may remarkably damage its mechanical properties. In this work, incorporation of microcracks into the finite element model allows the simulation to capture the influence of printing defects and significantly improve the predictive accuracy of the simulation.

Numerical Investigation on Precipitation Hardening of Mg-Gd Alloys.

The second-phase particles in magnesium alloys could affect the mechanical properties of the material significantly. In this work, 3D finite element models with explicit incorporation of second-phase particles are established. The simulations are calibrated with the experimental results of the Mg-1Gd alloy. The influences of factors, such as the particle distribution, size, and orientation of cylindrical particles, on precipitation hardening are investigated in detail. Three interface conditions between particles and the matrix-perfect bonding and high- and low-strength bonding-are studied at the same time. The interface conditions are shown to exert a stronger influence on precipitation hardening compared to the factors of particle distribution and size. In contrast, the influence of the orientation of cylindrical particles at grain boundaries outweighs the effect of interface property. When second-phase particles are relatively large and all located at grain boundaries, the hardening effect can be improved, and the magnesium alloy shows relatively high flow stress. However, the high hardening effect from the second-phase particles could result in high local stress concentration and possible early failure or low ductility of Mg alloys.

Debunking Mental Health Misperceptions in Short-Form Social Media Videos: An Experimental Test of Scientific Credibility Cues.

In recent years, short-form social media videos have emerged as an important source of health-related advice. In this study, we investigate whether experts or ordinary users in such videos are more effective in debunking the common misperception that talking about suicide should be avoided. We also explore a new trend on TikTok and other platforms, in which users attempt to back up their arguments by displaying scientific articles in the background of their videos. To test the effect of source type (expert vs. ordinary user) and scientific references (present or absent), we conducted a 2 × 2 between-subject plus control group experiment (n = 956). In each condition, participants were shown a TikTok video that was approximately 30 seconds long. Our findings show that in all four treatment groups, participants reduced their misperceptions on the topic. The expert was rated as being more authoritative on the topic compared to the ordinary user. However, the expert was also rated as being less credible compared to the ordinary user. The inclusion of a scientific reference did not make a difference. Thus, both experts and ordinary users may be similarly persuasive in a short-form video environment.

Graphene sandwich-based biological specimen preparation for cryo-EM analysis.

High-quality specimen preparation plays a crucial role in cryo-electron microscopy (cryo-EM) structural analysis. In this study, we have developed a reliable and convenient technique called the graphene sandwich method for preparing cryo-EM specimens. This method involves using two layers of graphene films that enclose macromolecules on both sides, allowing for an appropriate ice thickness for cryo-EM analysis. The graphene sandwich helps to mitigate beam-induced charging effect and reduce particle motion compared to specimens prepared using the traditional method with graphene support on only one side, therefore improving the cryo-EM data quality. These advancements may open new opportunities to expand the use of graphene in the field of biological electron microscopy.

Recent advances in primary cilia in bone metabolism.

Primary cilia are microtubule-based organelles that are widespread on the cell surface and play a key role in tissue development and homeostasis by sensing and transducing various signaling pathways. The process of intraflagellar transport (IFT), which is propelled by kinesin and dynein motors, plays a crucial role in the formation and functionality of cilia. Abnormalities in the cilia or ciliary transport system often cause a range of clinical conditions collectively known as ciliopathies, which include polydactyly, short ribs, scoliosis, thoracic stenosis and many abnormalities in the bones and cartilage. In this review, we summarize recent findings on the role of primary cilia and ciliary transport systems in bone development, we describe the role of cilia in bone formation, cartilage development and bone resorption, and we summarize advances in the study of primary cilia in fracture healing. In addition, the recent discovery of crosstalk between integrins and primary cilia provides new insights into how primary cilia affect bone.

Simultaneous Delivery of Doxorubicin and EZH2-Targeting siRNA by Vortex Magnetic Nanorods Synergistically Improved Anti-Tumor Efficacy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The present study reports an engineered magnetic nanodrug based on Fe3 O4 vortex nanorods coated with a macrophage membrane loaded with doxorubicin (DOX) and Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) siRNA. This novel nanodrug displays excellent tissue penetration and preferential tumor accumulation. More importantly, it significantly increases tumor suppression compared to chemotherapy, suggesting the synergistic activity of the combination of doxorubicin and EZH2-inhibition. Importantly, owing to tumor-targeted delivery, nanomedicine shows an excellent safety profile after systemic delivery, unlike conventional chemotherapy. In summary, chemotherapy and gene therapy are combined into a novel magnetic nanodrug carrying doxorubicin and EZH2 siRNA, which shows promising clinical application potential in TNBC therapy.

Study on the preparation and mechanical properties of purple ceramics.

This paper aims at preparing a smart wearable purple ceramic that meet the color requirements of purple smart wear in the market after using zirconate neodymium as a chromogenic agent. However, the mechanical performance of zirconate neodymium purple ceramic is not satisfactory, especially it has an extremely low fracture toughness. To solve this, a 3 mol% yttria-stabilized zirconia (3YSZ) is added to zirconate neodymium in the preparation of multiphase ceramics to improve its mechanical properties. In this experiment, a series of ceramic samples with addition of increasing amount of 3YSZ 0, 20, 40, 50, 60, 70 and 80% were prepared in the 1400-1500 °C sintering temperature range. It was found that at the same temperature, the mechanical properties of the ceramic samples gradually improved with the increase in the 3YSZ content. Moreover, with the same content, the mechanical properties of the ceramic samples gradually improved with the decrease in temperature. The results show that when 3YSZ has a mass fraction of 80% and is sintered at 1400 °C, the fracture toughness of the prepared ceramic samples reaches 8.15 MPa‧m1/2, which is nearly two times higher than that of the monolithic neodymium zirconate 2.57 MPa‧m1/2. The Vickers hardness of the prepared ceramic samples reached 12.93 GPa, which is nearly 88% higher than the undoped neodymium zirconate. This indicates that the samples can be applied in smart wearables, such as mobile phone backplane, with a certain practical significance for engineering toughening of zirconate ceramics.

A flying Schrödinger's cat in multipartite entangled states.

Schrödinger's cat originates from the famous thought experiment querying the counterintuitive quantum superposition of macroscopic objects. As a natural extension, several "cats" (quasi-classical objects) can be prepared into coherent quantum superposition states, which is known as multipartite cat states demonstrating quantum entanglement among macroscopically distinct objects. Here, we present a highly scalable approach to deterministically create flying multipartite Schrödinger's cat states by reflecting coherent-state photons from a microwave cavity containing a superconducting qubit. We perform full quantum state tomography on the cat states with up to four photonic modes and confirm the existence of quantum entanglement among them. We also witness the hybrid entanglement between discrete-variable states (the qubit) and continuous-variable states (the flying multipartite cat) through a joint quantum state tomography. Our work provides an enabling step for implementing a series of quantum metrology and quantum information processing protocols based on cat states.

pH-Triggered Release Performance of Microcapsule-Based Inhibitor and Its Inhibition Effect on the Reinforcement Embedded in Mortar.

The smart release of healing agents is a key factor determining the inhibition efficiency of microcapsules-based corrosion inhibitors for reinforced concrete. In this study, the release behavior of benzotriazole (BTA) in microcapsule-based inhibitors was investigated in mortar sample to clarify the influence of different hydration products on the release process. The results indicated that under high pH environment (pH > 12.4), only about 5% reserved BTA was released from the mortar sample. pH drop resulted in the increased release of BTA from mortar sample. Most BTA in the microcapsule-based inhibitors was released from mortar sample in low pH environment, which was closely related to morphology/composition alterations of hydration products caused by pH drop of the environment. The smart release of BTA dramatically delayed corrosion initiation of reinforced mortar and halted corrosion product accumulation on the steel surface. Therefore, the corrosion resistance of the reinforced mortar was improved after corrosion initiation.

Anlotinib Combined with Cranial Radiotherapy for Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Retrospectively, Control Study.

INTRODUCTION: Cranial radiotherapy (CRT) is the main treatment for non-small cell lung cancer (NSCLC) with brain metastasis (BM) and non-EGFR/ALK/ROS1-TKIs indication, and anlotinib can improve overall prognosis. However, the clinical effects of CRT combined with anlotinib for the treatment of NSCLC with BM remain unclear. METHODS: We retrospectively analyzed the clinical effects of anlotinib + CRT versus CRT alone in NSCLC patients with BM and non-EGFR/ALK/ROS1-TKIs indication from September 2016 to June 2020. The progression-free survival (PFS) and overall survival (OS) of anlotinib + CRT versus CRT alone were analyzed. After evaluation of the clinical characteristics to generate a baseline, the independent prognostic factors for intracranial PFS (iPFS) and OS were subjected to univariate and multivariate analysis. Finally, subgroup analysis for iPFS and OS was performed to assess treatment effects using randomized stratification factors and stratified Cox proportional hazards models. RESULTS: This study included data for 73 patients with BM at baseline. Of the 73 patients, 45 patients received CRT alone, and 28 patients received CRT + anlotinib. There was no significant difference in clinical features between the two groups (P > 0.05). Compared with the CRT group, the combined group had longer iPFS (median iPFS [miPFS]: 3.0 months vs 11.0 months, P = 0.048). However, there were no significant differences in OS, extracranial PFS, and systemic PFS. For clinical features, univariate and multivariate analysis showed that the plus anlotinib treatment was an independent advantage predictor of iPFS (hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.27-0.95; P = 0.04), and age ≥57 years (HR 1.04, 95% CI 1.01-1.08, P = 0.014) and KPS score ≤80 (HR 1.04, 95% CI 1.01-1.08, P = 0.014) were independent disadvantage predictors of OS (P < 0.05). In addition, although this difference was not statistically significant (p > 0.05), the patients with the anlotinib + local CRT (LCRT) treatment had the longest iPFS (miPFS: 27.0 months) and OS (median OS [mOS]: 36 months). The miPFS and mOS values for the LCRT group were 11 months and 18 months, respectively, with shorter values for whole-brain RT (WBRT) + anlotinib group, WBRT + LCRT + anlotinib group, WBRT, and WBRT + LCRT. CONCLUSION: Anlotinib can improve the intracranial lesion control and survival prognosis of NSCLC patients with CRT.

Hyaluronan-fullerene/AIEgen nanogel as CD44-targeted delivery of tirapazamine for synergistic photodynamic-hypoxia activated therapy.

The therapeutic effect of oxygen-concentration-dependent photodynamic therapy (PDT) can be diminished in the hypoxic environment of solid tumours, the effective solution to this problem is utilising hypoxic-activated bioreduction therapy (BRT). In this research, a biocompatible HA-C60/TPENH2nanogel which can specifically bind to CD44 receptor was developed for highly efficient PDT-BRT synergistic therapy. The nanogel was degradable in acidic microenvironments of tumours and facilitated the release of biological reduction prodrug tirapazamine (TPZ). Importantly, HA-C60/TPENH2nanogel produced reactive oxygen species and consumed oxygen content in the cell to activate TPZ, leading to higher cytotoxicity than the free TPZ did. The intracellular observation of nanogel indicated that the HA-C60/TPENH2nanogel was self-fluorescence for cell imaging. This study applied PDT-BRT to design smart HA-based nanogel with targeted delivery, pH response, and AIEgen feature for efficient cancer therapy.

Carbon inserted defect-rich MoS2-X nanosheets@CdSnanospheres for efficient photocatalytic hydrogen evolution under visible light irradiation.

Carbon -MoS2-x@CdS (C-MoS2-x@CdS) core-shell nanostructures with controlled surface sulfur (S) vacancies were prepared via a glucose assisted hydrothermal growth method. The glucose acted as a reducing agent of C-MoS2-X to partially reduce Mo4+ ions to Mo3+ and served as a carbon source to insert the amorphous carbon into the layered MoS2-X simultaneously. The presence of Mo3+ result in the surface S-vacancies, which can provide more additional active sites and enhance the photocatalytic performance. Moreover, the inserted carbon in layered MoS2-X enhanced the electron mobility and decreased the resistance electron transfer. Density functional theory (DFT) calculation confirmed that the surface S-vacancies and the amorphous carbon increase the projected density of states at the conduct band edge, which could enhance the photo-absorption and photo-responsibility. The result is consistent with the photocatalytic H2 production experiment. C2-10%MoS2-x@CdS presented a high H2 evolution rate of 61,494 µmol h-1 g-1 under visible light irrigation (λ ≥ 420 nm), which is 1.98 times and 158 times higher than that of sample without S-vacancies (10%MoS2@CdS) and pure CdS, respectively.

Bidentate carboxylate linked TiO2 with NH2-MIL-101(Fe) photocatalyst: a conjugation effect platform for high photocatalytic activity under visible light irradiation.

Interfacial conjugation was employed to engineering preparation of TiO2@NH2-MIL-101(Fe) heterojunction photocataysts through carboxylate bidentate linkage with TiO2 and NH2-MIL-101(Fe), which can enhance the electron transfer capability from metal-organic frameworks (MOFs) to TiO2 and photocatalytic activity. The carbon nanospheres derived from glucose act as reducing agent and template to synthesize oxygen vacancies TiO2 hollow nanospheres. Then, the oxygen vacancies were employed as antennas to connect 2-aminoterephtalic acid as bidentate carboxylate chelating linkage on TiO2, which have been proved by the density functional theory (DFT) calculations. Subsequently, NH2-MIL-101(Fe) was coordinatingly formed on the surface of TiO2. The conjugation effects between TiO2 and NH2-MIL-101(Fe) enhanced the electron transfer capability and could also induce the band tail states to narrow bandgap of the composites. Thus, the photodegradability of methylene blue was remarkably enhanced under visible light irradiation. The degradation rate of TiO2@17%NH2-MIL-101(Fe) was 0.131 min-1, which was about 3.5 and 65 times higher than that of NH2-MIL-101(Fe) and TiO2, respectively.

Gastrointestinal Bioaccessibility and Colonic Fermentation of Fucoxanthin from the Extract of the Microalga Nitzschia laevis.

The extract of microalga Nitzschia laevis (NLE) is considered a source of dietary fucoxanthin, a carotenoid possessing a variety of health benefits. In the present study, the bioaccessibility and deacetylation of fucoxanthin were studied by simulated in vitro gastrointestinal digestion and colonic batch fermentation. In the gastric phase, higher fucoxanthin loss was observed at pH 3 compared to pH 4 and 5. Lipases are crucial for the deacetylation of fucoxanthin into fucoxanthinol. Fucoxanthinol production decreased significantly in the order: pure fucoxanthin (25.3%) > NLE (21.3%) > fucoxanthin-containing emulsion (11.74%). More than 32.7% of fucoxanthin and fucoxanthinol was bioaccessible after gastrointestinal digestion of NLE. During colon fermentation of NLE, a higher loss of fucoxanthin and changes of short-chain fatty acid production were observed but no fucoxanthinol was detected. Altogether, we provided novel insights on the fucoxanthin fate along the human digestion tract and showed the potential of NLE as a promising source of fucoxanthin.

Quantum generative adversarial learning in a superconducting quantum circuit.

Generative adversarial learning is one of the most exciting recent breakthroughs in machine learning. It has shown splendid performance in a variety of challenging tasks such as image and video generation. More recently, a quantum version of generative adversarial learning has been theoretically proposed and shown to have the potential of exhibiting an exponential advantage over its classical counterpart. Here, we report the first proof-of-principle experimental demonstration of quantum generative adversarial learning in a superconducting quantum circuit. We demonstrate that, after several rounds of adversarial learning, a quantum-state generator can be trained to replicate the statistics of the quantum data output from a quantum channel simulator, with a high fidelity (98.8% on average) so that the discriminator cannot distinguish between the true and the generated data. Our results pave the way for experimentally exploring the intriguing long-sought-after quantum advantages in machine learning tasks with noisy intermediate-scale quantum devices.

Numerical Simulation of Thermal Conductivity of Foam Glass Based on the Steady-State Method.

The effects of fly ash, sodium carbonate content, foaming temperature and foaming time on foam glass aperture sizes and their distribution were analyzed by the orthogonal experimental design. Results from the steady-state method showed a normal distribution of the number of apertures with change in average aperture, which ranges from 0.1 to 2.0 mm for more than 93% of apertures. For a given porosity, the thermal conductivity decreases with the increase of the aperture size. The apertures in the sample have obvious effects in blocking the heat flow transmission: heat flow is quickly diverted to both sides when encountered with the aperture. When the thickness of the sample is constant, the thermal resistance of the foam glass sample increases with increasing porosity, leading to better thermal insulation. Furthermore, our results suggest that the more evenly distributed and orderly arranged the apertures are in the foam glass material, the larger the thermal resistance of the material and hence, the better the thermal insulation.