HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

Mild synthesis of ultra-bright carbon dots with solvatochromism for rapid lipid droplet monitoring in varied physiological processes.

Lipid droplets (LDs) participating in various cellular activities and are increasingly being emphasized. Fluorescence imaging provides powerful tool for dynamic tracking of LDs, however, most current LDs probes remain inconsistent performance such as low Photoluminescence Quantum Yield (PLQY), poor photostability and tedious washing procedures. Herein, a novel yellow-emissive carbon dot (OT-CD) has been synthesized conveniently with high PLQY up to 90%. Besides, OT-CD exhibits remarkable amphiphilicity and solvatochromic property with lipid-water partition coefficient higher than 2, which is much higher than most LDs probes. These characters enable OT-CD high brightness, stable and wash-free LDs probing, and feasible for in vivo imaging. Then, detailed observation of LDs morphological and polarity variation dynamically in different cellular states were recorded, including ferroptosis and other diseases processes. Furthermore, fast whole imaging of zebrafish and identified LD enrichment in injured liver indicate its further feasibility for in vivo application. In contrast to the reported studies to date, this approach provides a versatile conventional synthesis system for high-performance LDs targeting probes, combing the advantages of easy and high-yield production, as well as robust brightness and stability for long-term imaging, facilitating investigations into organelle interactions and LD-associated diseases.

The Relationship Between Gene Mutations and the Clinicopathological Features and Prognosis of Gastric Cancer.

Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation genes linked to GC, including TP53 (60%), PIK3CA (19%), LRP1B (13%), and ERBB2 (12%), ARID1A (9%), KMT2C (9%), and KRAS (7%). The KMT2C, KRAS, CDK6, and ARID1A wild-type genes were dominant in diffuse-type GC (P < .05), but mutations did not influence prognosis. Patients with APC (6%) and CDH1 (8%) wild-type GC presented with vascular invasion (P < .05). Patients with ATR (2%) wild-type GC were prone to lymph node metastasis (P < .05). Patients with ARID1A (9%) wild-type GC had reduced programmed death ligand 1 expression (<1, P < .05). We found that patients who received chemotherapy had a better prognosis than those who did not (although there was no statistical difference), with platinum-based group having better prognosis and uracil combined with paclitaxel group having worse prognosis.

Efficacy of ultrasound-guided radiofrequency ablation of papillary thyroid microcarcinoma after one year.

OBJECTIVE: This study aims to evaluate the feasibility and safety of percutaneous radiofrequency ablation guided by ultrasound for treating papillary thyroid microcarcinoma. METHOD: At our institution, fifty people who had been treated for micropapillary thyroid cancer with ultrasound-guided radiofrequency ablation were chosen. Thyroid function was evaluated after one month, and the volume of the ablation region was assessed immediately, 3, 6, and 12 months after treatment. At the same time, the complications or adverse reactions after treatment were evaluated. RESULTS: As time passed, the volume of the ablation area decreased gradually, showing a regression trend. There was a significant difference in the volume of the ablation area between adjacent groups (P < 0.05), and the tumor volume reduction ratio (VRR) of the ablation area was a statistically significant difference between adjacent groups (P < 0.05). There was no significant difference between the indexes related to thyroid function before and after treatment(P > 0.05). No local recurrence or distant metastasis was found during follow-up; The most common complication after the operation was a slight pain in the neck. A few patients had toothache and neck swelling symptoms, and the above symptoms subsided within 24 h after the operation. CONCLUSION: Ultrasound-guided radiofrequency ablation is safe and effective for treating single-focus micropapillary thyroid carcinoma while retaining thyroid function, with few and minor complications, which can be used as an ideal surgical option.

Nanofluidic Membrane with Spent Battery Residues for Efficient Energy Generation.

Harvesting energy in the ambient environment has become a dominant energy source and is promising toward a sustainable perspective. However, developing an energy generator with readily available raw materials and continuous output performance remains a challenge. Herein, we have demonstrated that a nanofluidic membrane with an asymmetric structure device (ASD) design by using available raw materials spent battery residues can achieve continuous power generation. The ASD can generate a voltage of ∼0.5 V by dropping 0.1 mL of water. Detailed experimental results reveal that ions in water play a synergistic role in enhancing output performance. By dropping 0.1 mL of seawater, the power output of ∼46.67 mW m-2 can be readily derived with voltage of ∼0.7 V. The work opens a viable way to generate electric power by environmental energy with facile structure design and easy-to-access materials. The output energy will greatly promote practical applications such as the power supply of low-power devices.

Exostoisns (EXT1/2) in Head and Neck Cancers: An In Silico Analysis and Clinical Correlates.

OBJECTIVES: The exostosins (EXT), which are responsible for heparan sulfate backbone synthesis and play a vital role in tissue homeostasis, have been reported to be correlated with prognosis of various cancers. However, the expression, prognostic value, and immune infiltration of EXT1 and EXT2 in head and neck squamous cell carcinoma (HNSC) remain uncertain. METHODS: GEPIA, UALCAN, and Xiantao bioinformatics tools were used to explore the EXT1 and EXT2 expression level in HNSC. GEPIA and Sangerbox were utilised to obtain the prognostic value of EXT1 and EXT2 in HNSC. Genetic alterations, immune cell infiltration, and single-cell analysis were conducted in cBioPortal, TIMER, and TISCH2. In addition, the expressions of EXT1 and EXT2 were validated by real-time polymerase chain reaction (PCR) in HNSC samples. RESULTS: EXT1 and EXT2 were highly expressed in HNSC, especially in malignant cells. Only EXT2 was significantly negatively correlated to the prognosis of patients with HNSC. EXT1 and EXT2 were found to be associated with focal adhesin and cell adhesin molecule binding. EXT1 expression levels were considerably connected with CD8+ T cell infiltrating levels, whilst EXT2 expression levels were considerably negatively connected with infiltrating levels of CD4+ T cells, macrophages, neutrophils, and dendritic cells in HNSC. The gene mutation rates of EXT1 and EXT2 in HNSC were 7% and 2.8%, respectively. Moreover, EXT2 was validated to be highly expressed in HNSC samples by real-time PCR. CONCLUSION: EXT2 was highly expressed and presented negative correlation with the prognosis and immune infiltration of HNSC, which might be a potential biomarker for HNSC.

Achieving Solar-Thermal-Electro Integration Evaporator Nine-Grid Array with Asymmetric Strategy for Simultaneous Harvesting Clean Water and Electricity.

Water evaporation is a ubiquitous and spontaneous phase transition process. The utilization of solar-driven interface water evaporation that simultaneously obtains clean water and power generation can effectively alleviate people's concerns about fresh water and energy shortages. However, it remains a great challenge to efficiently integrate the required functions into the same device to reduce the complexity of the system and alleviate its dependence on solar energy to achieve full-time operation. In this work, a multifunctional device based on reduced graphene oxide (RGO)/Mn3 O4 /Al2 O3 composite nanomaterials is realized by an asymmetric strategy for effective solar-thermal-electro integration that can induce power generation by water evaporation in the presence/absence of light. Under one sun irradiation, the solar-driven evaporation rate and output voltage are 1.74 kg m-2  h-1 and 0.778 V, respectively. More strikingly, the nine-grid evaporation/power generation array integrated with multiple devices in series has the advantages of small volume, large evaporation area, and high power generation, and can light up light-emitting diodes (LEDs), providing the possibility for large-scale production and application. Based on the high photothermal conversion efficiency and power production capacity of the RGO/Mn3 O4 /Al2 O3 composite evaporation/generator, it will be a promising energy conversion device for future sustainable energy development and applications.

Evolution Law of Structural Form and Heat Transfer Performance of Thermal Insulation System.

Building thermal insulation and energy conservation have become urgent problems in the field of civil engineering because they are important for achieving the goal of carbon neutralization. Thermal conductivity is an important index for evaluating the thermal insulation of materials. To study the influence of different porosity levels on the thermal conductivity of materials, this paper established a random distribution model using MATLAB and conducted a comparative analysis using COMSOL finite element software and classical theoretical numerical calculation formulas. The thermal conductivity of composite materials was determined based on a theoretical calculation formula and COMSOL software simulations, and the theoretical calculation results and simulation results were compared with the measured thermal conductivity of the composites. Furthermore, the influence of the width of the gaps between the materials on the heat transfer process was simulated in the fabricated roof structure. The results showed the following: (1) The thermal conductivity values calculated using the Zimmerman model were quite different from those calculated using the Campbell-Allen model and those calculated using the COMSOL software; (2) The thermal conductivity values calculated using the theoretical calculation formula were lower than the measured data, and the maximum relative error was more than 29%. The COMSOL simulation results were in good agreement with the measured data, and the relative error was less than 5%; (3) When the gap width was less than 60 mm, it increased linearly with the heat transfer coefficient. The heat transfer coefficient increased slowly when the gap width was greater than 60 mm. This was mainly due to the thermal bridge effect inside the insulation system. Based on these research results, a thermal insulation system was prepared in a factory.

Photoactivated DNA Nanodrugs Damage Mitochondria to Improve Gene Therapy for Reversing Chemoresistance.

Multidrug resistance (MDR) is a major cause of chemotherapy failure in oncology, and gene therapy is an excellent measure to reverse MDR. However, conventional gene therapy only modulates the expression of MDR-associated proteins but hardly affects their existing function, thus limiting the efficiency of tumor treatment. Herein, we designed a photoactivated DNA nanodrug (MCD@TMPyP4@DOX) to improve tumor chemosensitivity through the downregulation of MDR-related genes and mitochondria-targeted photodynamic therapy (PDT). The self-assembled DNA nanodrug encodes the mucin 1 (MUC1) aptamer and the cytochrome C (CytC) aptamer to facilitate its selective targeting to the mitochondria in tumor cells; the encoded P-gp DNAzyme can specifically cleave the substrate and silence MDR1 mRNA with the help of Mg2+ cofactors. Under near-infrared (NIR) light irradiation, PDT generates reactive oxygen species (ROS) that precisely damage the mitochondria of tumor cells and break single-stranded DNA (ssDNA) to activate MCD@TMPyP4@DOX self-disassembly for release of DOX and DNAzyme. We have demonstrated that this multifunctional DNA nanodrug has high drug delivery capacity and biosafety. It enables downregulation of P-gp expression while reducing the ATP on which P-gp pumps out drugs, improving the latency of gene therapy and synergistically reducing DOX efflux to sensitize tumor chemotherapy. We envision that this gene-modulating DNA nanodrug based on damaging mitochondria is expected to provide an important perspective for sensitizing tumor chemotherapy.

Bright Green-Emissive Carbon Nanodots for Sensing and Intracellular Imaging of Cu2+ and Glutathione.

Green-emissive carbon nanodots (CDs) with high quantum yield are prepared. The abundant functional groups on the surfaces of CDs can selectively interact with Cu2+. The formed cupric amine complexes induce significant fluorescence quenching. The "on-off" switching can be further adjusted to the fluorescence "on" mode by the introduction of glutathione (GSH), which hinders the interactions between CDs and Cu2+. Based on the fantastic optical behavior of CDs, highly sensitive detection of Cu2+ and GSH can be achieved. Intracellular imaging of the two targets is also validated.

A review of hydrogels used in endoscopic submucosal dissection for intraoperative submucosal cushions and postoperative management.

Endoscopic submucosal dissection (ESD) has been clinically proved to have prominent advantages in the treatment of early gastrointestinal cancers over traditional surgery, including less trauma, fewer complications, a quicker recovery and lower costs. During the procedure of ESD, appropriate and multifunctional submucosal injected materials (SIMs) as submucosal cushions play an important role, however, even with many advances in design strategies of SIMs over the past decades, the performance of the submucosal cushions with postoperative management function seems to be still unsatisfactory. In this review, we gave a brief historical recount about the clinical development of SIMs, then some common applications of hydrogels used as SIMs in ESD were summarized, while an account of the universal challenges during ESD procedure was also outlined. Going one step further, some cutting-edge functional strategies of hydrogels for novel applications in ESD were exhibited. Finally, we concluded the advantages of hydrogels as SIMs for ESD as well as the treatment dilemma clinicians faced when it comes to deeply infiltrated lesions, some technical perspectives about linking the clinical demand with commercial supply were also proposed. Encompassing the basic elements of SIMs used in ESD surgery and the corresponding postoperative management requirements, this review could be a good reference for relevant practitioners in expanding the research horizon and improving the well-being index of patients.

Effect of prone trunk-extension on lumbar and lower limb muscle stiffness.

This study investigated the effect of the prone trunk extension test (PTE) on lumbar and lower limb muscle stiffness to explore the optimal angle for lumbar muscle training, understand the peripheral muscle force transmission effect, and determine the modulation strategy and interaction mode of different muscles during PTE. Twenty healthy young females were recruited for this study, and the stiffness of the erector spinae (ES), semitendinosus (ST), biceps femoris (BF), medial head of the gastrocnemius (MG), and lateral head of the gastrocnemius (LG) was measured by MyotonPRO under four angular PTE conditions (0° horizontal position, 10°, 20°, and 30°). With the increasing angle, the stiffness of ES decreased gradually, while ST and BF increased first and then decreased. The stiffness of MG and LG increased first, then decreased, then increased. There was a moderate to strong negative correlation between ES stiffness variation and ST (r = -0.819 to -0.728, p < 0.001), BF (r = -0.620 to -0.527, p < 0.05), MG (r = -788 to -0.611, p < 0.01), and LG (r = -0.616 to -0.450, p < 0.05). Horizontal PTE maximizes the activation of ES. There is a tension transfer between the ES, hamstrings, and gastrocnemius, mainly between the ES, ST, and LG. The study provides data to explore the effect of peripheral muscle force transmission and the modulation strategies of different muscles during trunk extension.

Black Phosphorus Nanosheets Grafted with Gold Nanorods and Carbon Nanodots for Synergistic Antitumor Therapy.

Synergetic photothermal/photodynamic/chemotherapy receives significant attention for precise in vivo cancer treatment. Despite plenty of encouraging photosensitizers explored, integrated nanoagents with multiple functions are still highly desired. In this study, novel nanocomposites coupling black phosphorus (BP) nanosheets, gold nanorods (AuNRs), carbon nanodots (CDs), and doxorubicin (Dox) are prepared. The nanoagents exhibit high antitumor activity on account of their broad light absorption, excellent catalytic ability, and significant photothermal and photodynamic effects. CDs not only emit bright fluorescence for accurate diagnosis and guiding of tumor treatment but also catalyze the generation of ROS for photodynamic therapy (PDT). The released Dox induces apoptosis of cells and increases the levels of H2O2 to promote PDT. AuNRs are the main photothermal therapy (PTT) material that converts light into heat. Moreover, BP can be used to enhance both PTT and PDT efficiencies, and the two therapy modes can be cooperatively reinforced. It is also found that the local immune microenvironment of the tumors is activated. The strategy makes good use of the features of each component. Satisfactory antitumor phenomena are well confirmed by in vitro and in vivo results. This study provides new insights into enhanced synergetic therapy, highlighting the great utility of BP-based nanoagents in the field of nanomedicine.

Flexible and temperature-responsive hydrogel dressing for real-time and remote wound healing monitoring.

Wound management is highly clinically desirable due to the complexity and diversity of the wound repair process. However, it is still a major clinical challenge to develop a wound dressing with the capabilities of real-time and remote monitoring during wound healing. Herein, we have designed a polymer-based wound dressing in the form of a conductive, soft, temperature-responsive, antibacterial and biocompatible hydrogel, which is composed of polyacrylic acid (PAA)-grafted poly(N-isopropylacrylamide) (PNIPAM), vinyl-based polyacrylamide (PAM) and silver nanowires (AgNWs). In this hydrogel dressing, PAA-grafted PNIPAM acts as conformal interface and intrinsic temperature-responsive matrix, PAM helps to construct semi-penetrating polymer networks (SIPNs) to improve the mechanical properties, while the AgNWs introduce a three-dimensional conductive hydrogel network with antibacterial properties and sensing properties. The constructed hydrogel matrix was connected to a Bluetooth module to transmit the temperature changes wirelessly to a smart device. The design integrating a conductive hydrogel dressing with a wireless transmission module realized the real-time and wireless monitoring of the wound temperature, which is helpful to provide an early diagnosis of infection. This proof-of-concept study is highly promising in the development of new strategies to significantly improve wound management and other pathological diagnostics or treatments.

Potential noninvasive biomarkers for the malignant transformation of oral leukoplakia: A systematic review and meta-analysis.

BACKGROUND: The rising cancer incidence in patients with oral leukoplakia (OL) highlights the importance of identifying potential biomarkers for high-risk individuals and lesions because these biomarkers are useful in developing personalized management strategies for OL patients. This study systematically searched and analyzed the literature on potential saliva and serum biomarkers for OL malignant transformation. METHODS: PubMed and Scopus were searched for studies published up to April 2022. The primary outcome of this study was the difference in biomarker concentrations in saliva or serum samples from healthy control (HC), OL and oral cancer (OC) populations. Cohen's d with 95% credible interval was calculated and pooled using the inverse variance heterogeneity method. RESULTS: A total of seven saliva biomarkers were analyzed in this paper, including interleukin-1alpha, interleukin-6 (IL-6), interleukin-6-8, tumor necrosis factor alpha (TNF-α), copper, zinc, and lactate dehydrogenase. IL-6 and TNF-α exhibited statistically significant deviations in comparisons between HC versus OL and OL versus OC. A total of 13 serum biomarkers were analyzed, including IL-6, TNF-α, C-reactive protein, total cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, albumin, protein, ß2-microglobulin, fucose, lipid-bound sialic acid (LSA), and total sialic acid (TSA). LSA and TSA exhibited statistically significant deviations in comparisons between HC versus OL and OL versus OC. CONCLUSION: IL-6 and TNF-α in saliva have strong predictive values for OL deterioration, and LSA and TSA concentration levels in serum also have the potential to serve as biomarkers for OL deterioration.