Cascade Self-Generation of Carbon Monoxide Triggered by Photoinduced Holes for Efficient Hypoxic Tumors Therapy.

It still remains challenging to design multifunctional therapeutic reagents for effective cancer therapy under a unique tumor microenvironment including insufficient endogenous H2O2 and O2, low pH, and a high concentration of glutathione (GSH). In this work, a CO-based phototherapeutic system triggered by photogenerated holes, which consisted of ionic liquid (IL), the CO prodrug Mn2(CO)10, and iridium(III) porphyrin (IrPor) modified carbonized ZIF-8-doped graphitic carbon nitride nanocomposite (IL/ZCN@Ir(CO)), was designed for cascade hypoxic tumors. Upon light irradiation, the photogenerated holes on IL/ZCN@Ir(CO) oxidize water into H2O2, which subsequently induces Mn2(CO)10 to release CO. Meanwhile, IrPor can convert H2O2 to hydroxyl radical (•OH) and subsequent singlet oxygen (1O2), which further triggers CO release. Moreover, the degraded MnO2 shows activity for glutathione (GSH) depletion and mimics peroxidase, leading to GSH reduction and •OH production in tumors. Thus, this strategy can in situ release high concentrations of CO and reactive oxygen species (ROS) and deplete GSH to efficiently induce cell apoptosis under hypoxic conditions, which has a high inhibiting effect on the growth of tumors, offering an attractive strategy to amplify CO and ROS generation to meet therapeutic requirements in cancer treatment.

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline.

A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE).

MiR-143-3p regulates chondrogenic differentiation of synovium derived mesenchymal stem cells under mechanical stress through the BMPR2-Smad signalling pathway by targeting BMPR2.

BACKGROUND: Mesenchymal stem cells (MSCs) derived from the synovium, known as synovium mesenchymal stem cells (SMSCs), exhibit significant potential for articular cartilage regeneration owing to their capacity for chondrogenic differentiation. However, the microRNAs (miRNAs) governing this process and the associated mechanisms remain unclear. While mechanical stress positively influences chondrogenesis in MSCs, the miRNA-mediated response of SMSCs to mechanical stimuli is not well understood. OBJECTIVE: This study explores the miRNA-driven mechano-transduction in SMSCs chondrogenesis under mechanical stress. METHODS: The surface phenotype of SMSCs was analysed by flow cytometry. Chondrogenesis capacities of SMSCs were examined by Alcian blue staining. High throughput sequencing was used to screen mechano-sensitive miRNAs of SMSCs. The RNA expression level of COL2A1, ACAN, SOX9, BMPR2 and miR-143-3p of SMSCs were tested by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-143-3p and TLR4 was confirmed by luciferase reporter assays. The protein expression levels of related genes were assessed by western blot. RESULTS: High-throughput sequencing revealed a notable reduction in miR-143-3p levels in mechanically stressed SMSCs. Gain- or loss-of-function strategies introduced by lentivirus demonstrated that miR-143-3p overexpression hindered chondrogenic differentiation, whereas its knockdown promoted this process. Bioinformatics scrutiny and luciferase reporter assays pinpointed a potential binding site for miR-143-3p within the 3'-UTR of bone morphogenetic protein receptor type 2 (BMPR2). MiR-143-3p overexpression decreased BMPR2 expression and phosphorylated Smad1, 5 and 8 levels, while its inhibition activated BMPR2-Smad pathway. CONCLUSION: This study elucidated that miR-143-3p negatively regulates SMSCs chondrogenic differentiation through the BMPR2-Smad pathway under mechanical tensile stress. The direct targeting of BMPR2 by miR-143-3p established a novel dimension to our understanding of mechano-transduction mechanism during SMSC chondrogenesis. This understanding is crucial for advancing strategies in articular cartilage regeneration.

Probing ligand conformation and net dimensionality in a series of tetraphenylethene-based metal-organic frameworks.

Tetraphenylethene-based ligands with lowered symmetry are promising building blocks for the construction of novel luminescent metal-organic frameworks (MOFs). However, few examples have been reported, and predicting the ligand conformation and the dimensionality of the resulting MOF remains challenging. In order to uncover how synthetic conditions and accessible ligand conformations may affect the resulting MOF structure, four new MOF structures were synthesized under solvothermal conditions using the meta-coordinated tetraphenylethene-based ligand m-ETTC and paddlewheel SBUs composed of Co(II), Cu(II), and Zn(II). WSU-10 (WSU = Washington State University) is formed with either Zn or Cu comprising stacked psuedo-2D layers. The dimensionality of WSU-10 can be intentionally increased through the addition of pyrazine as a pillar ligand into the synthesis, forming the 3D structure WSU-11. The third structure, WSU-20, is formed by the combination of Zn or Co with m-ETTC and is intrinsically 3D without the use of a pillar ligand; interestingly, this is the result of a distortion in the paddlewheel SBU. Finally, Cu was also found to form a new structure (WSU-12), which displays an m-ETTC conformation unique from that found in the other isolated MOFs. Structural features are compared across the series and a mechanistic relationship between WSU-10 and -20 is proposed, providing insight into the factors that can encourage the generation of frameworks with increased dimensionality.

Trends in temporal and spatial changes of Japanese encephalitis in Chinese mainland, 2004-2019: A population-based surveillance study.

BACKGROUND: Japanese encephalitis (JE) is a serious health concern in China, with approximately 80 % of global infections occurring in China. To develop effective prevention and control strategies, this study explored the epidemiological characteristics of JE in China based on spatiotemporal data, to understand the patterns and trends of JE incidence in different regions and time periods. METHOD: The incidence and mortality rates of JE were extracted from the Public Health Data Center, the official website of the National Health Commission of the People's Republic of China, and the National Notifiable Infectious Disease Surveillance System from 2004 to 2019. Joinpoint regression was applied to examine the spatiotemporal patterns and annual percentage change in incidence and mortality of the JE. RESULTS: From 2004 to 2019, a total of 43,569 cases of JE were diagnosed, including 2081 deaths. The annual incidence rate of JE decreased from 0.4171/100,000 in 2004 to 0.0298/100,000 in 2019, with an annual percentage change (APC) of -13.5 % (P < 0.001). The annual mortality rate of JE showed three stages of change, with inflection points in 2006 and 2014. The incidence and mortality rates of JE have declined in all provinces of China, and more cases were reported in 0-14 years of age, accounting for nearly 80 % of all patients. CONCLUSIONS: The morbidity and mortality rates of JE in China are generally on a downward trend, and emphasis should be placed on strengthening disease surveillance in special areas and populations, popularizing vaccination, and increasing publicity.

Whole-body deletion of Endospanin 1 protects from obesity-associated deleterious metabolic alterations.

The importance of the proper localization of most receptors at the cell surface is often underestimated, although this feature is essential for optimal receptor response. Endospanin 1 (Endo1) (also known as OBRGRP or LEPROT) is a protein generated from the same gene as the human leptin receptor and regulates the trafficking of proteins to the surface, including the leptin receptor. The systemic role of Endo1 on whole-body metabolism has not been studied so far. Here, we report that general Endo1-KO mice fed a high-fat diet develop metabolically healthy obesity with lipid repartitioning in organs and preferential accumulation of fat in adipose tissue, limited systematic inflammation, and better controlled glucose homeostasis. Mechanistically, Endo1 interacts with the lipid translocase CD36, thus regulating its surface abundance and lipid uptake in adipocytes. In humans, the level of Endo1 transcripts is increased in the adipose tissue of patients with obesity, but low levels rather correlate with a profile of metabolically healthy obesity. We suggest here that Endo1, most likely by controlling CD36 cell surface abundance and lipid uptake in adipocytes, dissociates obesity from diabetes and that its absence participates in metabolically healthy obesity.

Discovery of ITI-333, a Novel Orally Bioavailable Molecule Targeting Multiple Receptors for the Treatment of Pain and Other Disorders.

Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6bR,10aS)-8-[3-(4-fluorophenoxy)propyl]-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (compound 5, ITI-333), which exhibited potent binding affinity to serotonin 5-HT2A (Ki = 8.3 nM) and µ-opioid receptors (MOR, Ki = 11 nM) and moderate affinity to adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. ITI-333 acts as a 5-HT2A receptor antagonist, a MOR partial agonist, and an adrenergic α1A receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.

Deep learning nomogram for predicting neoadjuvant chemotherapy response in locally advanced gastric cancer patients.

PURPOSE: Developed and validated a deep learning radiomics nomogram using multi-phase contrast-enhanced computed tomography (CECT) images to predict neoadjuvant chemotherapy (NAC) response in locally advanced gastric cancer (LAGC) patients. METHODS: This multi-center study retrospectively included 322 patients diagnosed with gastric cancer from January 2013 to June 2023 at two hospitals. Handcrafted radiomics technique and the EfficientNet V2 neural network were applied to arterial, portal venous, and delayed phase CT images to extract two-dimensional handcrafted and deep learning features. A nomogram model was built by integrating the handcrafted signature, the deep learning signature, with clinical features. Discriminative ability was assessed using the receiver operating characteristics (ROC) curve and the precision-recall (P-R) curve. Model fitting was evaluated using calibration curves, and clinical utility was assessed through decision curve analysis (DCA). RESULTS: The nomogram exhibited excellent performance. The area under the ROC curve (AUC) was 0.848 [95% confidence interval (CI), 0.793-0.893)], 0.802 (95% CI 0.688-0.889), and 0.751 (95% CI 0.652-0.833) for the training, internal validation, and external validation sets, respectively. The AUCs of the P-R curves were 0.838 (95% CI 0.756-0.895), 0.541 (95% CI 0.329-0.740), and 0.556 (95% CI 0.376-0.722) for the corresponding sets. The nomogram outperformed the clinical model and handcrafted signature across all sets (all P < 0.05). The nomogram model demonstrated good calibration and provided greater net benefit within the relevant threshold range compared to other models. CONCLUSION: This study created a deep learning nomogram using CECT images and clinical data to predict NAC response in LAGC patients undergoing surgical resection, offering personalized treatment insights.

Effects of dietary metabolizable energy level on hepatic lipid metabolism and cecal microbiota in aged laying hens.

Lipid metabolic capacity, feed utilization, and the diversity of gut microbiota are reduced in the late laying stage for laying hens. This experiment aimed to investigate the effects of different levels of dietary metabolizable energy (ME) on hepatic lipid metabolism and cecal microbiota in late laying hens. The 216 Peking Pink laying hens (57-wk-old) were randomly assigned to experimental diets of 11.56 (HM = high ME), 11.14 (MM = medium ME), or 10.72 (LM = low ME) MJ of ME/kg, with each dietary treatment containing 6 replicates per group and 12 chickens per replicate. The HM group showed higher triglyceride (TG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) concentrations in the liver compared with the LM group; second, the HM group showed higher TG concentration and the LM group showed lower T-CHO concentration compared with MM group; finally, the HM group showed a lower hepatic lipase (HL) activity compared with the MM and LM groups (P < 0.05). There was a significant difference in the microbial community structure of the cecum between the HM and MM groups (P < 0.05). The decrease of dietary ME level resulted in a gradual decrease relative abundance of Proteobacteria. At the genus level, beneficial bacteria were significantly enriched in the LM group compared to the MM group, including Faecalibacterium, Lactobacillus, and Bifidobacterium, (linear discriminant analysis [LDA] >2, P <0.05). In addition, at the species level, Lactobacillus crispatus, Parabacteroides gordonii, Blautia caecimuris, and Lactobacillus johnsonii were significantly enriched in the LM group (LDA>2, P < 0.05). The HM group had a higher abundance of Sutterella spp. compared to the LM group (LDA>2, P <0.05). In conclusion, this research suggests that the reduction in dietary energy level did not adversely affect glycolipid metabolism or low dietary ME (10.72 MJ/kg). The findings can be helpful for maintaining intestinal homeostasis and increasing benefit for gut microbiota in late laying hens.

Superb Silk Hydrogels with High Adaptability, Bioactivity, and Versatility Enabled by Photo-Cross-Linking.

The exceptional biocompatibility and adaptability of hydrogels have garnered significant interest in the biomedical field for the fabrication of biomedical devices. However, conventional synthetic hydrogels still exhibit relatively weak and fragile properties. Drawing inspiration from the photosynthesis process, we developed a facile approach to achieve a harmonious combination of superior mechanical properties and efficient preparation of silk fibroin hydrogel through photo-cross-linking technology, accomplished within 60 s. The utilization of riboflavin and H2O2 enabled a sustainable cyclic photo-cross-linking reaction, facilitating the transformation from tyrosine to dityrosine and ultimately contributing to the formation of highly cross-linked hydrogels. These photo-cross-linking hydrogels exhibited excellent elasticity and restorability even after undergoing 1000 cycles of compression. Importantly, our findings presented that hydrogel-encapsulated adipose stem cells possess the ability to stimulate cell proliferation along with stem cell stemness. This was evidenced by the continuous high expression levels of OCT4 and SOX2 over 21 days. Additionally, the utilization of photo-cross-linking hydrogels can be extended to various material molding platforms, including microneedles, microcarriers, and bone screws. Consequently, this study offered a significant approach to fabricating biomedical hydrogels capable of facilitating real-time cell delivery, thereby introducing an innovative avenue for designing silk devices with exceptional machinability and adaptability in biomedical applications.

Oxidative Upcycling of Polyethylene to Long Chain Diacid over Co-MCM-41 Catalyst.

Plastic pollution is an emerging global threat due to lack of effective methods for transforming waste plastics into useful resources. Here, we demonstrate a direct oxidative upcycling of polyethylene into high-value and high-volume long chain (C10-C20) saturated dicarboxylic acids in high carbon yield of 85.9% over cobalt-doped MCM-41 molecular sieves, in the absence of any solvent or precious metal catalyst. The distribution of the dicarboxylic acids can be controllably adjusted from short-chain (C4-C10) to long-chain ones (C10-C20) through changing cobalt loading of MCM-41 under nanoconfinement. Highly and sparsely dispersed cobalt along with confined space of mesoporous structure enables complete degradation of polyethylene and high selectivity of dicarboxylic acid in mild condition. So far, this is the first report on highly selective one-step preparation of long chain dicarboxylic acids. The approach provides an attractive solution to tackle plastic pollution and a promising alternative route to long chain diacids.

Constructing Ionic Interfaces for Stable Electrochemical CO2 Reduction.

The electrochemical CO2 reduction reaction (CO2RR) has emerged as a promising approach for sustainable carbon cycling and valuable chemical production. Various methods and strategies have been explored to boost CO2RR performance. One of the most promising strategies includes the construction of stable ionic interfaces on metallic or molecular catalysts using organic or inorganic cations, which has demonstrated a significant improvement in catalytic performance. The stable ionic interface is instrumental in adjusting adsorption behavior, influencing reactive intermediates, facilitating mass transportation, and suppressing the hydrogen evolution reaction, particularly under acidic conditions. In this Perspective, we provide an overview of the recent advancements in building ionic interfaces in the electrocatalytic process and discuss the application of this strategy to improve the CO2RR performance of metallic and molecular catalysts. We aim to convey the future trends and opportunities in creating ionic interfaces to further enhance carbon utilization efficiency and the productivity of CO2RR products. The emphasis of this Perspective lies in the pivotal role of ionic interfaces in catalysis, providing a valuable reference for future research in this critical field.

Learning Motion Primitives for the Quantification and Diagnosis of Mobility Deficits.

The severity of mobility deficits is one of the most critical parameters in the diagnosis and rehabilitation of Parkinson's disease (PD). The current approach for severity evaluation is clinical scaling that relies on a clinician's subjective observations and experience, and the observation in laboratories or clinics may not suffice to reflect the severity of motion deficits as compared to daily living activities. The paper presents an approach to modeling and quantifying the severity of mobility deficits from motion data by using nonintrusive wearable physio-biological sensors. The approach provides a user-specific metric that measures mobility deficits in terms of the quantities of motion primitives that are learned from motion tracking data. The proposed method achieved 99.84% prediction accuracy on laboratory data and 93.95% prediction accuracy on clinical data. This approach presents the potential to supplant traditional observation-based clinical scaling, providing an avenue for real-time feedback to fortify positive progression throughout the course of rehabilitation.

Dual-branch information extraction and local attention anchor-free network for defect detection.

In the production process, the presence of surface defects seriously affects the quality of industrial products. Existing defect detectors are not suitable for surface with scattered distribution and complex texture of defects. In this study, a dual-branch information extraction and local attention anchor-free network for defect detection (DLA-FCOS), which is based on the fully convolutional one-stage network, is proposed to accurately locate and detect surface defects of industrial products. Firstly, a dual-branch feature extraction network (DFENeT) is proposed and used to improve the extraction ability of complex defects. Then, a local feature enhancement module is proposed, and a residual connection is established to enrich local semantic information. Meanwhile, the self-attention mechanism is introduced to form local attentional residual feature pyramid networks (LA-RFPN) to eliminate the influences of feature misalignments. The mean average accuracy (mAP) and frames per second (FPS) of the proposed DLA-FCOS on the cut layer of the tobacco packet defect dataset (CLTP-DD) are 96.8% and 20.7, respectively, which meets the requirements for accurate and real-time defect detection. Meanwhile, the average accuracy of the proposed DLA-FCOS on the NEU-DET and GC10-DET datasets is 78.4% and 67.7%, respectively. The results demonstrate that the DLA-FCOS has good feasibility and high generalization capability to perform defect detection tasks of industrial products.

Boosting humoral and cellular immunity with enhanced STING activation by hierarchical mesoporous metal-organic framework adjuvants.

Vaccination is essential for preventing and controlling infectious diseases, along with reducing mortality. Developing safe and versatile adjuvants to enhance humoral and cellular immune responses to vaccines remains a key challenge in vaccine development. Here, we designed hierarchical mesoporous MOF-801 (HM801) using a Cocamidopropyl betaine (CAPB) and a Pluronics F127 in an aqueous phase system. Meanwhile, we synthesized a novel SARS-CoV-2 nanovaccine (R@M@HM801) with a high loading capacity for both the STING agonist (MSA-2) and the Delta receptor binding domain (Delta-RBD) antigen. R@M@HM801 enhanced MSA-2 and RBD utilization and effectively co-delivered MSA-2 and RBD antigens to antigen-presenting cells in the draining lymph nodes, thereby promoting the activation of both T and B cells. Lymphocyte single-cell analysis showed that R@M@HM801 stimulated robust CD11b+CD4+ T cells, CXCR5+CD4+ T follicular helper (Tfh), and durable CD4+CD44+CD62L-, CD8+CD44+CD62L- effector memory T cell (TEM) immune responses, and promoted the proliferative activation of CD26+ B cells in vivo. Meanwhile, R@M@HM801 induced stronger specific antibodies and neutralization of pseudovirus against Delta compared to the RBD + MAS-2 and RBD + MAS-2 + Alum vaccines. Our study demonstrated the efficacy of a hierarchical mesoporous HM801 and its potential immune activation mechanism in enhancing adaptive immune responses against viruses and other diseases.

Induction of ferroptosis by natural products in non-small cell lung cancer: a comprehensive systematic review.

Lung cancer is one of the leading causes of cancer-related deaths worldwide that presents a substantial peril to human health. Non-Small Cell Lung Cancer (NSCLC) is a main subtype of lung cancer with heightened metastasis and invasion ability. The predominant treatment approaches currently comprise surgical interventions, chemotherapy regimens, and radiotherapeutic procedures. However, it poses significant clinical challenges due to its tumor heterogeneity and drug resistance, resulting in diminished patient survival rates. Therefore, the development of novel treatment strategies for NSCLC is necessary. Ferroptosis was characterized by iron-dependent lipid peroxidation and the accumulation of lipid reactive oxygen species (ROS), leading to oxidative damage of cells and eventually cell death. An increasing number of studies have found that exploiting the induction of ferroptosis may be a potential therapeutic approach in NSCLC. Recent investigations have underscored the remarkable potential of natural products in the cancer treatment, owing to their potent activity and high safety profiles. Notably, accumulating evidences have shown that targeting ferroptosis through natural compounds as a novel strategy for combating NSCLC holds considerable promise. Nevertheless, the existing literature on comprehensive reviews elucidating the role of natural products inducing the ferroptosis for NSCLC therapy remains relatively sparse. In order to furnish a valuable reference and support for the identification of natural products inducing ferroptosis in anti-NSCLC therapeutics, this article provided a comprehensive review explaining the mechanisms by which natural products selectively target ferroptosis and modulate the pathogenesis of NSCLC.

The prognostic value of cancer stem cell markers in thyroid cancer: a systematic review.

Introduction: Thyroid cancer stem cells (TCSCs) play a crucial role in the pathogenesis, metastasis, and therapeutic response of thyroid cancer, making them promising biomarkers and potential targets for clinical intervention. This systematic review aims to qualitatively assess the impact of commonly used TCSC markers on the prognosis of thyroid cancer using qualitative methods. Methods: In total, the analysis encompassed five articles. Results: Six TCSC markers were involved, among which CD133, CD44, CD24, CD15 and ALDH1 were associated with the prognosis of thyroid cancer. Conclusions: However, the utility of these TCSC markers in clinical practice for predicting the prognosis of thyroid cancer requires further research to provide additional evidence supporting their effectiveness.

TIPE1 limits virus replication by disrupting PKM2/ HIF-1α/ glycolysis feedback loop.

OBJECTIVE: Virus infection is a major threat to human health and remains a significant cause of death to date. Macrophages are important innate immune cells that exhibit indispensable roles in controlling virus replication. It was recently reported that metabolic adaption determines the functional state of macrophages. Thus, to further unravel the crucial factors involving in metabolic adaption of macrophages might provide the potential candidates for optimizing their anti-viral capabilities. METHODS: RT-PCR, Western blotting, virus plaque assay and HE were used to evaluate the viral load in virus-infected Tipe1M-KO and Tipe1f/f mice or cultured macrophages. RNA sequencing were performed with Tipe1M-KOor Tipe1f/f BMDMs upon virus infection. Extracellular acidification rate (ECAR) was applied for analyzing glycolysis rate in virus-infected BMDMs. Co-immunoprecipitation (Co-IP) assay and LC-MS/MS were used to determine the potential interacting proteins of TIPE1. RESULTS: TIPE1 level was significantly reduced in BMDMs infected with either RNA viruses or DNA virus. Deficiency of Tipe1 in macrophages increased viral load and aggravated tissue damage. Mechanistically, TIPE1 suppressed the glycolytic capacity of macrophages through interacting with PKM2 and promoting its ubiquitination degradation, which in turn decreased HIF1α transcription and viral replication in macrophages. CONCLUSIONS: TIPE1 functions as a novel regulator for metabolic reprogramming and virus infection in macrophages.