Nanomaterial-based regulation of redox metabolism for enhancing cancer therapy.

Altered redox metabolism is one of the hallmarks of tumor cells, which not only contributes to tumor proliferation, metastasis, and immune evasion, but also has great relevance to therapeutic resistance. Therefore, regulation of redox metabolism of tumor cells has been proposed as an attractive therapeutic strategy to inhibit tumor growth and reverse therapeutic resistance. In this respect, nanomedicines have exhibited significant therapeutic advantages as intensively reported in recent studies. In this review, we would like to summarize the latest advances in nanomaterial-assisted strategies for redox metabolic regulation therapy, with a focus on the regulation of redox metabolism-related metabolite levels, enzyme activity, and signaling pathways. In the end, future expectations and challenges of such emerging strategies have been discussed, hoping to enlighten and promote their further development for meeting the various demands of advanced cancer therapies. It is highly expected that these therapeutic strategies based on redox metabolism regulation will play a more important role in the field of nanomedicine.

Highly Branched Au Superparticles as Efficient Photothermal Transducers for Optical Neuromodulation.

Precise neuromodulation is critical for interrogating cellular communication and treating neurological diseases. Nanoscale transducers have emerged as effective interfaces to exert photothermal effects and modulate neural activities with a high spatiotemporal resolution. Ideal materials for this application should possess strong light absorption, high photothermal conversion efficiency, and great biocompatibility for clinical translation. Here, we show that the structurally designed 3D Au superparticles with a highly branched morphology can be promising candidates for nongenetic and remote neuromodulation. The structure-induced blackbody-like absorption endows Au superparticles with photothermal conversion efficiency over 90%, much higher than that of conventional Au nanorods. With the biocompatible polydopamine ligands, Au superparticles can be readily interfaced with primary mouse hippocampal neurons and other cells and can photostimulate or inhibit their activities in both cell networks or with a single-cell resolution. These findings highlight the importance of structural designs as powerful tools to promote the performance of plasmonic materials in neuromodulation and related research of neuroscience and neuroengineering.

Autocatalytic DNA circuitries.

Autocatalysis, a self-sustained replication process where at least one of the products functions as a catalyst, plays a pivotal role in life's evolution, from genome duplication to the emergence of autocatalytic subnetworks in cell division and metabolism. Leveraging their programmability, controllability, and rich functionalities, DNA molecules have become a cornerstone for engineering autocatalytic circuits, driving diverse technological applications. In this tutorial review, we offer a comprehensive survey of recent advances in engineering autocatalytic DNA circuits and their practical implementations. We delve into the fundamental principles underlying the construction of these circuits, highlighting their reliance on DNAzyme biocatalysis, enzymatic catalysis, and dynamic hybridization assembly. The discussed autocatalytic DNA circuitry techniques have revolutionized ultrasensitive sensing of biologically significant molecules, encompassing genomic DNAs, RNAs, viruses, and proteins. Furthermore, the amplicons produced by these circuits serve as building blocks for higher-order DNA nanostructures, facilitating biomimetic behaviors such as high-performance intracellular bioimaging and precise algorithmic assembly. We summarize these applications and extensively address the current challenges, potential solutions, and future trajectories of autocatalytic DNA circuits. This review promises novel insights into the advancement and practical utilization of autocatalytic DNA circuits across bioanalysis, biomedicine, and biomimetics.

Programming Fast DNA Amplifier Circuits with Versatile Toehold Exchange Pathway.

DNA amplifier circuits establish powerful tools to dynamically control molecular assembly for computation, sensing, and biological applications. However, the slow reaction speed remains a major barrier to their practical utility. Here, diverse fast DNA amplifier circuits termed toehold exchange polymerization (TEP) and toehold exchange catalysis (TEC) using toehold exchange-mediated assembly as a fundamental mechanism are built. Both TEP and TEC with a duplex and a hairpin can respond within minutes to diverse nucleic acid inputs with high fidelity. In addition, the circuits can amplify live-cell signals for fluorescence imaging target RNA dynamics and discriminating different cell lines. Compared with existing DNA circuits that involve time scales of hours for transducing small signals, TEP and TEC exhibit much faster dynamics, simpler design, and comparable sensitivity. These features make TEP and TEC promising platforms to develop programmable nucleic acid tools and devices and to create fast sensing and processing systems, amenable to wide practical applications.

The relationships between quality of life with health literacy, social support and resilience in older stroke survivors: A structural equation model.

AIM: To the determinants and the underlying mechanism of health literacy, social support, and resilience on the health-related quality of life (HRQoL) among older stroke survivors. DESIGN: A cross-sectional design was applied at four comprehensive hospitals in Chongqing via convenience sampling from January 2020 to June 2021. METHODS: Health literacy, social support, and resilience were designed as independent variables, and HRQoL was measured as a dependent variable. Structural equation modelling with the bootstrap method was used to test the hypotheses. RESULTS: The theoretically derived model exhibited a good fit (χ2/df ratio = 2.830, GFI = 0.987, CFI = 0.978, RMSEA = 0.066). Health literacy (ß = 0.12, p < 0.05) and social support (ß = 0.14, p < 0.05) directly affect HRQoL. Resilience (ß = 0.40, p < 0.01) also mediated the relationship between health literacy, social support, and HRQoL. The three variables explaining 29.0% of HRQoL variance. PATIENT OR PUBLIC CONTRIBUTION: There was no direct patient or public involvement in the design, conduct, or reporting of this study. Participants were recruited through convenience sampling from four comprehensive hospitals in Chongqing, and their perspectives or contributions were not explicitly sought. The study focused on examining the determinants and underlying mechanism of health literacy, social support, and resilience on the health-related quality of life among older stroke survivors. Nonetheless, the findings of this research may inform the development of interventions aimed at improving the health-related quality of life in post-stroke older patients.

ClickRNA-PROTAC for Tumor-Selective Protein Degradation and Targeted Cancer Therapy.

Proteolysis-targeting chimeras (PROTACs) show promise in tumor treatment. However, the E3 ligases VHL and CRBN, commonly used in PROTAC, are highly expressed in only a few tumors, thus limiting the application scope and efficacy of PROTAC drugs. Furthermore, the lack of tumor specificity in PROTAC drugs can result in toxic side effects. Therefore, there is an urgent need to develop tumor-selective PROTAC drugs that do not rely on endogenous E3 ligases. In this study, we introduce the ClickRNA-PROTAC system, which involves the expression of a fusion protein of the E3 ubiquitin ligase SIAH1 and SNAPTag through mRNA transfection and recruits the protein of interest (POI) using bio-orthogonal click chemistry. ClickRNA-PROTAC can effectively degrade various proteins such as BRD4, KRAS, and NFκB simply by replacing the warhead molecules. By employing a tumor-specific mRNA-responsive translation strategy, ClickRNA-PROTAC can selectively degrade POIs in tumor cells. Furthermore, ClickRNA-PROTAC demonstrated strong efficacy in targeted cancer therapy in a xenograft mouse model of adrenocortical carcinoma. In conclusion, this approach offers several advantages, including independence from endogenous E3 ubiquitin ligases, tumor specificity, and programmability, thereby paving the way for the development of PROTAC drugs.

A disposable fiber-optic plasmonic sensor for chemical sensing.

The integration of fiber optics and plasmonic sensors is promising to improve the practical usability over conventional bulky sensors and systems. To achieve high sensitivity, it typically requires fabrication of well-defined plasmonic nanostructures on optical fibers, which greatly increases the cost and complexity of the sensors. Here, we present a fiber-optic sensor system by using chemical absorption of gold nanoparticles and a replaceable configuration. By functioning gold nanoparticles with aptamers or antibodies, we demonstrate the applications in chemical sensing using two different modes. Measuring shift in resonance wavelength enables the Pb2+ detection with a high linearity and a limit of detection of 0.097 nM, and measuring absorption peak amplitude enables the detection of E. coli in urinary tract infection with a dynamic range between 103 to 108 CFU/mL. The high sensitivity, simple fabrication and disposability of this sensing approach could pave the way for point-of-care testing with fiber-optic plasmonic sensors.

The Use of Identified Hypoxia-related Genes to Generate Models for Predicting the Prognosis of Cerebral Ischemia‒reperfusion Injury and Developing Treatment Strategies.

Cerebral ischemia‒reperfusion injury (CIRI) is a type of secondary brain damage caused by reperfusion after ischemic stroke due to vascular obstruction. In this study, a CIRI diagnostic model was established by identifying hypoxia-related differentially expressed genes (HRDEGs) in patients with CIRI. The ischemia‒reperfusion injury (IRI)-related datasets were downloaded from the Gene Expression Omnibus (GEO) database ( http://www.ncbi.nlm.nih.gov/geo ), and hypoxia-related genes in the Gene Cards database were identified. After the datasets were combined, hypoxia-related differentially expressed genes (HRDEGs) expressed in CIRI patients were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the HRDEGs were performed using online tools. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed with the combined gene dataset. CIRI diagnostic models based on HRDEGs were constructed via least absolute shrinkage and selection operator (LASSO) regression analysis and a support vector machine (SVM) algorithm. The efficacy of the 9 identified hub genes for CIRI diagnosis was evaluated via mRNA‒microRNA (miRNA) interaction, mRNA-RNA-binding protein (RBP) network interaction, immune cell infiltration, and receiver operating characteristic (ROC) curve analyses. We then performed logistic regression analysis and constructed logistic regression models based on the expression of the 9 HRDEGs. We next established a nomogram and calibrated the prediction data. Finally, the clinical utility of the constructed logistic regression model was evaluated via decision curve analysis (DCA). This study revealed 9 critical genes with high diagnostic value, offering new insights into the diagnosis and selection of therapeutic targets for patients with CIRI. : Not applicable.

Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery.

Nanoparticles are promising for drug delivery applications, with several clinically approved products. However, attaining high nanoparticle accumulation in solid tumours remains challenging. Here we show that tumour cell-derived small extracellular vesicles (sEVs) block nanoparticle delivery to tumours, unveiling another barrier to nanoparticle-based tumour therapy. Tumour cells secrete large amounts of sEVs in the tumour microenvironment, which then bind to nanoparticles entering tumour tissue and traffic them to liver Kupffer cells for degradation. Knockdown of Rab27a, a gene that controls sEV secretion, decreases sEV levels and improves nanoparticle accumulation in tumour tissue. The therapeutic efficacy of messenger RNAs encoding tumour suppressing and proinflammatory proteins is greatly improved when co-encapsulated with Rab27a small interfering RNA in lipid nanoparticles. Together, our results demonstrate that tumour cell-derived sEVs act as a defence system against nanoparticle tumour delivery and that this system may be a potential target for improving nanoparticle-based tumour therapies.

3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review.

Bone implantation is one of the recognized and effective means of treating bone defects, but osteoporosis and bone tumor-related bone abnormalities have a series of problems such as susceptibility to infection, difficulty in healing, and poor therapeutic effect, which poses a great challenge to clinical medicine. Three-dimensional things may be printed using 3D printing. Researchers can feed materials through the printer layer by layer to create the desired shape for a 3D structure. It is widely employed in the healing of bone defects, and it is an improved form of additive manufacturing technology with prospective future applications. This review's objective is to provide an overview of the findings reports pertaining to 3D printing biopolymers in recent years, provide an overview of biopolymer materials and their composites with black phosphorus for 3D printing bone implants, and the characterization methods of composite materials are also summarized. In addition, summarizes 3D printing methods based on ink printing and laser printing, pointing out their special features and advantages, and provide a combination strategy of photothermal therapy and bone regeneration materials for black phosphorus-based materials. Finally, the associations between bone implant materials and immune cells, the bio-environment, as well as the 3D printing bone implants prospects are outlined.

Delivery Systems Developed for Treatment Combinations to Improve Adoptive Cell Therapy.

Adoptive cell therapy (ACT) has shown great success in the clinic for treating hematologic malignancies. However, solid tumor treatment with ACT monotherapy is still challenging, owing to insufficient expansion and rapid exhaustion of adoptive cells, tumor antigen downregulation/loss, and dense tumor extracellular matrix. Delivery strategies for combination cell therapy have great potential to overcome these hurdles. The delivery of vaccines, immune checkpoint inhibitors, cytokines, chemotherapeutics, and photothermal reagents in combination with adoptive cells, have been shown to improve the expansion/activation, decrease exhaustion, and promote the penetration of adoptive cells in solid tumors. Moreover, the delivery of nucleic acids to engineer immune cells directly in vivo holds promise to overcome many of the hurdles associated with the complex ex vivo cell engineering strategies. Here, these research advance, as well as the opportunities and challenges for integrating delivery technologies into cell therapy s are discussed, and the outlook for these emerging areas are criticlly analyzed.

Preamplification-free viral RNA diagnostics with single-nucleotide resolution using MARVE, an origami paper-based colorimetric nucleic acid test.

The evolution and mutation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgent concerns as they pose the risk of vaccine failure and increased viral transmission. However, affordable and scalable tools allowing rapid identification of SARS-CoV-2 variants are not readily available, which impedes diagnosis and epidemiological surveillance. Here we present a colorimetric nucleic acid assay named MARVE (multiplexed, preamplification-free, single-nucleotide-resolved viral evolution) that is convenient to perform and yields single-nucleotide resolution. The assay integrates nucleic acid strand displacement reactions with enzymatic amplification to colorimetrically sense viral RNA using a metal ion-incorporated DNA probe (TEprobe). We provide detailed guidelines to design TEprobes for discriminating single-nucleotide variations in viral RNAs, and to fabricate a test paper for the detection of SARS-CoV-2 variants of concern. Compared with other nucleic acid assays, our assay is preamplification-free, single-nucleotide-resolvable and results are visible via a color change. Besides, it is smartphone readable, multiplexed, quick and cheap ($0.30 per test). The protocol takes ~2 h to complete, from the design and preparation of the DNA probes and test papers (~1 h) to the detection of SARS-CoV-2 or its variants (30-45 min). The design of the TEprobes requires basic knowledge of molecular biology and familiarity with NUPACK or the Python programming language. The fabrication of the origami papers requires access to a wax printer using the CAD and PDF files provided or requires users to be familiar with AutoCAD to design new origami papers. The protocol is also applicable for designing assays to detect other pathogens and their variants.

Causality of metabolites and metabolic pathways on cholestatic liver diseases: a Mendelian randomization study.

Background and Aims: Blood metabolite abnormalities have revealed an association with cholestatic liver diseases (CLDs), while the underlying metabolic mechanisms have remained sluggish yet. Accordingly, the present evaluation aims to investigate the causal relationship between blood metabolites and the risk of two major CLDs, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Methods: Univariable and multivariable Mendelian randomization (MR) approaches were employed to uncover potential causal associations between blood metabolites and 2 CLDs, including PBS and PSC, through extracting instrumental variables (IVs) for metabolites from genome-wide association studies (GWAS) conducted on European individuals. The GWAS summary data of PBC or PSC were sourced from two distinct datasets. The initial analysis employed inverse variance weighted (IVW) and an array of sensitivity analyses, followed by replication and meta-analysis utilizing FinnGen consortium data. Finally, a multivariable MR analysis was carried out to ascertain the independent effects of each metabolite. Furthermore, the web-based tool MetaboAnalyst 5.0 was used to perform metabolic pathway examination. Results: A genetic causality between 15 metabolites and CLDs was recognized after preliminary analysis and false discovery rate (FDR) correction. Subsequently, 9 metabolites consistently represented an association through replication and meta-analysis. Additionally, the independent causal effects of 7 metabolites were corroborated by multivariable MR analysis. Specifically, the metabolites isovalerylcarnitine (odds ratio [OR] = 3.146, 95% confidence intervals [CI]: 1.471-6.726, p = 0.003), valine (OR = 192.44, 95%CI: 4.949-7483.27, p = 0.005), and mannose (OR = 0.184, 95%CI: 0.068-0.499, p < 0.001) were found to have a causal relationship with the occurrence of PBC. Furthermore, erythrose (OR = 5.504, 95%CI: 1.801-16.821, p = 0.003), 1-stearoylglycerophosphocholine (OR = 6.753, 95%CI: 2.621-17.399, p = 7.64 × 10-5), X-11847 (OR = 0.478, 95%CI: 0.352-0.650, p = 2.28 × 10-6), and X-12405 (OR = 3.765, 95%CI: 1.771-8.005, p = 5.71 × 10-4) were independently associated with the occurrence of PSC. Furthermore, the analysis of metabolic pathways identified seven significant pathways in two CLDs. Conclusion: The findings of the present study have unveiled robust causal relationships between 7 metabolites and 2 CLDs, thereby providing novel insights into the metabolic mechanisms and therapeutic strategies for these disorders.

Discovery of A G-Quadruplex Unwinder That Unleashes the Translation of G-Quadruplex-Containing mRNA without Inducing DNA Damage.

To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate and intervene in intracellular G4 structures using small molecular tools. While hundreds of G4 stabilizers have been developed, there is a significant gap in the availability of G4 unwinding agents. Here, we propose a strategy to disrupt G-quadruplexes by forming G-C hydrogen bonds with chemically modified cytidine trimers. We validated a good G4 unwinder, the 2'-F cytidine trimer (2'-F C3). 2'-F C3 does not inhibit cell growth nor cause severe DNA damage at a concentration below 10 µM. Moreover, 2'-F C3 does not affect gene transcription nor RNA splicing, while it significantly enhances the translation of G4-containing mRNA and upregulates RNA splicing, RNA processing and cell cycle pathways. The discovery of this G4 unwinder provides a functional tool for the chemical modulation of G4s in living cells.

Five new species of the genus Stigmus Panzer (Hymenoptera, Crabronidae) from China, with a key to all Chinese species.

Five new species of the genus Stigmus Panzer, 1804 are described and illustrated from Yunnan and Shaanxi provinces of China: S.carinannulatus Li & Ma, sp. nov., S.clypeglabratus Li & Ma, sp. nov., S.flagellipilaris Li & Ma, sp. nov., S.rugidensus Li & Ma, sp. nov., and S.sulciconspicus Li & Ma, sp. nov. In addition, S.solskyi Morawitz, 1864 is recorded in China for the first time. An illustrated key to known and new species of the genus Stigmus Panzer from China is provided.

Enhanced Mineralization of Organic Pollutants through Atomic Hydrogen-Mediated Alternative Transformation Pathways.

Electrocatalytic hydrogen atom-hydroxyl radical (H*-·OH) redox system is a promising approach for contaminant removal and mineralization. However, its working mechanism, especially the effect of H*, remains unclear, hindering its practical application. Herein, we constructed an electrochemical reactor equipped with our self-made Pd-loaded Ti/TiO2 nanotube cathode and a commercial boron-doped diamond anode. After fulfilling the electrode characterization and free radical detection, we employed coumarin and 7-azido-4-methylcoumarin as probes to confirm the participation of H* in the transformation of organic compounds. A comprehensive study on the degradation kinetics, reaction, and mineralization mechanisms using benzoic acid (BA) and 4-chlorophenol (4-CP) as model compounds was further conducted. The rate constants and total organic carbon removal of BA and 4-CP in the redox system increased compared with those of the individual oxidation and reduction processes. Theoretical calculations demonstrate that H* opens up alternative pathways for BA and 4-CP ring cleavage, forming quinones as reactive intermediates. Furthermore, H* facilitates the mineralization of the typical intermediates, maleic acid and fumaric acid, through C=C bond addition and H-abstraction from the 1,1-diol structure. The presence of H* provides alternative pathways for pollutant transformation, consequently reducing the treatment duration.

Single-Cell Imaging of mRNA by Target RNA-Initiated RCA.

We present a powerful method for direct mRNA detection based on ligation-based recognition and in situ amplification, capable of single-cell imaging mRNA at single-nucleotide and single-molecule resolution. Attributed to the use of Splint R ligase that can ligate padlock probe with RNA as target template, this method can efficiently detect mRNA in the absence of reverse transcription. This method enables spatial localization and correlation analysis of gene expression in single cells, which helps us to elucidate gene function and regulatory mechanisms.

Reverse Separation of Carbon Dioxide and Acetylene in Two Isostructural Copper Pyridine-Carboxylate Frameworks.

Separating acetylene from carbon dioxide is important but highly challenging due to their similar molecular shapes and physical properties. Adsorptive separation of carbon dioxide from acetylene can directly produce pure acetylene but is hardly realized because of relatively polarizable acetylene binds more strongly. Here, we reverse the CO2 and C2H2 separation by adjusting the pore structures in two isoreticular ultramicroporous metal-organic frameworks (MOFs). Under ambient conditions, copper isonicotinate (Cu(ina)2), with relatively large pore channels shows C2H2-selective adsorption with a C2H2/CO2 selectivity of 3.4, whereas its smaller-pore analogue, copper quinoline-5-carboxylate (Cu(Qc)2) shows an inverse CO2/C2H2 selectivity of 5.6. Cu(Qc)2 shows compact pore space that well matches the optimal orientation of CO2 but is not compatible for C2H2. Neutron powder diffraction experiments confirmed that CO2 molecules adopt preferential orientation along the pore channels during adsorption binding, whereas C2H2 molecules bind in an opposite fashion with distorted configurations due to their opposite quadrupole moments. Dynamic breakthrough experiments have validated the separation performance of Cu(Qc)2 for CO2/C2H2 separation.

Functional Interface for Glycoprotein Sensing: Focusing on Biosensors.

Glycosylated proteins or glycoproteins make up a large family of glycoconjugates, and they participate in a variety of fundamental biological events. Glycoproteins have become important biomarkers in the diagnosis and treatment of a number of tumors. Biosensors are quite suitable for glycoprotein detection. The design and fabrication of a functional sensing interface play a crucial role in the biosensor construction to target glycoproteins. The functional interface, particularly receptors, typically determines the key characteristics of a biosensor, such as selectivity and sensitivity. Antibody, peptide, aptamer, boronic acid derivative, lectin, and molecularly imprinted polymer are all capable receptors for glycoprotein recognition, and each of these will be discussed. Most glycoproteins exist in low abundance, thus rendering signal amplification techniques indispensable. Nucleic acid-mediated and nanomaterial-mediated signal amplification for the detection of glycoproteins will be focused on herein. This review aims to highlight these different functional interfaces for glycoprotein sensing.

Emerging trends in management of long COVID with a focus on pulmonary rehabilitation: A review.

Long COVID, or post-acute sequelae of COVID-19 (PASC), represents a complex condition with persistent symptoms following SARS-Cov-2 infection. The symptoms include fatigue, dyspnoea, cognitive impairment, decreased quality of life in variable levels of severity. Potential mechanisms behind long COVID include vascular damage, immune dysregulation and viral persistence. Diagnosing long COVID involves medical evaluation by multidisciplinary team and assessment of persistent symptoms with scoring systems in development. Treatment strategies are symptom-focused, encompassing multidisciplinary care, rehabilitation and tailored exercise programmes. Pulmonary rehabilitation, an effective and critical component of long COVID management, has shown promise, particularly for patients with respiratory symptoms such as dyspnoea. These programmes, which combine exercise, breathing techniques, education and psychological support, improve symptoms, quality of life and overall recovery. Innovative technologies, such as telemedicine, wearable devices, telerehabilitation, are transforming long COVID management. Telemedicine facilitates consultations and interventions, eliminating healthcare access barriers. Wearable devices enable remote and continuous monitoring of patients during their rehabilitation activities. Telerehabilitation has proven to be safe and feasible and to have high potential for COVID-19 recovery. This review provides a concise overview of long COVID, encompassing its definition, prevalence, mechanisms, clinical manifestations, diagnosis and management approaches. It emphasizes the significance of multidisciplinary approach in diagnosis and treatment of long COVID, with focus on pulmonary rehabilitation and innovative technology advances to effectively address the management of long COVID.