Thermal-Accelerated Urease-Driven Bowl-Like Polydopamine Nanorobot for Targeted Photothermal/Photodynamic Antibiotic-Free Antibacterial Therapy.

The problem of antibiotic resistance seriously affects the treatment of bacterial infections, so there is an urgent need to develop novel antibiotic-independent antimicrobial strategies. Herein, a urease-driven bowl-like mesoporous polydopamine nanorobot (MPDA@ICG@Ur@Man) based on single-wavelength near-infrared (NIR) remote photothermal acceleration to achieve antibiotic-free phototherapy(photothermal therapy, PTT, plus photodynamic therapy, PDT) is first reported. The smart nanorobots can perform active movement by decomposing urea to produce carbon dioxide and ammonia. Particularly, the elevated local temperature during PTT can increase urease activity to enhance the autonomous movement and thus increase the contact between the antimicrobial substance and bacteria. Compared with a nanomotor propelled by urea only, the diffusion coefficient (De) of photothermal-accelerated nanorobots is increased from 1.10 to 1.26 µm2 s-1. More importantly, urease-driven bowl-like nanorobots with photothermal enhancement can specifically identify Escherichia coli (E. coli) and achieve simultaneous PTT/PDT at a single wavelength with 99% antibactericidal activity in vitro. In a word, the urease-driven bowl-like nanorobots guided by photothermal-accelerated strategy could provide a novel perspective for increasing PTT/PDT antibacterial therapeutic efficacy and be promising for various antibiotic-free sterilization applications.

Mn(iii)-mediated carbon-centered radicals generate an enhanced immunotherapeutic effect.

A strategy for designing cancer therapeutic nanovaccines based on immunogenic cell death (ICD)-inducing therapeutic modalities is particularly attractive for optimal therapeutic efficacy. In this work, a highly effective cancer therapeutic nanovaccine (denoted as MPL@ICC) based on immunogenic photodynamic therapy (PDT) was rationally designed and fabricated. MPL@ICC was composed of a nanovehicle of MnO2 modified with a host-guest complex using amino pillar[6]arene and lactose-pyridine, a prodrug of isoniazid (INH), and chlorine e6 (Ce6). The nanovaccine exhibited excellent biosafety, good targeting ability to hepatoma cells and enrichment at tumor sites. Most importantly, it could modulate the tumor microenvironment (TME) to facilitate the existence of Mn(iii) and Mn(iii)-mediated carbon-centered radical generation with INH released from the prodrug in situ to further strengthen ICD. This is the first report on Mn(iii)-mediated generation of carbon-centered radicals for successful anti-tumor immunotherapy using ICD, which provides a novel strategy for designing highly efficient cancer therapeutic nanovaccines.

A Paramagnetic Metal-Organic Framework Enhances Mild Magnetic Hyperthermia Therapy by Downregulating Heat Shock Proteins and Promoting Ferroptosis via Aggravation of Two-Way Regulated Redox Dyshomeostasis.

Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep-seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac-FcMOF, a lactose derivative (Lac-NH2 ) modified paramagnetic metal-organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac-FcMOF aggravates two-way regulated redox dyshomeostasis (RDH) via magnetothermal-accelerated ferricenium ions-mediated consumption of glutathione and ferrocene-catalyzed generation of ∙OH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti-cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22-tumor-bearing mice treated with Lac-FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two-way regulated RDH.

The Efficiency of Pest Control Options against Two Major Sweet Corn Ear Pests in China.

Helicoverpa armigera (Hübner) and Ostrinia furnacalis (Guenée) are the most devastating insect pests at the ear stage of maize, causing significant losses to the sweet corn industry. Pesticide control primarily relies on spraying during the flowering stage, but the effectiveness is inconsistent since larvae are beneath husks within hours to a day, making pesticide treatments simpler to avoid. Insufficient understanding of pest activity patterns impedes precise and efficient pesticide control. H. armigera and O. furnacalis in corn fields were monitored in the last few years in Beijing China, and we observed a higher occurrence of both moths during the R1 stage of sweet corn. Moth captures reached the maximum during this stage, with 555-765 moths per hectare corn field daily. The control efficiency of nine synthetic insecticides and five biopesticides was assessed in the field during this period. Virtako, with mineral oil as the adjuvant, appeared to be the most effective synthetic insecticide, with the efficiencies reaching 88% and 87% on sweet and waxy corn, respectively. Pesticide residue data indicated that the corn is safe after 17 days of its use. The most effective bioinsecticide was Beauveria bassiana combined with mineral oil, with 88% and 80% control efficiency in sweet and waxy corn, respectively. These results suggested that spraying effective insecticides 5 days after corn silking could effectively control corn ear pests H. armigera and O. furnacalis. Our findings provide valuable insights for the development of ear pest management strategies in sweet corn.

Quantifying the impacts of posture changes on office worker productivity: an exploratory study using effective computer interactions as a real-time indicator.

BACKGROUND: Working in a standing posture is considered to improve musculoskeletal comfort and can help enhance office workers' performance in the long term. However, there is a lack of a quantitative, real-time measure that reflects on whether office workers can immediately become more concentrated and work more efficiently when they switch to a standing posture. METHODS: To tackle this problem, this study proposed that the number of effective computer interactions could be used as a real-time indicator to measure the productivity of office workers whose work is primarily computer-based. Using this metric, we conducted an exploratory study to investigate the correlation between posture and productivity changes at a 10-minute resolution for eight participants. RESULTS: The study found that when allowed to use sit-stand desks to adjust postures, participants chose to switch to standing posture for about 47 min on average once a day; standing work was most frequent between 2:30 - 4:00 pm, followed by 10:30 - 11:30 am, during which time the number of computer interactions also became higher, showing a significant positive correlation. In addition, participants were approximately 6.5% more productive than when they could only work in a sitting posture. CONCLUSION: This study revealed that posture changes could have an immediate improvement in productivity.

Epidemiology of hand, foot and mouth disease and genomic surveillance of coxsackievirus A10 circulating in Zhejiang Province, China during 2017 to 2022.

BACKGROUND: Coxsackievirus A10 (CA10) is one of the etiological agents associated with hand, foot and mouth disease (HFMD). OBJECTIVES: We aimed to perform a retrospective analysis of the molecular epidemiological characteristics and genetic features of HFMD associated with CA10 infections in Zhejiang Province from 2017 to 2022. STUDY DESIGN: Epidemiologic features were summarized. Throat swab specimens were collected and tested. The VP1 regions were sequenced for genotyping. CA10 positive samples were isolated. Whole genomes of CA10 isolations were sequenced. Nucleotide and amino acid changes were characterized. Phylogenetic trees were constructed. RESULTS: The number of HFMD cases fluctuated from 2017 to 2022. Children aged below 3 years accounted for the majority (66.29%) and boys were more frequently affected than girls. Cases peaked in June. The positivity rate of HEV was 62.69%. A total of 90 strains of CA10 were isolated and 53 genomes were obtained. All CA10 in this study could be assigned to two genogroups, C (C2) and F (F1 and F3). CONCLUSION: The clinical manifestations of HFMD associated with HEV are complex and diverse. CA10 infection may be emerging as a new and major cause of HFMD because an upward trend was observed in the proportion of CA10 cases after the use of EV71 vaccines. Different genogroups of CA10 had different geographic distribution patterns. Surveillance should be strengthened and further comprehensive studies should be continued to provide a scientific basis for HFMD prevention and control.

A hyaluronic acid modified cuprous metal-organic complex for reversing multidrug resistance via redox dyshomeostasis.

Multidrug resistance (MDR) which is often related to the overexpression of P-glycoprotein (P-gp) in drug-resistant cancer cells has been a major problem faced by current cancer chemotherapy. Reversing P-gp-related MDR by disrupting tumor redox homeostasis that regulates the expression of P-gp is a promising strategy. In this work, a hyaluronic acid (HA) modified nanoscale cuprous metal-organic complex (HA-CuTT) was developed to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis, which was achieved by both Cu+-catalyzed generation of •OH and disulfide bonds-mediated depletion of glutathione (GSH). In vitro studies reveal that the DOX-loaded complex (HA-CuTT@DOX) has excellent targeting ability to HepG2-ADR cells due to the modification of HA and effectively induces redox dyshomeostasis in HepG2-ADR cells. Moreover, HA-CuTT@DOX can cause mitochondrial damage, decrease ATP level, and downregulate the P-gp expression, thereby leading to the reversal of MDR and the increased drug accumulation in HepG2-ADR cells. Importantly, in vivo experimental results show that it can achieve effective inhibition (89.6 %) of tumor growth in nude mice bearing HepG2-ADR cells. This is the first work to reverse P-gp-related MDR via two-way regulated redox dyshomeostasis based on a HA modified nanoscale cuprous metal-organic complex, providing a new therapeutic paradigm for effective treatment of MDR-related cancer.

An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer for synergistically enhanced cancer therapeutic effectiveness.

An L-arginine-functionalized pillar[5]arene-based supramolecular photosensitizer LAP5⊃NBSPD was constructed by host-guest interactions, which could self-assemble into nano-micelles to achieve effective delivery and selective release of LAP5 and NBS in cancer cells. In vitro studies revealed that LAP5⊃NBSPD NPs exhibited excellent cancer cell membrane disruption and ROS generation properties, which provides a novel route for synergistically enhanced cancer therapeutic effectiveness.

Supramolecular nanoprodrug based on a chloride channel blocker and glycosylated pillar[5]arenes for targeted chemoresistance cancer therapy.

A supramolecular nanoprodrug (DOX@GP5⊃Pro-NFA) was constructed based on the host-guest complexation of chloride channel blocker prodrug (Pro-NFA) and glycosylated pillar[5]arene (GP5), which could target tumor cells via galactose and release DOX/NFA responsively under esterase stimulation. In vitro studies revealed that this supramolecular nanoprodrug can overcome drug resistance through inhibiting chloride channels as well as inhibiting the migration of HepG2/ADR cells. This strategy can therefore achieve enhanced potency in chemotherapy through reverse chemoresistance.

Three-in-one self-assembled metallo-nanophotosensitizers for photodynamic/chemodynamic/chemo multimodal synergistic cancer therapy.

A three-in-one self-assembled metallo-nanophotosensitizer system (NLCD) was constructed by cooperative coordination of amphiphilic L-arginine-modified photosensitizer NBS-L-Arg and DOX in the presence of Cu2+via the synergy of coordination, hydrophobic, and π-π stacking interactions. The resulting NLCD NPs possessed uniform size, well-defined nanosphere structure, and GSH-responsive ability. In vitro studies exhibited that NLCD NPs integrating photodynamic/chemodynamic/chemo multimodal therapy achieved an enhanced therapeutic effect.

Covalently bridged pillararene-based polymers: structures, synthesis, and applications.

Covalently bridged pillararene-based polymers (CBPPs) are a special class of macrocycle-based polymers in which multiple pillararene monomers are attached to the polymer structures by covalent bonds. Owing to the unique molecular structures including the connection components or the spatial structures, CBPPs have become increasingly popular in applications ranging from environmental science to biomedical science. In this review, CBPPs are divided into three types (linear polymers, grafted polymers, and cross-linked polymers) according to their structural characteristics and described from the perspective of synthesis methods comprehensively. In addition, the applications of CBPPs are presented, including selective adsorption and separation, fluorescence sensing and detection, construction of supramolecular gels, anticancer drug delivery, artificial light-harvesting, catalysis, and others. Finally, the current challenging issues and comprehensive prospects of CBPPs are discussed.

Acousto-dielectric tweezers for size-insensitive manipulation and biophysical characterization of single cells.

The intrinsic biophysical properties of cells, such as mechanical, acoustic, and electrical properties, are valuable indicators of a cell's function and state. However, traditional single-cell biophysical characterization methods are hindered by limited measurable properties, time-consuming procedures, and complex system setups. This study presents acousto-dielectric tweezers that leverage the balance between controllable acoustophoretic and dielectrophoretic forces applied on cells through surface acoustic waves and alternating current electric fields, respectively. Particularly, the balanced acoustophoretic and dielectrophoretic forces can trap cells at equilibrium positions independent of the cell size to differentiate between various cell-intrinsic mechanical, acoustic, and electrical properties. Experimental results show our mechanism has the potential for applications in single-cell analysis, size-insensitive cell separation, and cell phenotyping, which are all primarily based on cells' intrinsic biophysical properties. Our results also show the measured equilibrium position of a cell can inversely determine multiple biophysical properties, including membrane capacitance, cytoplasm conductivity, and acoustic contrast factor. With these features, our acousto-dielectric tweezing mechanism is a valuable addition to the resources available for biophysical property-based biological and medical research.

A dynamic reversible phenylboronic acid sensor for real-time determination of protein-carbohydrate interactions on living cancer cells.

Real-time detection of glycosylation on label-free cancer cell surfaces is of significance for the diagnosis and treatment of cancer. In this work, we have successfully developed a novel dynamic reversible sensor based on pH-sensitive phenylboronic esters to determine in real-time the binding kinetics of protein-carbohydrate interactions on suspension cancer cell surfaces using a quartz crystal microbalance (QCM) technique.

Core-shell metal-organic frameworks with pH/GSH dual-responsiveness for combined chemo-chemodynamic therapy.

A novel core-shell metal organic framework (MOF), Cu-MOF@SMON/DOX-HA, was fabricated using 3-amino-1,2,4-triazole (3-AT) and organosilicon for combined chemo-chemodynamic therapy with high drug-loading capacity, pH/GSH dual-responsiveness, and good biocompatibility. The Cu-MOF@SMON/DOX-HA could not only generate reactive oxygen species, but also effectively consume glutathione (GSH) to induce cell ferroptosis. This work involves the modification of organosilicon on the surface of MOFs, which possess good performance in high drug-loading ability and pH/GSH dual-responsive degradation for combined chemo-chemodynamic therapy.

A disulfide-induced supra-amphiphilic co-assembly for glycosylated pro-drug-photosensitizer nanoparticles in combination therapies.

A disulfide-induced supra-amphiphilic co-assembly strategy for hydrophobic drug co-delivery in combination therapies was proposed based on a disulfide bond containing hydrophobic pro-drug-photosensitizer (BG) and a hydrophilic/targeting dimer lactose molecule (Lac-SS-Lac). The anti-tumor efficiency was significantly enhanced by the combination therapies of epidermal growth factor receptor (EGFR) targeted therapy and phototherapy in EGFR-positive and/or galectin overexpressed tumors.

A supramolecular nano-delivery system based on AIE PARP inhibitor prodrug and glycosylated pillar[5]arene for drug-resistance therapy.

A supramolecular nano-delivery system GP5⊃Pro-ANI based on the host-guest complex of glycosylated pillar[5]arene (GP5) and an amide linked fluorescent PARP inhibitor (4-amino-1,8-naphthimide, ANI) was constructed. The PARP inhibitor ANI, capable of inhibiting the ability of DNA damage repair, was modified into an AIE prodrug (Pro-ANI), which allows for the visualization of real-time cancer cellular drug uptake tracing and selective drug release. In vitro studies revealed that the DOX-loaded GP5⊃Pro-ANI achieved targeted drug delivery and dual-drug synergistic chemotherapy for DNA repair interference and tumor DNA collapse aggravation, which enhanced the chemosensitivity and overcame tumor drug resistance and migration. This strategy paves a new avenue for utilizing PARP inhibitors to construct AIE supramolecular nano-delivery systems for drug uptake visualization and synergistic chemotherapy.

A glutathione activatable bioprobe for detection of hepatocellular carcinoma cells in peripheral blood via carbohydrate-protein interaction.

Due to high recurrence and metastasis rates leading to high mortality of hepatocellular carcinoma (HCC), detection of HCC circulating tumor cells (HCC-CTCs), which are regarded as an HCC blood marker, holds great significance in HCC early diagnosis, metastasis evolution, and prognosis. However, current existing circulating tumor cell (CTC) detection methods require multiple steps, and have low accuracy due to extremely rare CTCs in peripheral blood (PB). Thus, a simple and sensitive HCC-CTCs detection method is urgently needed. Here, a glutathione (GSH) activatable bioprobe (LacCC) targeting HCC cells was first developed through coordinating copper ions (Cu2+) to lactose modified coumarin derivative (LacC). Owing to the carbohydrate-protein interaction between lactose group and asialoglycoprotein receptors (ASGPRs) overexpressed on the membrane of HCC cells, LacCC displays selectivity towards HCC cells. The fluorescence of LacCC recovers rapidly within 2 min upon demetallation by high concentration of GSH in HCC cells. In simulated PB samples, as low as 10 HepG2 cells were detected via CLSM after removing red blood cells (RBCs) and culturing with LacCC. By coupling with flow cytometry, LacCC can achieve quantitative detection of HCC cells with low detection limit (LOD) of 3 cells per sample. Thus, this bioprobe possessing ASGPRs targetability and fast GSH responsiveness shows ultrasensitive detectability towards HCC cells in PB, which may have the potential for simple yet highly sensitive HCC-CTCs detection.

Detection of S2- in Water by a Glucose Enhanced Water-Soluble Fluorescent Bioprobe.

That sulfide anions (S2-) in aquatic environments are produced by microorganisms through degrading sulfur-containing proteins and other organics are harmful to human health. Thus, it is of significance to develop a convenient method for the detection of S2- in water. Small molecular fluorescent probes are very popular for their advantages of visualization, real-time, high sensitivity, and convenience. However, low solubility in water limits the application of existing S2- probes. In this work, we found that our previously developed water-soluble glycosylated fluorescent bioprobe Cu[GluC] can achieve detection of S2- in water. Cu[GluC] can restore fluorescence within 20 s when it encounters S2- and shows good sensitivity towards S2- with a detection limit of 49.6 nM. Besides, Cu[GluC] derived fluorescent test strips were obtained by immersion and realized conveniently visual S2- detection in water by coupling with a UV lamp and a smartphone app. This work provides a fluorescent bioprobe with good water solubility as well as its derived fluorescent test strip for sensitive and simple detection of S2- in water, which shows good prospects in on-site water quality monitoring.

pH-responsive Mannose-modified ferrocene Metal-Organic frameworks with rare earth for Tumor-targeted synchronous Chemo/Chemodynamic therapy.

The combination of chemodynamic therapy (CDT) and chemotherapy is a promising strategy to achieve enhanced anticancer effects. Metal-organic frameworks (MOFs), as multifunctional drug delivery vehicles, have received extensive attention in the biomedical field. Carbohydrate has excellent biocompatibility and targeting ability, which can be used as a targeting ligand due to a specific recognition with glycoprotein receptors that overexpress on cancer cell membranes. Herein, the pH-responsive mannose-modified ferrocene MOFs with rare earth metal were synthesized via coordination-driven self-assembly of 1,1'-Ferrocenedicarboxylic acid and ytterbium chloride. Subsequently, DOX@Fc-MOFs-Mann nanoparticles (NPs) were obtained by loading doxorubicin (DOX) and modifying mannose (Mann), where DOX@Fc-MOFs-Mann NPs were able to precisely target HepG2 cells via mannose receptor and slowly decompose in the acidic environment of tumor to release ferrocene, DOX, and Yb3+. Fe2+ in ferrocene effectively activated Fenton reaction to produce high levels of reactive oxygen species (ROS) for irreversible induction of cell apoptosis or necroptosis. Combined with the chemotherapy (CT) ability of DOX, Yb3+ further induced cell death through its own toxicity to successfully achieved the rare earth metal synergistic CDT and CT combination therapy. This synergistic CDT and CT strategy not only opens up new horizons for rare earth metals in biomedical applications but also provides new inspiration into the construction of glycosyl-modified MOFs.

Chemokine PF4 Inhibits EV71 and CA16 Infections at the Entry Stage.

Platelet factor 4 (PF4) or the CXC chemokine CXCL4 is the most abundant protein within the α-granules of platelets. Previous studies found that PF4 regulates infections of several viruses, including HIV-1, H1N1, hepatitis C virus (HCV), and dengue virus. Here, we show that PF4 is an inhibitor of enterovirus A71 (EV71) and coxsackievirus A16 (CA16) infections. The secreted form of PF4 from transfected cells or soluble purified PF4 from Escherichia coli, even lacking signal peptide affected secretion, obviously inhibited the propagation of EV71 and CA16. Mechanistically, we demonstrated that PF4 blocked the entry of the virus into the host cells by interactions with VP3 proteins of EV71/CA16 and the interaction with SCARB2 receptor-mediated EV71 and CA16 endocytosis. As expected, the incubation of anti-PF4 antibody with PF4 blocked PF4 inhibition on EV71 and CA16 infections further supported the above conclusion. Importantly, pretreatment of EV71 viruses with PF4 significantly protected the neonatal mice from EV71 lethal challenge and promoted the survival rate of infected mice. PF4 derived from natural platelets by EV71/CA16 activation also presented strong inhibition on EV71 and CA16. In summary, our study identified a new host factor against EV71 and CA16 infections, providing a novel strategy for EV71 and CA16 treatment. IMPORTANCE The virus's life cycle starts with binding to cell surface receptors, resulting in receptor-mediated endocytosis. Targeting the entry of the virus into target cells is an effective strategy to develop a novel drug. EV71 and CA16 are the major pathogens that cause hand, foot, and mouth disease (HFMD) outbreaks worldwide since 2008. However, the treatment of EV71 and CA16 infections is mainly symptomatic because there is no approved drug. Therefore, the underlying pathogenesis of EV71/CA16 and the interaction between host-EV71/CA16 need to be further investigated to develop an inhibitor. Here, we identified PF4 as a potent entry inhibitor of EV71 and CA16 via binding to VP3 proteins of EV71 and CA16 or binding to receptor SCARB2. In the EV71 infection model, PF4 protected mice from EV71 lethal challenge and promoted the survival rate of EV71-infected mice. Our study suggests that PF4 represents a potential candidate host factor for anti-EV71 and CA16 infections.