Biomimetic piezoelectric nanomaterial-modified oral microrobots for targeted catalytic and immunotherapy of colorectal cancer.

Lactic acid (LA) accumulation in the tumor microenvironment poses notable challenges to effective tumor immunotherapy. Here, an intelligent tumor treatment microrobot based on the unique physiological structure and metabolic characteristics of Veillonella atypica (VA) is proposed by loading Staphylococcus aureus cell membrane-coating BaTiO3 nanocubes (SAM@BTO) on the surface of VA cells (VA-SAM@BTO) via click chemical reaction. Following oral administration, VA-SAM@BTO accurately targeted orthotopic colorectal cancer through inflammatory targeting of SAM and hypoxic targeting of VA. Under in vitro ultrasonic stimulation, BTO catalyzed two reduction reactions (O2 → •O2- and CO2 → CO) and three oxidation reactions (H2O → •OH, GSH → GSSG, and LA → PA) simultaneously, effectively inducing immunogenic death of tumor cells. BTO catalyzed the oxidative coupling of VA cells metabolized LA, effectively disrupting the immunosuppressive microenvironment, improving dendritic cell maturation and macrophage M1 polarization, and increasing effector T cell proportions while decreasing regulatory T cell numbers, which facilitates synergetic catalysis and immunotherapy.

Dynamic analyses of a soft tissue-implant interface: Biological responses to immediate versus delayed dental implants.

AIM: To qualitatively and quantitatively evaluate the formation and maturation of peri-implant soft tissues around 'immediate' and 'delayed' implants. MATERIALS AND METHODS: Miniaturized titanium implants were placed in either maxillary first molar (mxM1) fresh extraction sockets or healed mxM1 sites in mice. Peri-implant soft tissues were evaluated at multiple timepoints to assess the molecular mechanisms of attachment and the efficacy of the soft tissue as a barrier. A healthy junctional epithelium (JE) served as positive control. RESULTS: No differences were observed in the rate of soft-tissue integration of immediate versus delayed implants; however, overall, mucosal integration took at least twice as long as osseointegration in this model. Qualitative assessment of Vimentin expression over the time course of soft-tissue integration indicated an initially disorganized peri-implant connective tissue envelope that gradually matured with time. Quantitative analyses showed significantly less total collagen in peri-implant connective tissues compared to connective tissue around teeth around implants. Quantitative analyses also showed a gradual increase in expression of hemidesmosomal attachment proteins in the peri-implant epithelium (PIE), which was accompanied by a significant inflammatory marker reduction. CONCLUSIONS: Within the timeframe examined, quantitative analyses showed that connective tissue maturation never reached that observed around teeth. Hemidesmosomal attachment protein expression levels were also significantly reduced compared to those in an intact JE, although quantitative analyses indicated that macrophage density in the peri-implant environment was reduced over time, suggesting an improvement in PIE barrier functions. Perhaps most unexpectedly, maturation of the peri-implant soft tissues was a significantly slower process than osseointegration.

Safety and benefit of modified mesohepatectomy in the treatment of bilobar involvement congenital biliary dilatation.

BACKGROUND: The diseased bile duct in bilobar congenital biliary dilatation is extensive and often requires major hepatectomy or liver transplantation associated with a higher risk. We aimed to evaluate the safety and benefit of modified mesohepatectomy, in comparison with trisectionectomy, to treat bilobar congenital biliary dilatation. METHODS: This study included 28 patients with type IV and V bilobar congenital biliary dilatation. An innovative mesohepatectomy comprising the hepatectomy technique beyond the P/U point and bile duct shaping was applied to 14 patients to address the extensively diseased bile duct and difficulty in hepaticojejunostomy. Another 14 patients received trisectionectomy. The perioperative and long-term outcomes of these patients were compared. RESULTS: The ratio of residual liver volume to standard liver volume in the mesohepatectomy group was higher (78.68% vs. 40.90%, p = 0.005), while the resection rate of the liver parenchyma was lower (28.25% vs. 63.97%, p = 0.000), than that in trisectionectomy group. The mesohepatectomy group had a lower severe complication (>Clavein III, 0% vs. 57.70%, p = 0.019) and incidence of posthepatectomy liver failure (7.14% vs. 42.86%, p = 0.038). No significant difference was observed in blood loss and bile leakage (p > 0.05). All the patients in the mesohepatectomy group achieved optimal results in the long-term follow-up. CONCLUSIONS: mesohepatectomy provides an efficient treatment option for bilobar congenital biliary dilatation and can achieve radical resection, retain more liver parenchyma, and reduce the difficulty of hepaticojejunostomy, especially for patients that are not eligible for major hepatectomy and liver transplantation.

Progress of lymphocyte activation gene 3 and programmed cell death protein 1 antibodies for cancer treatment: A review.

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

Hydroxychloroquine-induced hyperpigmentation of the skin and bull's-eye maculopathy in rheumatic patients: a case report and literature review.

Hydroxychloroquine (HCQ) is used as a traditional disease-modifying antirheumatic drugs (DMARDs), for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it can cause serious adverse reactions, including hyperpigmentation of the skin and bull's-eye macular lesions. Here, we present a case of HCQ-induced hyperpigmentation of the skin and bull's-eye macular lesions in a patient who received HCQ for RA. A 65-year-old female patient developed blurred vision and hyperpigmentation of multiple areas of skin over the body for one month after 3 years of HCQ treatment for RA. Based on clinical presentation, ophthalmological examination and dermatopathological biopsy, a diagnosis of drug-induced cutaneous hyperpigmentation and bullous maculopathy of the right eye was made. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient 's skin was gradually reduced, and the symptoms of blurred vision were not significantly improved. We also reviewed the available literature on HCQ-induced cutaneous hyperpigmentation and bull's-eye macular lesions and described the clinical features of HCQ-induced cutaneous hyperpigmentation and bull's-eye macular lesions. In conclusion, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.

Scale-Up Preparation of Manganese-Iron Prussian Blue Nanozymes as Potent Oral Nanomedicines for Acute Ulcerative Colitis.

Prussian blue (PB) nanozymes are demonstrated as effective therapeutics for ulcerative colitis (UC), yet an unmet practical challenge remains in the scalable production of these nanozymes and uncertainty over their efficacy. With a novel approach, a series of porous manganese-iron PB (MnPB) colloids, which are shown to be efficient scavengers for reactive oxygen species (ROS) including hydroxyl radical, superoxide anion, and hydrogen peroxide, are prepared. In vitro cellular experiments confirm the capability of the nanozyme to protect cells from ROS attack. In vivo, the administration of MnPB nanozyme through gavage at a dosage of 10 mg kg-1 per day for three doses in total potently ameliorates the pathological symptoms of acute UC in a murine model, resulting in mitigated inflammatory responses and improved viability rate. Significantly, the nanozyme produced at a large scale can be achieved at an unprecedented yield weighting ≈11 g per batch of reaction, demonstrating comparable anti-ROS activities and treatment efficacy to its small-scale counterpart. This work represents the first demonstration of the scale-up preparation of PB analog nanozymes for UC without compromising treatment efficacy, laying the foundation for further testing of these nanozymes on larger animals and promising clinical translation.

Biomimetic Self-Propelled Asymmetric Nanomotors for Cascade-Targeted Treatment of Neurological Inflammation.

The precise targeted delivery of therapeutic agents to deep regions of the brain is crucial for the effective treatment of various neurological diseases. However, achieving this goal is challenging due to the presence of the blood-brain barrier (BBB) and the complex anatomy of the brain. Here, a biomimetic self-propelled nanomotor with cascade targeting capacity is developed for the treatment of neurological inflammatory diseases. The self-propelled nanomotors are designed with biomimetic asymmetric structures with a mesoporous SiO2 head and multiple MnO2 tentacles. Macrophage membrane biomimetic modification endows nanomotors with inflammatory targeting and BBB penetration abilities The MnO2 agents catalyze the degradation of H2 O2 into O2 , not only by reducing brain inflammation but also by providing the driving force for deep brain penetration. Additionally, the mesoporous SiO2 head is loaded with curcumin, which actively regulates macrophage polarization from the M1 to the M2 phenotype. All in vitro cell, organoid model, and in vivo animal experiments confirmed the effectiveness of the biomimetic self-propelled nanomotors in precise targeting, deep brain penetration, anti-inflammatory, and nervous system function maintenance. Therefore, this study introduces a platform of biomimetic self-propelled nanomotors with inflammation targeting ability and active deep penetration for the treatment of neurological inflammation diseases.

Programmed microalgae-gel promotes chronic wound healing in diabetes.

Chronic diabetic wounds are at lifelong risk of developing diabetic foot ulcers owing to severe hypoxia, excessive reactive oxygen species (ROS), a complex inflammatory microenvironment, and the potential for bacterial infection. Here we develop a programmed treatment strategy employing live Haematococcus (HEA). By modulating light intensity, HEA can be programmed to perform a variety of functions, such as antibacterial activity, oxygen supply, ROS scavenging, and immune regulation, suggesting its potential for use in programmed therapy. Under high light intensity (658 nm, 0.5 W/cm2), green HEA (GHEA) with efficient photothermal conversion mediate wound surface disinfection. By decreasing the light intensity (658 nm, 0.1 W/cm2), the photosynthetic system of GHEA can continuously produce oxygen, effectively resolving the problems of hypoxia and promoting vascular regeneration. Continuous light irradiation induces astaxanthin (AST) accumulation in HEA cells, resulting in a gradual transformation from a green to red hue (RHEA). RHEA effectively scavenges excess ROS, enhances the expression of intracellular antioxidant enzymes, and directs polarization to M2 macrophages by secreting AST vesicles via exosomes. The living HEA hydrogel can sterilize and enhance cell proliferation and migration and promote neoangiogenesis, which could improve infected diabetic wound healing in female mice.

Advances in methane emissions from agricultural sources: Part I. Accounting and mitigation.

Methane is one of the major greenhouse gases (GHGs) and agriculture is recognized as its primary emitter. Methane accounting is a prerequisite for developing effective agriculture mitigation strategies. In this review, methane accounting methods and research status for various agricultural emission source including rice fields, animal enteric fermentation and livestock and poultry manure management were overview, and the influencing factors of each emission source were analyzed and discussed. At the same time, it analyzes the different research efforts involving agricultural methane accounting and makes recommendations based on the actual situation. Finally, mitigation strategies based on accounting results and actual situation are proposed. This review aims to provide basic data and reference for agriculture-oriented countries and regions to actively participate in climate action and carry out effective methane emission mitigation.

A Colletotrichum tabacum effector Cte1 targets and stabilizes NbCPR1 to suppress plant immunity.

Colletotrichum tabacum, causing anthracnose in tobacco, is a disreputable plant pathogen threatening tobacco production globally. The underlying mechanisms of C. tabacum effectors that interfere with plant defense are not well known. Here, we identified a novel effector Cte1 from C. tabacum, and its expression was up-regulated in the biotrophic stage. We found that Cte1 depresses plant cell death initiated by BAX and inhibits ROS bursts triggered by flg22 and chitin in Nicotiana benthamiana. The CTE1 knockout mutants decrease the virulence of C. tabacum to N. benthamiana, and the Cte1 transgenic N. benthamiana increase susceptibility to C. tabacum, verifying that Cte1 is involved in the pathogenicity of C. tabacum. We demonstrated that Cte1 interacted with NbCPR1, a Constitutive expresser of Plant Resistance (CPR) protein in plants. Silencing of NbCPR1 expression attenuated the infection of C. tabacum, indicating that NbCPR1 negatively regulates plant immune responses. Cte1 stabilizes NbCPR1 in N. benthamiana. Together, our study showed that Cte1 suppresses plant immunity to facilitate C. tabacum infection by intervening in the native function of NbCPR1.

Ipsilateral immunization after a prior SARS-CoV-2 mRNA vaccination elicits superior B cell responses compared to contralateral immunization.

mRNA vaccines have proven to be pivotal in the fight against COVID-19. A recommended booster, given 3 to 4 weeks post the initial vaccination, can substantially amplify protective antibody levels. Here, we show that, compared to contralateral boost, ipsilateral boost of the SARS-CoV-2 mRNA vaccine induces more germinal center B cells (GCBCs) specific to the receptor binding domain (RBD) and generates more bone marrow plasma cells. Ipsilateral boost can more rapidly generate high-affinity RBD-specific antibodies with improved cross-reactivity to the Omicron variant. Mechanistically, the ipsilateral boost promotes the positive selection and plasma cell differentiation of pre-existing GCBCs from the prior vaccination, associated with the expansion of T follicular helper cells. Furthermore, we show that ipsilateral immunization with an unrelated antigen after a prior mRNA vaccination enhances the germinal center and antibody responses to the new antigen compared to contralateral immunization. These findings propose feasible approaches to optimize vaccine effectiveness.

Simultaneous and sensitive detection of SARS-CoV-2 proteins spike and nucleocapsid based on long-range SERS biosensor.

BACKGROUND: Early diagnosis of SARS-CoV-2 infection is still critical to control COVID-19 outbreak. Traditional polymerase chain reaction, enzyme-linked immunosorbent assay or lateral flow immunoassay performed poorly on detection times, sample preparation process and accuracy. Surface-enhanced Raman scattering (SERS)-based detection has emerged as a powerful analytical technique, which overcomes the above limitations. However, due to the near-field effect of traditional substrate, it is difficult to monitor the binding event of aptamers with proteins. It is obvious that a novel SERS substrate thatsupportedextended and stronger electromagnetic fields was required to hold long-range effects and allow for binding event testing. RESULTS: Driven by this challenge, we reported a long-range SERS-active substrate, which was built by inserting bowtie nanoaperture arrays in a refractive-index-symmetric environment and Au mirror surfaces, for SARS-CoV-2 protein binding event detection. Then, a double-π structure aptasensor was simply designed through the hybridization of spike (S) and nucleocapsid (N) proteins aptamers, and a corresponding complementary strand. This kind of double-π structure would dissociate when targets proteins S and N existed and led to the SERS responses decreased, which established the detection basis of our system. What's more, due to two Raman labels were involved, both proteins S and N can be sensed simultaneously. Our proposed method showed improved sensitivity with a low limit of detection for multiplex detection (1.6 × 10-16 g/mL for protein S and 1.0 × 10-16 g/mL for protein N) over a wide concentration range. SIGNIFICANCE: This represents the first long-range SERS apatasensor platform for detection of S and N proteins simultaneously. Our method showed high sensitivity, selectivity, reproducibility, stability and remarkable recoveries in human in saliva and serum samples, which is particularly important for the early diagnostics of COVID as well as for future unknown coronavirus.

Cross-Domain Identification of Multisite Major Depressive Disorder Using End-to-End Brain Dynamic Attention Network.

Establishing objective and quantitative imaging markers at individual level can assist in accurate diagnosis of Major Depressive Disorder (MDD). However, the clinical heterogeneity of MDD and the shift to multisite data decreased identification accuracy. To address these issues, the Brain Dynamic Attention Network (BDANet) is innovatively proposed, and analyzed bimodal scans from 2055 participants of the Rest-meta-MDD consortium. The end-to-end BDANet contains two crucial components. The Dynamic BrainGraph Generator dynamically focuses and represents topological relationships between Regions of Interest, overcoming limitations of static methods. The Ensemble Classifier is constructed to obfuscate domain sources to achieve inter-domain alignment. Finally, BDANet dynamically generates sample-specific brain graphs by downstream recognition tasks. The proposed BDANet achieved an accuracy of 81.6%. The regions with high attribution for classification were mainly located in the insula, cingulate cortex and auditory cortex. The level of brain connectivity in p24 region was negatively correlated ( [Formula: see text]) with the severity of MDD. Additionally, sex differences in connectivity strength were observed in specific brain regions and functional subnetworks ( [Formula: see text] or [Formula: see text]). These findings based on a large multisite dataset support the conclusion that BDANet can better solve the problem of the clinical heterogeneity of MDD and the shift of multisite data. It also illustrates the potential utility of BDANet for personalized accurate identification, treatment and intervention of MDD.

All-in-One Zinc-Doped Prussian Blue Nanozyme for Efficient Capture, Separation, and Detection of Copper Ion (Cu2+ ) in Complicated Matrixes.

Copper is a vital micronutrient for lives and an important ingredient for bactericides and fungicides. Given its indispensable biological and agricultural roles, there is an urgent need to develop simple, affordable, and reliable methods for detecting copper in complicated matrixes, particularly in underdeveloped regions where costly standardized instruments and sample dilution procedures hinder progress. The findings that zinc-doped Prussian blue nanoparticle (ZnPB NP) exhibits exceptional efficiency in capturing and isolating copper ions, and accelerates the generation of dissolved oxygen in a solution of H2 O2 with remarkable sensitivity and selectivity, the signal of which displays a positive correlation with the copper level due to the copper-enhanced catalase-like activity of ZnPB NP, are presented. Consequently, the ZnPB NP serves as an all-in-one sensor for copper ion. The credibility of the method for copper assays in human urine and farmland soil is shown by comparing it to the standard instrumentation, yielding a coefficient of correlation (R2 = 0.9890), but the cost is dramatically reduced. This ZnPB nanozyme represents a first-generation probe for copper ion in complicated matrixes, laying the groundwork for the future development of a practical copper sensor that can be applied in resource-constrained environments.

SERS detection of triazole pesticide residues on vegetables and fruits using Au decahedral nanoparticles.

Triazole pesticides are widely used in modern agricultural practices to improve agricultural production quality. Simultaneously, unreasonable and standardized use of triazole pesticides could induce a series of potential diseases of humans. Surface-enhanced Raman spectroscopy has attracted enormous research attention because of its label-free and fingerprint detection capability to noninvasively trace extremely low concentration analytes. To the best of our knowledge, there is a lack of systematic comparison regarding the Raman spectral information of triazole pesticides in existing literatures. In this work, we successfully captured the characteristic peaks of six different triazole pesticides individually and simultaneously using Au decahedral nanoparticles. The proposed method exhibited remarkable detection sensitivity, a wide dynamic range, and the capability for in-situ detection of multiple pesticide residues on bean, apple, and vegetable surfaces with satisfactory recovery rates. Therefore, our proposed SERS platform have great applications in agricultural products safety, environmental monitoring and other fields.

Piezoelectricity, Pyroelectricity, and Ferroelectricity in Biomaterials and Biomedical Applications.

Piezoelectric, pyroelectric, and ferroelectric materials are considered unique biomedical materials due to their dielectric crystals and asymmetric centers that allow them to directly convert various primary forms of energy in the environment, such as sunlight, mechanical energy, and thermal energy, into secondary energy, such as electricity and chemical energy. These materials possess exceptional energy conversion ability and excellent catalytic properties, which have led to their widespread usage within biomedical fields. Numerous biomedical applications have demonstrated great potential with these materials, including disease treatment, biosensors, and tissue engineering. For example, piezoelectric materials are used to stimulate cell growth in bone regeneration, while pyroelectric materials are applied in skin cancer detection and imaging. Ferroelectric materials have even found use in neural implants that record and stimulate electrical activity in the brain. This paper reviews the relationship between ferroelectric, piezoelectric, and pyroelectric effects and the fundamental principles of different catalytic reactions. It also highlights the preparation methods of these three materials and the significant progress made in their biomedical applications. The review concludes by presenting key challenges and future prospects for efficient catalysts based on piezoelectric, pyroelectric, and ferroelectric nanomaterials for biomedical applications.

Identification of hub genes and pathways associated with cellular senescence in diabetic foot ulcers via comprehensive transcriptome analysis.

This research aimed to find important genes and pathways related to cellular senescence (CS) in diabetic foot ulcers (DFU) and to estimate the possible pathways through which CS affects diabetic foot healing. The GSE80178 dataset was acquired from the Gene Expression Omnibus (GEO) database, containing six DFU and three diabetic foot skin (DFS) samples. The limma package was used to identify differentially expressed genes (DEGs). At the same time, DEGs associated with CS (CS-DEGs) were found using the CellAge database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the CS-DEGs. A protein-protein interaction (PPI) network was built using the String database, and the cytoHubba plug-in within Cytoscape helped identify hub genes. Lastly, the miRNA-TF-mRNA regulatory network for these hub genes was established. In total, 66 CS-DEGs were obtained. These genes mainly focus on CS, Kaposi sarcoma-associated herpesvirus infection and Toll-like receptor signalling pathway. Eight hub genes were identified to regulate cell senescence in DFU, including TP53, SRC, SIRT1, CCND1, EZH2, CXCL8, AR and CDK4. According to miRNA-TF-mRNA regulatory network, hsa-mir-132-3p/SIRT1/EZH2 axis is involved in senescence cell accumulation in DFU.

Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers.

Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a Kd value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.

Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies.

Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.