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Malignant tumors represent a formidable global health challenge, compelling the pursuit of innovative treatment modalities. Oncolytic therapy has emerged as a promising frontier in antitumor strategies. However, both natural agents (such as oncolytic bacteria or viruses) and synthetic oncolytic peptides confront formidable obstacles in clinical trials, which include the delicate equilibrium between safety and efficacy, the imperative for systemic administration with targeted therapy, and the need to counteract oncolysis-induced immunosuppression. To overcome these dilemmas, we have developed biomimetic nanoengineering to create oncolytic bacteria-inspired nanosystems (OBNs), spanning from hierarchical structural biomimicry to advanced bioactive biomimicry. Our OBNs harbor inherent oncolytic potential, including functionalized oligosaccharides mimicking bacterial cell walls for optimal blood circulation and tumor targeting, tumor acidity-switchable decoration for tumor-specific oncolysis, stereospecific tryptophan-rich peptides for robust oncolytic activity, encapsulated tumor immunomodulators for enhanced immunotherapy, and innate multimodal imaging potential for biological tracing. This work elucidates the efficacy and mechanisms of OBNs, encompassing primary tumor suppression, metastasis prevention, and recurrence inhibition. Systemic administration of d-chiral OBNs has demonstrated superior oncolytic efficacy, surpassing intratumoral injections of clinical-grade oncolytic peptides. This work heralds an era in biomimetic engineering on oncolytic agents, promising the revolutionization of contemporary oncolytic therapy paradigms for clinical translation.

Synthesizing biomimetic systems with stereospecific architectures and advanced bioactivity remains an enormous challenge in modern science. To fundamentally eliminate biosafety issues of natural oncolytic viruses, the development of synthetic virus-inspired particles with high oncolytic activity is urgently needed for clinical antitumor treatments. Here, we describe the design and synthesis of enantiomeric virus-inspired particles for efficient oncolytic therapy from homochiral building blocks to stereospecific supramolecular constructions. The L-virus-inspired oncolytic particles (L-VOPs) and D-VOPs possess similar biomimetic nanostructures but mirror-imaged enantiomeric forms. It is important that both L-VOPs and D-VOPs successfully mimic the pharmacological activity of oncolytic viruses, including direct tumor lysis and antitumor immune activation. D-VOPs provide quite better oncolytic efficacy than that of clinical-grade oncolytic agents (LTX-315, IC50= 53.00 μg mL–1) with more than 5-fold decrease in IC50value (10.93 μg mL–1) and close to 100% tumor suppression (98.79%) against 4T1 tumor-bearing mice, attributed to the chirality-dependent tumor recognition, interaction, antidegradation, and immunotherapy. This work provides a strategy for the synthesis of stereospecific biomimetic material systems as well as develops an advanced candidate for biomimetic oncolytic agents without biosafety risks.

The extracellular contractile injection systems (eCISs) are encoded in the genomes of a large number of bacteria and archaea. We have previously characterized the overall structure of PhotorhabdusVirulence Cassette (PVC), a typical member of the eCIS family. PVC resembles the contractile tail of bacteriophages and exerts its action by the contraction of outer sheath and injection of inner tube plus central spike. Nevertheless, the biological function of PVC effectors and the mechanism of effector translocation are still lacking. By combining cryo-electron microscopy and functional experiments, here we show that the PVC effectors Pdp1 (a new family of widespread dNTP pyrophosphatase effector in eCIS) and Pnf (a deamidase effector) are loaded inside the inner tube lumen in a “Peas in the Pod” mode. Moreover, we observe that Pdp1 and Pnf can be directly injected into J774A.1 murine macrophage and kill the target cells by disrupting the dNTP pools and actin cytoskeleton formation, respectively. Our results provide direct evidence of how PVC cargoes are loaded and delivered directly into mammalian macrophages.

The anticoagulation strategy of switching to rivaroxaban after one week of initial low-molecular-weight heparin (LMWH) therapy is recommended by a guideline for the treatment of acute iliofemoral deep vein thrombosis (DVT). However, the initial rivaroxaban dose in the switching strategy, as well as the effectiveness and safety of the early switching（less than one week ）to rivaroxaban, remain inadequately substantiated. We aimed to evaluate the effectiveness and safety of early switching from LMWH to maintenance therapy of rivaroxaban (20 mg once daily) for acute iliofemoral DVT.

Natural cartilage is a multiporous viscoelastic biological material with extremely high water content and a macroscopically curved surface. Due to the sampling frequency limitations of typical data systems, the dynamic properties of the contact of cartilage against other surfaces, including rubbing surface characteristics and coefficient of friction, is still not completely understood. In this study, cartilage samples were retrieved from 18- to 24-month-old bovine femora. Contact displacement and coefficient of friction of two typical rubbing pairs of for cartilage-on-glass and cartilage-on-cartilage were recorded using a UMT-2 testing rig using a high sampling frequency data system. A five-point sliding average method was adopted to analyze the experimental data. The results showed that contact displacement comprised cartilage deformation and nominal rubbing profile. Cartilage deformation increased nonlinearly with time while nominal rubbing profile was associated with the rubbing configuration and appeared to be a factor in the low surface sample configuration. Higher cartilage deformation resulted in more load being carried by the solid phase and coefficient of friction with the time as a whole, but the surface characteristics played a role in determining the coefficient of friction in the cartilage-on-cartilage configuration but a lesser role for cartilage-on-glass. Therefore, surface characteristics have a clear role in defining the dynamic properties of natural viscoelastic soft biological materials and these research results will help to evaluate in future the frictional properties of artificial cartilage biomaterials.

Electrochemical process is used in carbon fiber surface treatment predominantly. The cell parameters like voltage and current are usually given in average. However, because carbon fiber's resistance is quite high, the electricity potential along the fiber tow decreases rapidly, which affects not only the results but also the efficiency. Nevertheless, no literature has talked about this until now. In this paper we set up a model and got a series of formulas, apparently for the first time, capable of simulating the distributions of potential and current along a carbon fiber tow, and power consumption under different cell parameters such as fiber gauge and electrode distance. Through analysis we found that under a certain voltage between the fiber roller and the graphite cathode, the longer the fiber length soaked in the bath, the greater the attenuation of potential and current along fiber tow, and the more the useless power was consumed. It is probably considered that the distance between carbon fiber tow and graphite cathode should be as close as possible, however, when the distance was too close, the potential decayed much sharply, resulting in low efficiency. The model or the formulas can help find the optimum choice of cell parameters.

Tuberculosis (TB) is one of the leading causes of death worldwide, especially in developing countries. Neonatal BCG vaccination occurs in various regions, but the level of protection varies in different populations. Recently, Mycobacterium vaccaeis found to be an immunomodulating therapeutic agent that could confer a significant level of protection against TB. It is the only vaccine in a phase III trial from WHO to assess its efficacy and safety in preventing TB disease in people with latent TB infection. However, the mechanism of immunotherapy of M. vaccaeremains poorly understood. In this study, the full genome of M. vaccaewas obtained by next-generation sequencing technology, and a proteogenomic approach was successfully applied to further perform genome annotation using high resolution and high accuracy MS data. A total of 3,387 proteins (22,508 unique peptides) were identified, and 581 proteins annotated as hypothetical proteins in the genome database were confirmed. Furthermore, 38 novel protein products not annotated at the genome level were detected and validated. Additionally, the translational start sites of 445 proteins were confirmed, and 98 proteins were validated through extension of their translational start sites based on N terminus-derived peptides. The physicochemical characteristics of the identified proteins were determined. Thirty-five immunogenic proteins of M. vaccaewere identified by immunoproteomic analysis, and 20 of them were selected to be expressed and validated by Western blot for immunoreactivity to serum from patients infected with M. tuberculosis. The results revealed that eight of them showed strong specific reactive signals on the immunoblots. Furthermore, cellular immune response was further examined and one protein displayed a higher cellular immune level in pulmonary TB patients. Twelve identified immunogenic proteins have orthologous in H37Rv and BCG. This is the first study to obtain the full genome and annotation of M. vaccaeusing a proteogenomic approach, and some immunogenic proteins that were validated by immunoproteomic analysis could contribute to the understanding of the mechanism of M. vaccaeimmunotherapy.

ABSTRACTp-Aminosalicylic acid (PAS) is an important compound for treating multidrug-resistant tuberculosis (TB). Previous studies showed that thyAmutations are often related to PAS resistance in clinical isolates. We performed a systematic analysis of isolate genotypes and detected mutations in three folate pathway genes (folC, thyA, and ribD) in 61.1% (127/208) of PAS-resistant isolates, including 11 double mutants. This result expands our knowledge about the distribution and frequency of mutations related to PAS resistance in mycobacterial clinical isolates.

Increasing evidence demonstrates that antigen-specific cellular and humoral immunity plays an indispensable role in protection against Mycobacterium tuberculosisinfection. Antigen is a key element in the development of a successful diagnostic method and vaccine. However, few antigens are available, and a systemic study on M. tuberculosisORFeome-based antigen screening is still lacking. In the current study, a genome-wide examination was conducted on high-throughput M. tuberculosisencoding proteins and novel antigens were identified via a comprehensive investigation of serological and antigen-specific cellular responses. The serological immunoglobulin G level of each protein was detected in pooled sera from 200 pulmonary tuberculosis patients by means of semi-quantitative Western blot. Of the 1,250 detected proteins, 29 were present at a higher level relative to the commercialized 38-kDa protein. Furthermore, the top 12 of the 29 proteins had not been previously reported, and their antigenicity was validated in serum from each individual patient. Results confirmed that the 12 proteins displayed nearly identical immunoglobulin G antibody levels in patients with pulmonary and extrapulmonary tuberculosis. Antigen-specific cellular interferon-γ secretion was also evaluated using a cell-based ELISPOT assay. Thirty-four of the proteins were able to induce positive interferon-γ production by peripheral blood mononuclear cells from pulmonary tuberculosis patients as judged by positive (commercial ESAT-6 antigen) and negative controls. The top 4 candidates out of the 34 proteins displayed good accuracy ranging from 50% to 80% compared with the commercial ESAT-6 antigen. Subsequent epitope examination confirmed that a pool of peptides, including a 25aa peptide from Rv1198, demonstrated significant tuberculosis-specific cellular interferon-γ production. Overall, the current study draws significant attention to novel M. tuberculosisantigens, many of which have not been previously reported. This discovery provides a large amount of useful information for the diagnosis of tuberculosis and the development of vaccines to provide protection against tuberculosis.

Tuberculosis (TB) is an infectious bacterial disease that causes morbidity and mortality, especially in developing countries. Although its efficacy against TB has displayed a high degree of variability (0%–80%) in different trials, Mycobacterium bovisbacillus Calmette-Guérin (BCG) has been recognized as an important weapon for preventing TB worldwide for over 80 years. Because secreted proteins often play vital roles in the interaction between bacteria and host cells, the secretome of mycobacteria is considered to be an attractive reservoir of potential candidate antigens for the development of novel vaccines and diagnostic reagents. In this study, we performed a proteomic analysis of BCG culture filtrate proteins using SDS-PAGE and high-resolution Fourier transform mass spectrometry. In total, 239 proteins (1555 unique peptides) were identified, including 185 secreted proteins or lipoproteins. Furthermore, 17 novel protein products not annotated in the BCG database were detected and validated by means of RT-PCR at the transcriptional level. Additionally, the translational start sites of 52 proteins were confirmed, and 22 proteins were validated through extension of the translational start sites based on N-terminus-derived peptides. There are 103 secreted proteins that have not been reported in previous studies on the mycobacterial secretome and are unique to our study. The physicochemical characteristics of the secreted proteins were determined. Major components from the culture supernatant, including low-molecular-weight antigens, lipoproteins, Pro-Glu and Pro-Pro-Glu family proteins, and Mce family proteins, are discussed; some components represent potential predominant antigens in the humoral and cellular immune responses.

ABSTRACTThe presence of heteroresistance was represented by 23% of 235 fluoroquinolone (FQ)-resistant Mycobacterium tuberculosisisolates in Beijing, China, from 2008 to 2010. The main mechanism of FQ heteroresistance is due to the segregation of a single M. tuberculosisstrain in patients; the majority of isolates with multidrug-resistant tuberculosis contained a mixture of bacterial subpopulations consisting of various mutant types, suggesting that the improper use of FQ is the major cause of FQ resistance.

To evaluate the efficacy and safety of the Rotarex mechanical thrombectomy device in treating acute lower extremity arterial ischemia and to explore the appropriate indication of the Rotarex device.

A system for automatic null ellipsometric measurement, which uses a new kind of achromatic rhomb-type λ/4 retarder, is designed and constructed. By use of terbium glass as the modulator’s material, a magneto-optical modulator and its driving circuit are constructed. The polarized light is modulated by dc and ac. Combined with an ultra-low noise frequency-selective amplifier and a lock-in amplifier, the null time of the mechanical and photoelectric automatic null system can be less than 15 s. After the error of the mechanical parts is excluded, the repeatability standard deviation S_4 of nulling angles can be less than 0.00025 deg.

Objective To evaluate the effectiveness of inserting a retrievable inferior vena cava filter (IVCF) to prevent pulmonary embolism (PE) in patients with bone fractures and acute deep venous thrombosis (DVT) before major orthopedic surgery.Methods Clinical data of patients with fractures and acute DVT who underwent IVCF insertion were analyzed. The patients were divided into above-knee DVT (AKDVT), popliteal vein thrombosis (PVT), and below-knee DVT (BKDVT) groups.Results An IVCF was successfully implanted in 964 patients, among whom 929 were followed up (335, 470, and 124 in AKDVT, PVT, and BKDVT groups, respectively). There was no significant difference in the incidence of filter thrombosis among the groups (11.04%, 11.70%, and 8.06%, respectively). No symptomatic PE occurred during follow-up. The mean filter indwelling time was 18.4 ± 4.3 days, and the total filter removal rate was 76.87%. There was no significant difference in the rate of filter implantation, retrieval, complications, or mortality among the groups.Conclusions Retrievable filters can effectively prevent PE before orthopedic surgery in patients with fractures and acute DVT of the lower limbs. AKDVT more readily forms a ≥1-cm thrombus in the IVCF than does BKDVT, and PVT more readily forms a <1-cm thrombus than does AKDVT.

Electrochemical process is used in carbon fiber surface treatment predominantly. The cell parameters like voltage and current are usually given in average. However, because carbon fiber's resistance is quite high, the electricity potential along the fiber tow decreases rapidly, which affects not only the results but also the efficiency. Nevertheless, no literature has talked about this until now. In this paper we set up a model and got a series of formulas, apparently for the first time, capable of simulating the distributions of potential and current along a carbon fiber tow, and power consumption under different cell parameters such as fiber gauge and electrode distance. Through analysis we found that under a certain voltage between the fiber roller and the graphite cathode, the longer the fiber length soaked in the bath, the greater the attenuation of potential and current along fiber tow, and the more the useless power was consumed. It is probably considered that the distance between carbon fiber tow and graphite cathode should be as close as possible, however, when the distance was too close, the potential decayed much sharply, resulting in low efficiency. The model or the formulas can help find the optimum choice of cell parameters.