Polyethylene Glycol-grafted poly alpha-lipoic acid-dexamethasone nanoparticles for osteoarthritis

Osteoarthritis (OA) is a chronic inflammatory disease that causes synovial hyperplasia, cartilage destruction, and the formation of bone spurs. Macrophages play an indispensable role in the pathogenesis of OA by producing proinflammatory cytokines. To achieve the effect of arthritis, hormones can effectively inhibit the progression of inflammation by inhibiting the secretion of inflammatory cytokines by macrophages in traditional therapy. However, the drug is quickly cleared from the joint space, and the high injection site infection rate and low local drug concentration make the clinical efficacy of corticosteroids greatly reduced. We described the design and preparation of Polyethylene Glycol-grafted Poly Alpha-lipoic Acid-dexamethasone Nanoparticles (NPDXM/PPLA), elucidated the mechanism of action of NPDXM/PPLA in the treatment of OA in mice, and provided an experimental basis for investigating the treatment of OA with polymer nanoparticles loaded with dexamethasone. Flow cytometry and confocal laser scanning microscopy were used to confirm that NPDXM/PPLA was well absorbed and released by macrophages, and it was discovered that NPDXM/PPLA could efficiently reduce the proliferation of activated macrophages (RAW 264.7 cells). Enzyme-linked immunosorbent assay revealed that NPDXM/PPLA could efficiently reduce the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α. The knee bone structure of OA mice was investigated by MicroCT, and it was discovered that intraarticular injection of NPDXM/PPLA effectively alleviated the bone damage of the articular cartilage. Therefore, NPDXM/PPLA is a potential therapeutic nanomedicine for the treatment of OA

Construction and Evaluation of the Brucella Double Gene Knock-out Vaccine Strain MB6 Δbp26ΔwboA (RM6)

Brucellosis is a serious zoonotic infection worldwide. To date, vaccination is the most effective measure against brucellosis. This study was aimed at obtaining a vaccine strain that has high protective efficacy and low toxicity, and allows vaccination to be differentiated from infection. Using homologous recombination, we constructed a double gene-deletion Brucella strain MB6 Δbp26ΔwboA (RM6) and evaluated its characteristics, safety and efficacy. The RM6 strain had good proliferative ability and stable biological characteristics in vivo and in vitro. Moreover, it had a favorable safety profile and elicited specific immune responses in mice and sheep. The RM6 strain may have substantial practical application value

Development and Efficacy Evaluation of an SP01-adjuvanted Inactivated Escherichia Coli Mutant Vaccine Against Bovine Coliform Mastitis

Escherichia coli ( E. coli ) is one of the most common pathogens causing clinical mastitis in cattle, but no vaccine is available to prevent this disease in China. Therefore, development of an E. coli vaccine against bovine clinical mastitis is urgently needed. The candidate vaccine (Ch-O111-1) and challenge (LZ06) strains were screened from milk samples of cows with clinical mastitis. To extend the cross-protection of the Ch-O111-1 strain, we deleted the galE gene fragment of the Ch-O111-1 strain through homologous recombination between the Ch-O111-1 strain and pCVD442/ΔgalE plasmid, which was identified through conventional methods, including PCR, SDS-PAGE and sequencing. The Ch-O111-1/ΔgalE (Z9) strain was characterized by extensive cross-reactivity and attenuated virulence. We prepared inactivated Z9 vaccines with different adjuvants. Immunization of inactivated Z9 antigen induced adjuvant-, dosage- and inoculation time-dependent antibody titers in cows and mice. Furthermore, immunization with SP01-adjuvanted inactivated Z9 vaccine protected cows against severe clinical mastitis caused by LZ06 and protected mice against death due to LZ06. An SP01-adjuvanted inactivated Z9 vaccine was successfully developed and found to protect cows against severe mastitis caused by Escherichia coli

Preparation of Equine Immunoglobulin F(ab′) 2 against Smallpox and Evaluation of its Immunoprotective Effect

Smallpox, a severe infectious disease caused by the smallpox virus, causes a death rate as high as 30% within 15-20 days after infection. Therefore, development of anti-Smallpox product as a strategic reserve is urgently needed. We prepared and tested pepsin-digested F(ab′) 2 fragments of serum IgG from horses. Transmission electron microscopy indicated that the purified virus showed morphology consistent with VVTT. The titer was above 1.0 × 10 7 PFU/mL. The purity of the antigen exceeded 90%, according to HPLC. After purification and cleavage, the yield of the purified product F(ab′) 2 was approximately 1.3%, its purity exceeded 90%, and the neutralizing antibody titer exceeded 1:3200. F(ab′) 2 fragments had good preventive and therapeutic effects in mice at antibody doses of 5.2 mg/mL and 2.6 mg/mL. The viral loads of the drug-treated mice were suppressed to varying degrees, and the higher dose groups (5.2 and 2.6 mg/mL) showed a 2-3 fold lower viral load than that in the control group. A process for producing equine immunoglobulin F(ab′) 2 against VVTT was established. The prepared horse anti-smallpox immunoglobulin product had good neutralizing antibody effects on VVTT. The highly purified preparation may serve as a potential candidate for smallpox treatment

Purified Immunoglobulin F(ab′) 2 Protects Mice and Rhesus Monkeys against Lethal Ricin Intoxication

Ricin is a highly toxic ribosome-inactivating lectin derived from castor beans. To date, no antidote is available to treat ricin-poisoned patients, and the development of a safe and effective antidote is urgently needed. First, ricin was prepared and used to construct a mouse model and a rhesus monkey model of ricin intoxication. Second, pepsin-digested F(ab′) 2 fragments of serum IgG from horses injected with Freund’s-adjuvanted purified ricin were prepared. Third, the protective efficacy was evaluated in mouse and rhesus monkey models of lethal ricin intoxication. The purity quotient of the prepared ricin and F(ab′) 2 fragments exceeded 90% and 85% in the mouse and monkey models, respectively. The LD 50 of ricin in mice and rhesus monkeys was 2.7 and 9 μg/kg, respectively. A quantity of 6.25 and 1.85 mg/kg F(ab′) 2 was sufficient to treat lethal ricin intoxication in the mice and rhesus monkeys, respectively. Finally, the effect of this therapeutic antibody on peripheral blood immune cells was examined by analysis of peripheral blood immune cells through single cell sequencing. The underlying mechanism was found to involve restraining neutrophil activation, proliferation, and differentiation. Purified F(ab′) 2 fragments administered with needle-free devices fully protect mice and rhesus monkeys against lethal doses of ricin intoxication

Design of helical groove/hollow nanofibers via tri-fluid electrospinning

Electrospinning of multilevel structured micro/nanofibers have obtained considerable attention recently. In this study, inspired by the unique properties and functions of helical, groove and hollow structures in nature, we prepared a new type of multilevel structured nanofibers with helical and groove/hollow structures. Based on the fiber formation mechanism, a combination of cellulose acetate and other appropriate polymers were applied to generate helical groove/hollow nanofibers using a designed tri-fluid electrospinning system. By varying the capillary dispositions of the spinneret, the fibers with helical groove and helical hollow structures were obtained. To explore the forming process of the composite fibers, high speed photography was employed to record the Taylor cone and jet path under the spinnerets. By characterizing the morphologies and specific functions of the as-prepared nanofibers, the unique helical groove/hollow structure were generated and present good properties in wettability and mechanical behavior

Cognitive impairment after sleep deprivation: The role of precuneus related connectivity on the intra-individual variability changes

Objective: Intra-individual variability (IIV) in cognitive performance is thought to reflect the efficiency with which attentional resources are allocated in different circumstances requiring cognitive control. IIV in cognitive performance is associated with the strength of the negative correlation between task-positive network and default mode network (DMN) activity. In this study, we investigated the impact of sleep deprivation (SD) on functional connectivity (FC) between the DMN and psychomotor vigilance task-related network (PVT-RN), and its relationship with IIV in cognitive performance. Methods: Two analyses, network-level independent component analysis (NL-ICA) and region-level (RL)-ICA, were employed to compare the coefficient of variation (CV) of the PVT between normal sleep and SD conditions across 67 healthy participants. Results: After SD, in NL-ICA, the FC between the PVT-RN and DMN was positively correlated with the CV of the PVT, as well as the changes therein, compared with normal sleep. Using a mask derived from the DMN and PVT-RN, the RL-ICA revealed that 12 edges/connections between DMN and PVT independent components were associated with the CV of the PVT, with nine of these connections involving the precuneus. Conclusions: These findings suggest that the precuneus may play a crucial role in the interactions of various brain functions during the PVT, with the connections between the precuneus and frontoparietal and somatosensory networks being significantly altered after SD. Moreover, following SD, weakened negative FC between the precuneus and bilateral inferior parietal lobule may disrupt the balance between cognitive and executive control functions, leading to a decline in cognitive performance

Large strain consolidation of dredged slurries considering clogging effect with coupled vertical–radial flow

Dredged slurries improved by vacuum preloading methods were found to be still weak generally after the pore water drainage finished. Three reasons, including nonuniform consolidation, soil particles migration and blockage of the drain filter, have been proposed to explain the failure. Thus, finding out the principle factor is essential for modifying the vacuum improvement method effectively. In this paper, a large strain consolidation model with coupled vertical–radial flow is built to investigate the effects of the three factors. Blockage at the drain and clogging in the soil is found to be the main factors. Besides, the clogging in the soil shows a significant influence on the distribution of pore water pressure along the radius. Then, the consolidation behaviors and variations of water drainage direction are also analyzed under different upper boundary conditions compared to the results from a laboratory test. On that base, the hard shell boundary is found to be better in simulating the upper boundary conditions in the membrane system