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Targeted delivery of bioactive compounds such as proteins to the colon has numerous advantages for the therapeutic treatment of inflammatory bowel disease. The present study sought to ...fabricate alginate/chitosan microcapsules containing IL-1Ra (Alg/Chi/IL-1Ra MC) via a single-step electrospraying method. Two important factors of efficacy were measured—the pH-responsiveness of the microcapsule and the in-vitro drug release profile. The DSS-induced colitis mouse model was used to evaluate the therapeutic effect of the Alg/Chi/IL-1Ra microcapsules, with results showing the protective effect of the Alg/Chi microcapsules for the passage of IL-1Ra through the harsh environment of the upper gastrointestinal tract. This effect was owing to the pH-sensitive response of the microcapsule, which allowed the targeted release of IL-1Ra in the colon. DAI evaluation, colon length, colon tissue morphology, histologic damage scores and relative protein concentrations (MPO, TNF-α and IL-1β) demonstrated that the Alg/Chi/IL-1Ra microcapsules alleviated DSS-induced colitis in mice. The present study thus demonstrates a practical means of oral delivery of proteins, in-situ colon release, and a promising application of IL-1Ra in the treatment of autoimmune and inflammatory diseases.
Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory ...half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of α-galactosidase A in a Fabry disease mouse model, and find that an α2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.
The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene ...editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLAN
), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLAN
mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLAN
treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages.
Investigations have shown that storage bugs seriously harm grains during storage. In the interim, essential oils (EOs) have been proven to be a good botanical pesticide. The anti-
properties of
...essential oil, which was obtained by steam distillation, were evaluated using
-limonene, carvone, and their two optical isomer components using contact, repelling, and fumigation techniques. Simultaneously, the fumigation, contact, and repellent activities of carvone and its two optical isomers mixed with
-limonene against
were evaluated. The results showed that
its main components (
-carvone,
-limonene), and
-carvone exhibited both fumigations (LC
= 14.47, 4.42, 20.9 and 3.78 mg/L) and contact (LD
= 7.31, 4.03, 28.62 and 5.63 µg/adult) activity against
A binary mixture (1:1) of
-carvone and
-limonene displayed an obvious synergistic effect. A binary mixture (1:1) of carvone and its two optical isomers exhibited an obvious synergistic effect, too. Furthermore, the repellent activity of the EO, carvone, and its two optical isomers,
-limonene, and a combination of them varied. To stop insect damage during storage,
and its components can be utilized as bio-insecticides.
Adverse events were uncommon (reported in just over half of participants); gastrointestinal complaints were numerically more frequent in patients assigned to veverimer. ...veverimer achieved its ...primary and secondary efficacy endpoints, and no unexpected or disproportionate adverse effects were identified. ...we believe that neither trial participants nor site investigators might have been adequately masked to treatment; the investigators noted that the appearance and weight of the active drug and placebo were different, which led the investigators to have an independent staff member dispense and prepare the study drugs. ...although a placebo control provides the best assessment of the relative safety of veverimer, sodium bicarbonate would be a more relevant clinical comparator.
This paper studies the fixed-time stability of coordinated attitude tracking control under consideration of an input amplitude constraint. The attitude dynamics is described by rotation matrix, which ...avoids the unwinding phenomenon. By designing and analyzing the proposed nonsingular terminal sliding mode surfaces (NTSMSs) step by step, a novel saturated NTSMS is finally established. This NTSMS has theoretical and practical advantages over other existing NTSMSs, such as its fixed-time convergence property and boundedness. Based on it, two fixed-time coordinated controllers are developed. The first one effectively decreases the amplitude of the control input, whereas the second prevents saturation. Both controllers keep the attitude synchronization task be finished in fixed-time and provide better performance than existing controllers. Specific expressions of the regions to which the system states to converge are obtained using Lyapunov stability theory. Simulation results testify the correctness of the proposed theorems.
This paper discusses the problem of state estimation for non‐linear stochastic uncertain systems with time‐correlated additive noise and packet dropout compensations. Both process noise and ...measurement noise are additive forms of noise that can be described as Gaussian first‐order Markov processes. The stochastic uncertainty of the system is described by synchronous correlated white multiplicative noise. When the measurement information from the current epoch is lost, a compensation strategy based on measurement information prediction is used. First, the state information, process noise, and measurement noise are augmented to enable the construction of a new vector to be estimated, and the filter, predictor, and smoother of the system are designed using a Gaussian iterative estimation algorithm based on innovation analysis. The multiplicative noise in the process equation is estimated in real time. Second, a numerical implementation of the proposed algorithm is derived based on the third‐degree spherical‐radial Cubature Kalman filter(CKF). Finally, the proposed algorithm is compared with an extended Kalman filter (EKF) based on Taylor series expansion. The effectiveness of the proposed algorithm is verified by comparing the simulation results.
Background
Robot-assisted gastrectomy (RAG) for gastric cancer is still a controversial surgical technique for adequate tumor resection, lymphadenectomy, and postoperative outcome.
Methods
A ...meta-analysis analyzed updated clinical trials that have compared RAG with laparoscopy-assisted gastrectomy (LAG) to evaluate whether RAG is equivalent to LAG.
Results
Eight studies were included in the analysis, comprising 1,875 patients. RAG was associated with a longer operative time (
p
< 0.05), lower estimated blood loss (
p
< 0.05), and a longer distal margin (
p
< 0.05). RAG can be performed safely with lower estimated blood loss and a longer distal margin than with LAG. Complications, hospital stay, proximal margin, and harvested lymph nodes for RAG and LAG were similar.
Conclusions
RAG is as acceptable as LAG for obtaining safe complications and for performing radical gastrectomy.
Complement component C3 (C3) plays a central role in microglial neurotoxicity following cerebral ischemia/reperfusion (I/R) injury. In this study, we focused on the role of nanoparticles loaded with ...C3 siRNA (NPsiC3) in inhibiting microglial neurotoxicity after brain (I/R) injury. NPsiC3 inhibited the hypoxia/re-oxygenation-induced increase in C3 expression in microglia in vitro. Importantly, treatment with NPsiC3 decreased C3b deposition on neurons and reduced microglia-mediated neuronal damage under hypoxia/re-oxygen conditions. Nanoparticles could effectively deliver C3-siRNA from the blood into ischemic penumbra across the blood-brain barrier (BBB) and significantly decrease C3 expression in microglia and ischemic brain tissue, while reducing the number of infiltrating inflammatory cells and the concentration of pro-inflammatory factors in the penumbra. Furthermore, NPsiC3 also prevented neuronal apoptosis, reduced the volume of the ischemic zone, and substantially improved functional recovery after I/R injury. Therefore, the NPsiC3-induced inhibition of microglial neurotoxicity represents a novel therapeutic strategy for treating brain I/R injury.
This study aimed to explore the relationship between the blood urea nitrogen/creatinine (BUN/Cre) ratio and all-cause or cause-specific mortality in the general population.
Participants were enrolled ...from the National Health and Nutrition Examination Survey (NHANES) during 1999 to 2014. Baseline variables were acquired from questionnaires and examinations. Death status were ascertained from National Death Index records. Cox proportional hazards models with cubic spines were used to estimate hazard ratios (HRs) and 95% confidence interval (CI) of all-cause mortality, cardiovascular and cancer mortality.
A total of 42038 participants were enrolled in the study with a median 8.13 years of follow-up. Older people and women tend to have a higher BUN/Cre ratio. After multivariable adjustment, BUN/Cre ratio between 11.43 and 14.64 was associated with the lowest all-cause mortality compared with the participants with the lowest quartile (HR 0.83 0.76, 0.91; p < 0.001). The highest quartile of BUN/Cre ratio was associated with the lowest risk of cancer mortality (HR 0.64 0.53, 0.78; p < 0.001). Restricted cubic splines showed BUN/Cre was nonlinearly associated with all-cause mortality and linearly associated with cancer mortality.
This study confirmed a U-shape relationship between BUN/Cre ratio and all-cause mortality in the general population.
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