Efficient signal sequence of mRNA vaccines enhances the antigen expression to expand the immune protection against viral infection.

The signal sequence played a crucial role in the efficacy of mRNA vaccines against virus pandemic by influencing antigen translation. However, limited research had been conducted to compare and analyze the specific mechanisms involved. In this study, a novel approach was introduced by substituting the signal sequence of the mRNA antigen to enhance its immune response. Computational simulations demonstrated that various signal peptides differed in their binding capacities with the signal recognition particle (SRP) 54 M subunit, which positively correlated with antigen translation efficiency. Our data revealed that the signal sequences of tPA and IL-6-modified receptor binding domain (RBD) mRNA vaccines sequentially led to higher antigen expression and elicited more robust humoral and cellular immune protection against the SARS-CoV-2 compared to the original signal sequence. By highlighting the importance of the signal sequence, this research provided a foundational and safe approach for ongoing modifications in signal sequence-antigen design, aiming to optimize the efficacy of mRNA vaccines.

An Efficient Pulse Circuit Design for Magnetic Stimulation with Diversified Waveforms and Adjustable Parameters.

As a noninvasive neuromodulation technique, transcranial magnetic stimulation (TMS) has important applications both in the exploration of mental disorder causes and the treatment of mental disorders. During the stimulation, the TMS system generates the intracranial time-varying induced E-field (E-field), which alters the membrane potential of neurons and subsequently exerts neural regulatory effects. The temporal waveform of the induced E-fields is directly related to the stimulation effect. To meet the needs of scientific research on diversified stimulation waveforms and flexible adjustable stimulation parameters, a novel efficient pulse magnetic stimulation circuit (the EPMS circuit) design based on asymmetric cascaded multilevel technology is proposed in this paper. Based on the transient analysis of the discharge circuit, this circuit makes it possible to convert the physical quantity (the intracranial induced E-field) that needs to be measured after magnetic stimulation into easily analyzable electrical signals (the discharge voltage at both ends of the stimulation coil in the TMS circuit). This EPMS circuit can not only realize monophasic and biphasic cosine-shaped intracranial induced E-fields, which are widely used in the market, but also realize three types of new intracranial induced E-field stimulation waveform with optional amplitude and adjustable pulse width, including monophasic near-rectangular, biphasic near-rectangular and monophasic/biphasic ladder-shaped stimulation waveform, which breaks through the limitation of the stimulation waveform of traditional TMS systems. Among the new waveforms produced by the EPMS circuit, further research was conducted on the dynamic response characteristics of neurons under the stimulation of the biphasic four-level waveform (the BFL waveform) with controllable parameters. The relationship between TMS circuit parameters (discharge voltage level and duration) and corresponding neural response characteristics (neuron membrane potential change and neuronal polarizability ratio) was explained from a microscopic perspective. Accordingly, the biological physical quantities (neuronal membrane potential) that are difficult to measure can be transformed into easily analyzable electrical signals (the discharge voltage level and duration). Results showed that compared with monophasic and biphasic cosine induced E-fields with the same energy loss, the neuron polarization ratio is decreased by 54.5% and 87.5%, respectively, under the stimulation of BFL waveform, which could effectively enhance the neuromodulation effect and improve the stimulation selectivity.

[Prescription compatibility connotation and action mechanism of Siwu Decoction in treating primary dysmenorrhea].

The aim of this paper was to study the prescription compatibility connotation in the treatment of primary dysmenorrhea(PD) and verify the mechanism as predicted by network pharmacology of Siwu Decoction(SWD). Mice PD model was constructed by using estradiol benzoate-oxytocin. PD mice were randomly divided into 8 groups, namely normal group, model group, positive group, complete formula group, Rehmanniae Radix Praeparata-free group, Paeoniae Radix Alba-free group, volatile oil-free group, Chuan-xiong Rhizoma and Angelicae Sinensis Radix-free group. Latent time, writhing times, inhibition rate, prostaglandin F_2_α(PGF_2_α) and prostaglandin E_2(PGE_2) levels in serum, endothelin-1, Ca~(2+), expression levels of prostaglandin synthase 2 G/H(PTGS2), estrogen receptor(ESR1), glucocorticoid receptor gene(NR3 C1) mRNA and protein expression levels in the uterus homogenate and pathological changes of uterine tissue were index to explore the prescription compatibility connotation and verify the mechanism of SWD in the treatment of PD. Compared with the extraction liquid of the whole recipe, the effect of Rehmanniae Radix Praeparata-free group and Paeoniae Radix Alba-free group with volatile oil were slightly lower, the effect of essential oil-free group was significantly lower, and the effect of Chuanxiong Rhizoma and Angelicae Sinensis Radix-free group was worse than that of the whole recipe. The relative expression levels of PTGS2 protein and mRNA were significantly reduced by the SWD. The relative expressions of protein and mRNA of ESR1, NR3 C1 were significantly increased. SWD treats PD by regulating the expression of key proteins PTGS2, ESR1 and NR3 C1.Its main medicinal herbs were Angelicae Sinensis Radix and Chuanxiong Rhizoma. Active components were mainly in volatile oil, but Paeo-niae Radix Alba and Rehmanniae Radix Praeparata also had some contributions.

[Research progress on triptolide functionalized nanoparticulate drug delivery systems for tumor treatment].

Nowadays,the advantages of traditional Chinese medicine(TCM) for treatment of tumors are increasingly prominent.Triptolide shows wide-spectrum and highly effective anti-tumor activity. Moreover,nano-carrier-based triptolide drug delivery system is more powerful in improving water solubility and pharmacokinetic behavior of the drug,but it is easy to cause toxic and side effects that should not be neglected on human body. Because of tumor vascular heterogeneity and PEGylation dilemma,nanoparticulate drug delivery systems need to overcome multiple physiological and pathological barriers from drug administration to functioning. It is difficult for traditional triptolide nanoparticulate drug delivery systems to achieve active accumulation of nano-drug in tumor tissues and specific drug release in tumor target site solely relying on enhanced permeability and retention effect of solid tumor,limiting their application and clinical transformation in treatment of tumors. Based on the traditional nano-preparation system,the new functionalized nano-drug delivery system further enhances the nano-drug enrichment,penetration and controlled release at the tumor sites,which is of great significance in improving bioavailability,anti-tumor efficacy and reducing the side effects of drugs. In this paper,we summarized and analyzed the researches on new triptolide functionalized nano-drug delivery system from four perspectives,including tumor active targeting,tumor microenvironment response,polymer-drug conjugates,and multidrug co-delivery for tumor treatment,expecting to provide ideas for in-depth research and clinical application of triptolide and some other active anti-tumor TCM ingredients.

[Research progress on anti-tumor effects and mechanisms of triptolide and its combined application].

Tumors are major chronic diseases and seriously threaten human health all over the world. How to effectively control and cure tumors is one of the most pivotal problems in the medical field. At present,surgery,radiotherapy and chemotherapy are still the main treatment methods. However,the side effects of radiotherapy and chemotherapy cannot be underestimated. Therefore,it is of great practical significance to find new anti-cancer drugs with low toxicity,high efficiency and targeting to cancer cells. With the increasing incidence of tumor,the anti-tumor effect of traditional Chinese medicine has increasingly become a research hotspot. Triptolide,which is a natural diterpenoid active ingredient derived from of Tripterygium wilfordii,as one of the highly active components,has anti-inflammatory,immunosuppressive,anti-tumor and other multiple effects. A large number of studies have confirmed that it has good anti-tumor activity against various tumors in vivo and in vitro. It can play an anti-tumor role by inhibiting the proliferation of cancer cells,inducing apoptosis of cancer cells,inducing autophagy of cancer cells,blocking the cell cycle,inhibiting the migration,invasion and metastasis of cancer cells,reversing multidrug resistance,mediating tumor immunity and inhibiting angiogenesis. On the basis of literatures,this paper reviews the anti-tumor effect and mechanism of triptolide,and analyzes the current situation of triptolide combined with other chemotherapy drugs,in order to promote deep research and better clinical application about triptolide.

[Influence of the Experiment Energy Dispersive X-Ray Fluorescence Measurement of Uranium by Different Excitation Source].

Aiming at the self-excitation effect on the interference of measurements which exist in the process of Energy dispersive X-ray fluorescence method for uranium measurement. To solve the problem of radioactive isotopes only used as excitation source in determination of uranium. Utilizing the micro X-ray tube to test Self-excitation effect to get a comparison of the results obtained by three different uranium ore samples--109 Cd, 241 Am and Mirco X-ray tube. The results showed that self-excitation effect produced the area measure of characteristic X-ray peak is less than 1% of active condition, also the interference of measurements can be negligible. Photoelectric effect cross-section excited by 109 Cd is higher, corresponding fluorescence yield is higher than excited by 241 Am as well due to characteristics X-ray energy of 109 Cd, 22.11 & 24.95 KeV adjacent to absorption edge energy of L(α), 21.75 KeV, based on the above, excitation efficiency by 109 Cd is higher than 241 Am; The fact that measurement error excited by 241 Am is significantly greater than by 109 Cd is mainly due to peak region overlap between L energy peaks of uranium and Scattering peak of 241 Am, 26.35 keV, These factors above caused the background of measured Spectrum higher; The error between the uranium content in ore samples which the X-ray tube as the excitation source and the chemical analysis results is within 10%. Conclusion: This paper come to the conclusion that the technical quality of uranium measurement used X-ray tube as excitation source is superior to that in radioactive source excitation mode.

[Analyzer Design of Atmospheric Particulate Matter's Concentration and Elemental Composition Based on ß and X-Ray's Analysis Techniques].

Monitoring atmospheric particulate matter requires real-time analysis, such as particulate matter's concentrations, their element types and contents. An analyzer which is based on ß and X rays analysis techniques is designed to meet those demands. Applying ß-ray attenuation law and energy dispersive X-ray fluorescence analysis principle, the paper introduces the analyzer's overall design scheme, structure, FPGA circuit hardware and software for the analyzer. And the analyzer can measure atmospheric particulate matters' concentration, elements and their contents by on-line analysis. Pure elemental particle standard samples were prepared by deposition, and those standard samples were used to set the calibration for the analyzer in this paper. The analyzer can monitor atmospheric particulate matters concentration, 30 kinds of elements and content, such as TSP, PM10 and PM2.5. Comparing the measurement results from the analyzer to Chengdu Environmental Protection Agency's monitoring results for monitoring particulate matters, a high consistency is obtained by the application in eastern suburbs of Chengdu. Meanwhile, the analyzer are highly sensitive in monitoring particulate matters which contained heavy metal elements (such as As, Hg, Cd, Cr, Pb and so on). The analyzer has lots of characteristics through technical performance testing, such as continuous measurement, low detection limit, quick analysis, easy to use and so on. In conclusion, the analyzer can meet the demands for analyzing atmospheric particulate matter's concentration, elements and their contents in urban environmental monitoring.

[The Study of Advanced Fundamental Parameter Method in EDXRFA].

The X-ray Fluorescence Analysis(XRFA) is an important and efficient method on the element anylsis and is used in geology, industry and environment protection. But XRFA has a backdraw that the determination limit and accuracy are effected by the matrix of the sample. Now the fundamental parameter is usually used to calculate the content of elements in XRFA, and it is an efficient method if the matrix and net area of characteristic X-ray peak are obtained. But this is invalide in in-stu XRFA. Also the method of net area and the "black material" of sample are the key point of the fundamental parameter method when the Energy Dispersive X-ray Fluorescence Analysis(EDXRFA) method is used in the low content sample. In this paper a advanced fundamental parameter method is discussed. The advanced fundamental parameter method includes the spectra analysis and the fundamental parameter method, which inserts the overlapping peaks separation method into the iteration process of the fundamental parameter method. The advanced method can resolve the net area and the quantitative analysis. The advanced method is used to analyse the standard sample. Compare to the content obtained from the coefficient method, the precision of Cu, Ni and Zn is better than coeffieciency method. The result shows that the advanced method could improve the precision of the EDXRFA, so the advanced method is better than the coefficient method.

[Analyse Output Specurum in Miniature Transmission X-Ray Tube of Aluminum Window and Silver Target by MC Simulation].

The miniature transmission X-ray tube is widely used in energy dispersive X-ray Fluorescence Analysis (EDXRFA). The miniature transmission X-ray tube with a small, low power consumption, X-ray emission efficiency that can be made the excitation source of handheld X-ray energy dispersive fluorescence analyzer. Beryllium (Be) is the most commonly used X-ray window material. But beryllium is expensive and toxic. At the same time set filtering window by aluminum (Al) to reducing low-energy scattering rays. This paper be adopted Al for exit window material of miniature transmission X-ray tube, achieve high-energy rays transmission and low-energy scattered radiation shielding, at the same time reduce production cost and difficulty. The present paper simulate the X-ray tube output spectrum of silver (Ag) target and aluminum window with different thickness by MCNP5. We consider the X-ray of low energy part is completely shielded when aluminum windows thickness is greater than 1.5 mm. We can conclude that 2 µm and 0.8 mm are the best combination of target thickness and aluminum windows through comparative analysis of existing research results. Then we can get flux of high energy part is big and low energy part is small when the target is 2 µm thick Ag and the window is 0.8 mm thick Al.

[Application of the racial algorithm in energy dispersive X-ray fluorescence overlapped spectrum analysis].

In the energy dispersive X-ray fluorescence spectrum analysis, scintillation detector such as NaI (Tl) detector usually has a low energy resolution at around 8%. The low energy resolution causes problems in spectral data analysis especially in the high background and low counts condition, it is very limited to strip the overlapped spectrum, and the more overlapping the peaks are, the more difficult to peel the peaks, and the qualitative and quantitative analysis can't be carried out because we can't recognize the peak address and peak area. Based on genetic algorithm and immune algorithm, we build a new racial algorithm which uses the Euclidean distance as the judgment of evolution, the maximum relative error as the iterative criterion to be put into overlapped spectrum analysis, then we use the Gaussian function to simulate different overlapping degrees of the spectrum, and the racial algorithm is used in overlapped peak separation and full spectrum simulation, the peak address deviation is in +/- 3 channels, the peak area deviation is no more than 5%, and it is proven that this method has a good effect in energy dispersive X-ray fluorescence overlapped spectrum analysis.

Enhanced Anti-Inflammatory Activity of Tilianin Based on the Novel Amorphous Nanocrystals.

Tilianin (Til), a flavonoid glycoside, is well-known for its therapeutic promise in treating inflammatory disorders. Its poor water solubility and permeability limit its clinical applicability. In order to overcome these restrictions, an antisolvent precipitation and ultrasonication technique was used to prepare amorphous tilianin nanocrystals (Til NCs). We have adjusted the organic solvents, oil-to-water ratio, stabilizer composition, and ultrasonic power and time by combining single-factor and central composite design (CCD) methodologies. The features of Til NCs were characterized using powder X-ray diffraction (PXRD), scanning calorimetry (DSC), and transmission electron microscopy (TEM). Specifically, the optimized Til NCs were needle-like with a particle size ranging from 90 to 130 nm. PVA (0.3%, w/v) and TPGS (0.08%, w/v) stabilized them well. For at least two months, these Til NCs stayed amorphous and showed an impressive stability at 4 °C and 25 °C. Remarkably, Til NCs dissolved almost 20 times faster in simulated intestinal fluid (SIF) than they did in crude Til. In RAW264.7 cells, Til NCs also showed a better cellular absorption as well as safety and protective qualities. Til NCs were shown to drastically lower reactive oxygen species (ROS), TNF-α, IL-1ß, and IL-6 in anti-inflammatory experiments, while increasing IL-10 levels and encouraging M1 macrophages to adopt the anti-inflammatory M2 phenotype. Our results highlight the potential of amorphous Til NCs as a viable approach to improve Til's anti-inflammatory effectiveness, solubility, and dissolving rate.

Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment.

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

[Study on the effect of target thickness on output spectrum in transmission anode micro X-ray tube by MC method].

The transmission anode micro X-ray tube is a key component of energy dispersive X-ray Fluorescence Analysis (EDXRFA) as exciting source. So in EDXRFA we hope to get the primary X-ray spectrum which is simply distributed. In the present paper, the authors used the Monte Carlo (MC) method to study the spectrum character of the transmission anode micro X-ray tube with different thickness of target. We cut the spectrum into high energy (5keV-50keV) part and low energy (< 5 keV) part and compared them to each other. The result showed that the flux of high energy part is big and the flux of low energy part is small when the electron energy is 50 keV and the target is 4 microm thick Ag. This is better for EDXRFA.

[Theoretical calculation and simulation research on micro X-ray tube target thickness and spectra].

The present paper established a mathematical model, according to the structure of the end-window transmission micro X-ray tube anode. And we discussed the relationship between the average thickness of electron beam targeting and the high voltage. Also we obtained the spectral intensity distribution characteristics of the emitted X-ray on the angle, meanwhile by the use of Monte Carlo, the authors simulated the intensity distribution characteristics of the spectrum in the direction of 2pi. The results show that the average thickness of the micro X-ray tube anode target is about 2 microm, and we can get much better single-energy spectrum in the vertical direction of the incident electron beam within a few degrees. These conclusions have some theoretical significance for the structural design of the micro X-ray tube and the emitted spectrum monochrome applications.

[Research on the peak search method based on improved simulated annealing model for x-ray fluorescence spectrum].

In energy dispersive X-ray fluorescence analysis technical analysis, the spectrum information processing has been being the focus of researches, spectrum smooth, peak-search, and peak area processing are the top priority, tA peak search method is based on simulated annealing algorithm principle, and to establish a new search peak model algorithm, this algorithm uses the advantages of the global convergence properties of simulated annealing and the Metropolis criterion is used as a peak valley judgment basis. A new decision criteria on peak valley array is used in this method, too. At the same time, convergence is taken from both ends of the spectrum channel address, it ends up when convergence reaches to the same optimal solution. This paper compared the algorithm with the simple comparison method, third derivative method, and the contrast experiment results, showing that this algorithm has a strong ability on X-ray fluorescence spectrum peak-search and a certain value in the actual production.

A molecular, epidemiological and pathogenicity analysis of pigeon paramyxovirus type 1 viruses isolated from live bird markets in China in 2014-2021.

To expand our understanding of the epidemiology of pigeon paramyxovirus type 1 (PPMV-1) in China, risk-based active surveillance was undertaken with pigeon swabs collected from live bird markets in 2014-2021. Seventy-six PPMV-1 strains were isolated from 12 provinces (60%) of the 20 provinces surveyed, and the positive rates of PPMV-1 varied from 0.50% to 3.19% annually. The complete genomic sequences of 18 representative viruses were analyzed, revealing a genome of 15,192 nucleotides, with the gene order 3'-NP-P-M-F-HN-L-5'. All isolates contained the 112RRQKRF117 cleavage site in the fusion (F) protein, a characteristic generally associated with virulent Newcastle disease viruses (NDVs), and the intracerebral pathogenicity index values (1.05-1.41) of four isolates indicated their virulence. A challenge experiment also demonstrated that all four isolates are pathogenic to pigeons, with morbidity rates of 60-100% and mortality rates of 0-30%. A further analysis of the functional domains of the F and HN proteins revealed several mutations in the fusion peptide, signal peptide, neutralizing epitopes, heptad repeat region, and transmembrane domains, and the substitution of cysteine residue 25 (C25Y) and substitutions in the HRb region (V287I) of the F protein and the transmembrane domain (V45A) of the HN protein may play important roles in PPMV-1 virulence. In a phylogenetic analysis based on the complete sequences of the F gene, all eighteen isolates all clustered into sub-genotype VI.2.1.1.2.2 (VIb) in class II, and shared high nucleotide sequence identity, indicating that the PPMV-1 strains in sub-genotype VI.2.1.1.2.2 are the predominant PPMV-1 viruses in pigeons in China and that the variations in these viruses have been relatively stable over the past 8 years. This study identifies the genetic and pathogenicity characteristics of the PPMV-1 strains prevalent in China and extends our understanding of the prevalence of this virus in China.

Injectable thermo-responsive nano-hydrogel loading triptolide for the anti-breast cancer enhancement via localized treatment based on "two strikes" effects.

The clinical application of triptolide (TPL) in tumor therapy has been greatly limited by its toxicity and inefficient delivery. Herein, a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL. Based on the amphiphilic structure of poly (N-isopropylacrylamide-co-acrylic acid)-g-F68 copolymer, it was able to form nano-micelles to efficiently encapsulate TPL, and then turn into a hydrogel at 37 °C. TPL@nano-gel exhibited a sustained drug release profile in vitro and a stronger anticancer effect caused by "two strikes". The "first strike" was its enhanced cytotoxicity compared to free TPL, due to the enhanced pro-apoptosis effect observed in both MDA-MB-231 and MCF-7 cells caused by the regulation of endogenous mitochondrial pathways. Furthermore, TPL@nano-gel exhibited a "second-strike" through its anti-angiogenesis capabilities mediated through VEGFR-2 signaling inhibition. As expected, after intra-tumoral injection at a 0.45 mg/kg TPL-equivalent dose three times over 14 days in 4T1 tumor-bearing mice, TPL@nano-gel led to lower systemic toxicity and higher antitumor efficacy compared to multiple injections of TPL. In this regard, these findings indicate that this injectable thermo-responsive hydrogel carries great potential for TPL as a safe and effective cancer therapy.