A Polymer-Based Antigen Carrier Activates Two Innate Immune Pathways for Adjuvant-Free Subunit Vaccines.

The activation of multiple Pattern Recognition Receptors (PRRs) has been demonstrated to trigger inflammatory responses and coordinate the host's adaptive immunity during pathogen infections. The use of PRR agonists as vaccine adjuvants has been reported to synergistically induce specific humoral and cellular immune responses. However, incorporating multiple PRR agonists as adjuvants increases the complexity of vaccine design and manufacturing. In this study, we discovered a polymer that can activate both the Toll-like receptor (TLR) pathway and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. The polymer was then conjugated to protein antigens, creating an antigen delivery system for subunit vaccines. Without additional adjuvants, the antigen-polymer conjugates elicited strong antigen-specific humoral and cellular immune responses. Furthermore, the antigen-polymer conjugates, containing the Receptor Binding Domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein or the Monkeypox Antigen M1R as the antigens, were found to induce potent antigen-specific antibodies, neutralizing antibodies, and cytotoxic T cells. Immunization with M1R-polymer also resulted in effective protection in a lethal challenge model. In conclusion, this vaccine delivery platform offers an effective, safe, and simple strategy for inducing antigen-specific immunity against infectious diseases.

Exploring and Predicting the Drivers of Ongoing HIV-1 Transmission in Guangyuan, Sichuan.

Purpose: Guangyuan was selected as the first pilot city of molecular transmission network in Sichuan Province to implement dynamic monitoring. This study aim to insight the characteristics of HIV-1 molecular epidemiology and explore the influencing factors of transmission dynamics. Furthermore, it predict the driving factors of network expansion by established a transmission risk prediction model. Patients and Methods: A longitudinal cohort study was conducted to obtain a total of 1434 plasma samples from newly diagnosed HIV-infected patients from 2010 to June 2022. Phylogenetic relationship and cluster analysis were performed using HIV-1 polymerase (pol) gene sequences to study the risk factors of clustering. We applied Logistic ML algorithms to establish a transmission risk prediction model, and model performance was checked using 10-fold cross-validation in the training set and receiver operating characteristic (ROC) curve analysis. Results: A total of 1360 pol sequences linked demographics obtained in this study cover approximately 94.8% of newly notified infections from 2010 to June 2022. The major epidemic genotypes were CRF07_BC, CRF01_AE, CRF08_BC and B subtypes, accounting for 93.82% of all. The differences of some clinical and demographic factors (eg, age, marital status) were statistically significant (P<0.05). We identified 136 clusters containing 654 HIV-1 pol sequences and observed that some characteristics (eg, over 50 years, married) were more likely to associated to the clusters (P<0.05). The predictive model showed excellent predictive ability to forecast cluster growth. Conclusion: The epidemic genotypes were relatively complex and diverse in Guangyuan. There was a potential transmission association caused widely spread in local area after the new strains entering. The transmission risk prediction model showed excellent predictive ability to forecast cluster growth which can predict the risk factors causing clusters expansion and provide a guidance for precise intervention strategies.

Engineered Histidine-Rich Peptides Enhance Endosomal Escape for Antibody-Targeted Intracellular Delivery of Functional Proteins.

Currently, the clinical application of protein/peptide therapeutics is mainly limited to the modulation of diseases in extracellular spaces. Intracellular targets are hardly accessed, owing largely to the endosomal entrapment of internalized proteins/peptides. Here, we report a strategy to design and construct peptides that enable endosome-to-cytosol delivery based on an extension of the "histidine switch" principle. By substituting the Arg/Lys residues in cationic cell-penetrating peptides (CPPs) with histidine, we obtained peptides with pH-dependent membrane-perturbation activity. These peptides do not randomly penetrate cells like CPPs, but imitate the endosomal escape of CPPs following cellular uptake. Working with one such 16-residue peptide (hsLMWP) with high endosomal escape capacity, we engineered modular fusion proteins and achieved antibody-targeted delivery of diverse protein cargoes-including the pro-apoptotic protein BID (BH3-interacting domain death agonist) and Cre recombinase-into the cytosol of multiple cancer cell types. After extensive in vitro testing, an in vivo analysis with xenograft mice ultimately demonstrated that a trastuzumab-hsLMWP-BID fusion conferred strong anti-tumor efficacy without apparent side effects. Notably, our fusion protein features a modular design, allowing flexible applications for any antibody/cargo combination of choice. Therefore, the potential applications extend throughout life science and biomedicine, including gene editing, cancer treatment, and immunotherapy.

One-Step Crank-Nicolson Direct-Splitting Algorithm with Enhanced Absorption to Evaluate Low-Pressure Discharge for Satellite Sensors in Outer Space.

Low-pressure discharge causes air ionization resulting in performance degeneration or failure for the satellite sensors in outer space. Here, a one-step Crank-Nicolson Direct-Splitting (CNDS) algorithm is proposed to evaluate the electrical behavior of satellite sensors under the low-pressure discharge circumstance. To be more specific, the CNDS algorithm is proposed in the Lorentz medium, which can accurately analyze the ionized air and generated plasma. Higher order perfectly matched layer (PML) is modified in the Lorentz medium to efficiently terminate the unbounded lattice. It can be concluded that the proposed algorithm shows entire considerable performance in the low-pressure discharge evaluation. The proposed PML formulation behaviors enhanced absorbing performance compared with the existing algorithm. Through the experiments, it can be observed that the low-pressure discharge phenomenon causes performance variation, which shows a significant influence on the satellite sensors. Meanwhile, results show considerable agreement between the simulation and experiment results which indicates the effectiveness of the algorithm.

Displacements of a spatially limited light beam in the slant path of oceanic turbulence.

The new oceanic power spectrum of refractive-index of optical turbulent fluctuations in slant path is developed by oceanic temperature structure parameters with depth under weak wind and strong wind conditions. Based on the proposed oceanic power spectrum in slant channel, the analytical expression of the displacement variance of Gaussian beam propagation in slant oceanic turbulent channel is derived. Then the influence of oceanic turbulent parameters in slant path on the beam displacement is investigated. It's shown that oceanic turbulence in slant path with small inner scale, low ratio of temperature and salinity contributions, large tidal velocity and wind speed leads to small beam displacement. For a sufficiently large receiver radius, Gaussian beam with large initial beam radius propagating at large zenith angle can cause small beam displacement in slant path of oceanic turbulence.

Bridgehead Alkene-Enabled Strain-Driven Bioorthogonal Reaction.

Herein, we report a novel bioorthogonal reaction that hinges on a bridgehead alkene (BHA)-enabled inverse-electron-demand Diels-Alder (IEDDA) cycloaddition. Readily accessible from natural product ß-caryophyllene, the strained BHA displays high reactivity toward the IEDDA reaction while maintaining excellent biocompatibility. The developed IEDDA reaction has been applied to in vitro protein labeling and pretargeted live cell imaging.

Narrow-Bandpass One-Step Leapfrog Hybrid Implicit-Explicit Algorithm with Convolutional Boundary Condition for Its Applications in Sensors.

A large number of sensors work in the narrow bandpass circumstance. Meanwhile, some of them hold fine details merely along one and two dimensions. In order to efficiently simulate these sensors and devices, the one-step leapfrog hybrid implicit-explicit (HIE) algorithm with the complex envelope (CE) method and absorbing boundary condition is proposed in the narrow bandpass circumstance. To be more precise, absorbing boundary condition is implemented by the higher order convolutional perfectly matched layer (CPML) formulation to further enhance the absorption during the entire simulation. Numerical examples and their experiments are carried out to further illustrate the effectiveness of the proposed algorithm. The results show considerable agreement with the experiment and theory resolution. The relationship between the time step and mesh size can break the Courant-Friedrichs-Levy condition which indicates the physical size/selection mesh size. Such a condition indicates that the proposed algorithm behaviors are considerably accurate due to the rational choice in discretized mesh. It also shows decrement in simulation duration and memory consumption compared with the other algorithms. In addition, absorption performance can be improved by employing the proposed higher order CPML algorithm during the whole simulation.

Chemical trigger-enabled bioconjugation reaction.

Development of conceptually novel and practically useful bioconjugation reactions has been an intense pursuit of chemical biology research. Herein, we report an unprecedented bioconjugation reaction that hinges on a chemical trigger-enabled inverse-electron-demand Diels-Alder (IEDDA) cycloaddition of trans-cycloheptene (TCH) with tetrazine. Unlike the conventional strain-promoted bioconjugation reactions that utilize built-in strained alkenes as reactants, the current one features a "trigger-release-conjugate" reaction model, in which a highly strained TCH species is released from a bench-stable bicyclic N-nitrosourea (BNU) derivative upon treatment with an external stimulus. It is noteworthy that the reactivity-stability balance of BNU derivatives could be tuned by manipulating their N-1 substituents. As a proof-of-concept case, this new chemical trigger-enabled IEDDA reaction has been applied to in vitro protein labeling and pretargeted cell imaging. This work opens a new avenue to utilize BNU derivatives as a new class of chemical reporters in bioconjugate chemistry.

Responses of plant growth, physiological, gas exchange parameters of super and non-super rice to rhizosphere temperature at the tillering stage.

Temperature is one of the critical factors affecting rice growth and yield production. This study investigated the effects of rhizosphere temperature at the tillering stage on the growth, physiological parameters and gas exchange attributes of two rice cultivars, i.e., the super rice cultivar Yuxiangyouzhan and the non-super rice cultivar Xiangyaxiangzhan, under hydroponic conditions. Three rhizosphere temperature treatments, i.e., a low-rhizosphere-temperature treatment (LT, nutrient solution at 17.5 ± 1.5 °C), an ambient-temperature treatment (AT, nutrient solution at 27.5 ± 1.5 °C), and a high-rhizosphere-temperature treatment (HT, nutrient solution at 37.5 ± 1.5 °C), were applied in this study. The results showed significant differences in most of the rice growth and physiological and gas exchange parameters as a result of cultivar and rhizosphere temperature as well as their interaction. In addition, the marked reduction in total dry weight was positively correlated with a notable reduction in plant morphological parameters, such as the fresh and dry weight of the leaves and stem sheaths, and changes in gas exchange parameters. Moreover, antioxidant reactions were active in response to high and low rhizosphere temperatures, which varied in different plant tissues. These results suggested that the super and non-super rice were sensitive to high and low rhizosphere temperatures, respectively.