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Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals1,2. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis3, and thus, alternative therapeutic approaches are urgently needed2,3. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.Adoptive transfer of macrophages, transfected with vitamin C lipid nanoparticles that deliver an antimicrobial peptide and cathepsin B mRNA, can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice.

Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy. Antibodies targeting OX40 or CD137, two T cell costimulatory receptors, have been shown to improve antitumor immunity. Here the authors design a phospholipid-derived nanoparticle to deliver OX40 or CD137 mRNA to T cells in vivo, improving efficacy of anti-OX40 and anti-CD137 antibody therapy in preclinical tumor models.

A high-performance large-scale-integrated organic phototransistor needs a semiconductor layer that maintains its photoelectric conversion ability well during high-resolution pixelization. However, lacking a precise design for the nanoscale structure, a trade-off between photoelectric performance and device miniaturization greatly limits the success in commercial application. Here we demonstrate a photovoltaic-nanocell enhancement strategy, which overcomes the trade-off and enables high-performance organic phototransistors at a level beyond large-scale integration. Embedding a core–shell photovoltaic nanocell based on perovskite quantum dots in a photocrosslinkable organic semiconductor, ultralarge-scale-integrated (>2 21  units) imaging chips are manufactured using photolithography. 27 million pixels are interconnected and the pixel density is 3.1 × 10 6  units cm −2 , at least two orders of magnitude higher than in existing organic imaging chips and equivalent to the latest commercial full-frame complementary metal–oxide–semiconductor camera chips. The embedded photovoltaic nanocells induce an in situ photogating modulation and enable photoresponsivity and detectivity of 6.8 × 10 6  A W −1 and 1.1 × 10 13  Jones (at 1 Hz), respectively, achieving the highest values of organic imaging chips at large-scale or higher integration. In addition, a very-large-scale-integrated (>2 16  units) stretchable biomimetic retina based on photovoltaic nanocells is manufactured for neuromorphic imaging recognition with not only resolution but also photoresponsivity and power consumption approaching those of the biological counterpart. This work reports core–shell photovoltaic nanocells to enhance the photoresponse of the active layer and realize photolithographic manufacturing of large-scale-integrated organic phototransistors for high-resolution biomimetic vision.

Cpf1, a type-V CRISPR–Cas effector endonuclease, exhibits gene-editing activity in human cells through a single RNA-guided approach. Here, we report the design and assessment of an array of 42 types of engineered Acidaminococcus sp. Cpf1 (AsCpf1) CRISPR RNA (crRNA) and 5 types of AsCpf1 mRNA in human cell lines. We show that the top-performing modified crRNA (cr3′5F, containing five 2′-fluoro ribose at the 3′ terminus) and AsCpf1 mRNA (full ψ-modification) improved gene-cutting efficiency by, respectively, 127% and 177%, with respect to unmodified crRNA and plasmid-encoding AsCpf1. We also show that the combination of cr3′5F and ψ-modified AsCpf1 or Lachnospiraceae bacterium Cpf1 (LbCpf1) mRNA augmented gene-cutting efficiency by over 300% with respect to the same control, and discovered that 11 out of 16 crRNAs from Cpf1 orthologues enabled genome editing in the presence of AsCpf1. Engineered CRISPR–Cpf1 systems should facilitate a broad range of genome editing applications. An array of chemically engineered CRISPR RNAs and AsCpf1 messenger RNAs leads to improvements in gene-cutting efficiency up to about 300% with respect to unmodified CRISPR RNA and plasmid-encoding AsCpf1.

Triple-negative breast cancer (TNBC) is one type of the most aggressive breast cancers with poor prognosis. It is of great urgency to develop new therapeutics for treating TNBC. Based on current treatment guideline and genetic information of TNBC, a combinational therapy platform integrating chemotherapy drugs and mRNA encoding tumor suppressor proteins may become an efficacious strategy. In this study, we developed paclitaxel amino lipid (PAL) derived nanoparticles (NPs) to incorporate both chemotherapy drugs and P53 mRNA. The PAL P53 mRNA NPs showed superior properties compared to Abraxane ® and Lipusu ® used in the clinic including high paclitaxel loading capacity (24 wt.%, calculated by paclitaxel in PAL), PAL encapsulation efficiency (94.7% ± 6.8%) and mRNA encapsulation efficiency (88.7% ± 0.7%). Meanwhile, these NPs displayed synergetic cytotoxicity of paclitaxel and P53 mRNA in cultured TNBC cells. More importantly, we demonstrated in vivo anti-tumor efficacy of PAL P53 mRNA NPs in an orthotopic TNBC mouse model. Overall, these chemotherapy drugs derived mRNA NPs provide a new platform to integrate chemotherapy and personalized medicine using tumor genetic information, and therefore represent a promising approach for TNBC treatment.

Integrity monitoring ensures the reliability of Real-Time Precise Point Positioning (RT-PPP) by calculating the Protection Level (PL) in maritime applications. Overbounding the non-ideal observation errors for the PL plays a vital role in suppressing Misleading Information (MI) and improving system availability, including significant non-Gaussian errors such as multipath. The traditional two-step overbounding algorithm always uses a global overbounding coefficient with the largest value to envelop all non-ideal distribution of observation errors. The non-Gaussian errors, like multipath, can cause severe the non-ideal distortion of low-elevation-angle satellite observation errors, leading to the generation of larger overbounding coefficients. Furthermore, the PL can be constructed based on the traditional two-step overbounding algorithm in the position-domain to envelope Positioning Error (PE), and the MI can also be avoided. However, the constructed PL suffers from excessive conservation, and may reduce system availability. Therefore, a non-ideal observation error overbounding method considering elevation-related distribution characteristics is developed for maritime RT-PPP integrity monitoring. The method integrates the two-step overbounding algorithm to determine the differentiated overbounding coefficients related to different elevation intervals. Meanwhile, it is validated using two sets of real maritime experimental data in offshore and ocean areas. The results demonstrate that the developed method generates PL that more closely matches the PE The availability of the integrity monitoring system is improved by 16.18% and 11.88% for the two scenarios, respectively. The developed method can enhance the availability level of integrity monitoring. It can be applied to the dynamic positioning system of offshore vessels, thereby reducing the risks in precise operations.

The absorption and scattering properties of water can cause various distortions in underwater images, which limit the ability to investigate underwater resources. In this paper, we propose a two-stage network called WaterFormer to address this issue using deep learning and an underwater physical imaging model. The first stage of WaterFormer uses the Soft Reconstruction Network (SRN) to reconstruct underwater images based on the Jaffe–McGramery model, while the second stage uses the Hard Enhancement Network (HEN) to estimate the global residual between the original image and the reconstructed result to further enhance the images. To capture long dependencies between pixels, we designed the encoder and decoder of WaterFormer using the Transformer structure. Additionally, we propose the Locally Intended Multiple Layer Perceptron (LIMP) to help the network process local information more effectively, considering the significance of adjacent pixels in enhancing distorted underwater images. We also proposed the Channel-Wise Self-Attention module (CSA) to help the network learn more details of the distorted underwater images by considering the correlated and different distortions in RGB channels. To overcome the drawbacks of physical underwater image enhancement (UIE) methods, where extra errors are introduced when estimating multiple physical parameters separately, we proposed the Joint Parameter Estimation method (JPE). In this method, we integrated multiple parameters in the Jaffe–McGramery model into one joint parameter (JP) through a special mathematical transform, which allowed for physical reconstruction based on the joint parameter (JP). Our experimental results show that WaterFormer can effectively restore the color and texture details of underwater images in various underwater scenes with stable performance.

This study aimed to investigate the effects of dietary crude protein (CP) and lysine levels on growth performance, slaughter performance, meat quality, and myofiber characteristics of slow-growing chicken. A 3 × 3 factorial experiment was arranged, and the chickens were fed with 3 levels of dietary CP (16.0%, 17.0%, 18.0%) and 3 levels of dietary lysine (0.69%, 0.84%, 0.99%). A total of 540 8-week-old Beijing-You Chicken (BYC) female growing chickens were randomly allocated to 9 groups, 5 replicates per group, and 12 chickens per replicate. The birds were randomly allocated to one of the 9 experimental diets. Growth performance, slaughter performance, meat quality, and myofiber characteristics were determined at 16 weeks of age. The results showed that dietary CP level and the interaction of dietary CP and lysine levels affected average feed intake (AFI) (p < 0.05). The AFI in the 16.0% CP and 17.0% CP groups was higher than in the 18.0% CP group (p < 0.05). Dietary CP levels significantly affected body weight gain (BWG) (p < 0.05) at 9 to 16 weeks. The 18.0% CP group had the highest BWG (93.99 g). Dietary CP levels affected the percentage of leg muscle yield, and the percentage of leg muscle yield of the 16.0% CP group was significantly lower than that in the other two groups (p < 0.05). Dietary CP and lysine levels alone and their interactions did not affect pH24h, drip loss, and cooking loss of breast muscle (p > 0.05). The shear force of the 18.0% CP group (29.55 N) was higher than that in the other two groups (p < 0.01). Dietary CP level affected myofiber characteristic (p < 0.01), with the lowest myofiber density (846.35 p·mm−2) and the largest myofiber diameter (30.92 μm) at 18.0% CP level. Dietary lysine level affected myofiber diameter, endomysium thickness, perimysium thickness (p < 0.01), with the largest myofiber diameter (29.29 μm) obtained at 0.84% lysine level, the largest endomysium thickness (4.58 μm) at 0.69% lysine level, and the largest perimysium thickness (9.26 μm) at 0.99% lysine level. Myofiber density was negatively correlated with myofiber diameter and endomysium thickness (R = −0.883, R = −0.523, p < 0.01); perimysium thickness had a significant negative correlation with shear force (R = −0.682, p < 0.05). Therefore, reducing dietary CP level and adding appropriate lysine can reduce myofiber diameter and increase perimysium thickness, reducing shear force and improving meat tenderness. A high lysine level (0.99%) in the low-CP (16.0%) diet can improve meat tenderness by regulating the myofiber characteristic without affecting production performance.

Hyperuricemia is a metabolic disease with an increasing incidence in recent years. It is critical to identify potential technology opportunities for hyperuricemia drugs to assist drug innovation. A technology roadmap (TRM) can efficiently integrate data analysis tools to track recent technology trends and identify potential technology opportunities. Therefore, this paper proposes a systematic data-driven TRM approach to identify potential technology opportunities for hyperuricemia drugs. This data-driven TRM includes the following three aspects: layer mapping, content mapping and opportunity finding. First we deal with layer mapping. The BERT model is used to map the collected literature, patents and commercial hyperuricemia drugs data into the technology layer and market layer in TRM. The SAO model is then used to analyze the semantics of technology and market layer for hyperuricemia drugs. We then deal with content mapping. The BTM model is used to identify the core SAO component topics of hyperuricemia in technology and market dimensions. Finally, we consider opportunity finding. The link prediction model is used to identify potential technological opportunities for hyperuricemia drugs. This data-driven TRM effectively identifies potential technology opportunities for hyperuricemia drugs and suggests pathways to realize these opportunities. The results indicate that resurrecting the pseudogene of human uric acid oxidase and reducing the toxicity of small molecule drugs will be potential opportunities for hyperuricemia drugs. Based on the identified potential opportunities, comparing the DNA sequences from different sources and discovering the critical amino acid site that affects enzyme activity will be helpful in realizing these opportunities. Therefore, this research provides an attractive option analysis technology opportunity for hyperuricemia drugs.

To explore the effects of pulsed electric field treatment on the germination of Scutellaria baicalensis seeds and the growth of seedlings, this study used the response surface methodology to design the working parameters of the pulsed electric field and treated and cultured Scutellaria baicalensis seeds. The results showed that the pulsed electric field treatment was beneficial for the germination of Scutellaria baicalensis seeds, improving the metabolic activity and stress resistance of seedlings. When the pulsed electric field treatment’s parameters were 0.5 kV·cm−1, 120 μs, and 99 pulses, the germination potential of seeds was significantly increased by 29.25% and the germination index significantly increased by 20.65%, compared to the control. From 5th to 15th day, the activities of SOD, POD, and α-amylase in the seedlings, and the contents of Pro, soluble sugars, and soluble proteins were significantly increased, compared to the control. This study provides a theoretical basis for improving the germination and seedling growth of medicinal herbs such as Scutellaria baicalensis and their practical application in production.