Monoclonal antibodies are one of the fastest growing classes of pharmaceutical products, however, their potential is limited by the high cost of development and manufacturing. Here we present a safe ...and cost-effective platform for in vivo expression of therapeutic antibodies using nucleoside-modified mRNA. To demonstrate feasibility and protective efficacy, nucleoside-modified mRNAs encoding the light and heavy chains of the broadly neutralizing anti-HIV-1 antibody VRC01 are generated and encapsulated into lipid nanoparticles. Systemic administration of 1.4 mg kg
of mRNA into mice results in ∼170 μg ml
VRC01 antibody concentrations in the plasma 24 h post injection. Weekly injections of 1 mg kg
of mRNA into immunodeficient mice maintain trough VRC01 levels above 40 μg ml
. Most importantly, the translated antibody from a single injection of VRC01 mRNA protects humanized mice from intravenous HIV-1 challenge, demonstrating that nucleoside-modified mRNA represents a viable delivery platform for passive immunotherapy against HIV-1 with expansion to a variety of diseases.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Lignin is a promising material due to its excellent properties. It is commonly used in electrochemical energy systems (including electrolytes, electrodes, diaphragms, and binders) due to its low ...price, sustainability and rich functional groups. However, lignin’s applications in energy storage systems have not been systematically reviewed in the current research. In this article, recent advances in the preparation and design of lignin-derived energy storage materials were reviewed. Starting with a brief overview of the basic chemistry of lignin and the separation process, progress in the preparation of lignin-based materials for lithium-ion batteries, supercapacitors, fuel cells, and solar cells were described, respectively. This review provides the basis for the application of lignin in the field of electrochemical energy systems. Also, the current bottleneck problems and perspectives of lignin-derived materials in improved energy storage device performance were presented for future developments.
is the popular pathogenic fungi fungus which lead to common root rot and leaf spot on wheat. Generally, chemical fungicides are used to control diseases. However, the environmental pollution ...resulting from fungicides should not be ignored. It is important to study the mode of antagonistic action between biocontrol microbes and plant pathogens to design efficient biocontrol strategies.
An antagonistic bacterium DB2 was isolated and identified as
. The inhibition rate of cell-free culture filtrate (
, 20%, v/v) of DB2 against
reached 92.67%. Light microscopy and scanning electron microscopy (SEM) showed that the
significantly altered the mycelial morphology of
and disrupted cellular integrity. Fluorescence microscopy showed that culture filtrate destroyed mycelial cell membrane integrity, decreased the mitochondrial transmembrane potential, induced reactive oxygen species (ROS) accumulation, and nuclear damage which caused cell death in
. Moreover, the strain exhibited considerable production of protease and amylase, and showed a significant siderophore and indole-3-acetic acid (IAA) production. In the detached leaves and potted plants control assay,
DB2 had remarkable inhibition activity against
and the pot control efficacy was 75.22%. Furthermore, DB2 suspension had a significant promotion for wheat seedlings growth.
DB2 can be taken as a potential biocontrol agent to inhibit
on wheat and promote wheat growth.
The expression level of miR-376c-3p is significantly lower in infants with neonatal hypoxic-ischemic encephalopathy (HIE) than in healthy infants. However, the biological function of this microRNA ...remains largely elusive.
We used PC-12 and SH-SY5Y cells to establish an oxygen-glucose deprivation (OGD) cell injury model to mimic HIE in vitro. The miR-376c-3p expression levels were measured using quantitative reverse transcription PCR. The CCK-8 assay and flow cytometry were utilized to evaluate OGD-induced cell injury. The association between miR-376c-3p and inhibitor of growth 5 (ING5) was validated using the luciferase reporter assay. Western blotting was conducted to determine the protein expression of CDK4, cyclin D1, Bcl-2 and Bax.
MiR-376c-3p was significantly downregulated in the OGD-induced cell injury model. Its overexpression elevated cell viability and impaired cell cycle G0/G1 phase arrest and apoptosis in PC-12 and SH-SY5Y cells after OGD. Downregulation of miR-376c-3p gave the opposite results. We further demonstrated that ING5 was a negatively regulated target gene of miR-376c-3p. Importantly, ING5 knockdown had a similar effect to miR-376c-3p-mediated protective effects against cell injury induced by OGD. Its overexpression abolished these protective effects.
Our data suggest that miR-376c-3p downregulated ING5 to exert protective effects against OGD-induced cell injury in PC-12 and SH-SY5Y cells. This might represent a novel therapeutic approach for neonatal HIE treatment.
Rhizoctonia cerealis is a major fungal pathogen of wheat that causes great yield losses in all wheat-growing regions of the world. The biocontrol agent Bacillus subtilis XZ18-3 was investigated for ...inhibiting R. cerealis growth in wheat. The results of the mycelial growth test showed that the sterile filtrate of B. subtilis XZ18-3 could significantly inhibit the mycelial growth of R. cerealis and cause swelling and rupture of the mycelium. Observation by transmission electron microscopy indicated that the sterile filtrate could penetrate the cellular membrane of Rhizoctoniacerealis, resulting in organelle destruction. The effect of the sterile filtrates on the pathogen cells, shown through fluorescent microscopy using different stains, revealed the mechanism by which the sterile filtrate caused DNA fragmentation, accumulation of ROS and changes in cell membrane permeability. To reach a better treatment of the soil-borne fungi, the components of a wettable powder were screened and an optimised formula determined (30.0% kaolin, 4.0% polyvinyl alcohol, 8.0% Tween-80, 2.0% polyethylene glycol and 100% fermentation broth). A quality index analysis revealed that the wetting powder reached acceptable biological pesticide standards. Pot control experiments showed that the wettable powder of B. subtilis XZ18-3 effectively controlled the pathogens with an efficacy of 88.28%. This study has provided the potential biocontrol agents (BCAs) for wheat sharp eyespot disease.
Common root rot, caused by Bipolaris sorokiniana, is one of the most prevalent diseases of wheat and has led to major declines in wheat yield and quality worldwide. Here, strain XZ34-1 was isolated ...from soil and identified as Bacillus amyloliquefaciens based on the morphological, physiological, biochemical characteristics and 16S rDNA sequence. Culture filtrate (CF) of strain XZ34-1 showed a high inhibition rate against B.sorokiniana and had a broad antifungal spectrum. It also remarkably inhibited the mycelial growth and spore germination of B. sorokiniana. In pot control experiments, the incidence and disease index of common root rot in wheat seedlings were decreased after treatment with CF, and the biological control efficacy was significant, up to 78.24%. Further studies showed XZ34-1 could produce antifungal bioactive substances and had the potential of promoting plant growth. Lipopeptide genes detection with PCR indicated that strain XZ34-1 may produce lipopeptides. Furthermore, activities of defense-related enzymes were enhanced in wheat seedlings after inoculation with B.sorokiniana and treatment with CF, which showed induced resistance could be produced in wheat to resist pathogens. These results reveal that strain XZ34-1 is a promising candidate for application as a biological control agent against B.sorokiniana.
Wheat sheath blight is a soil-borne fungal disease caused by Rhizoctonia cerealis and is a serious threat to wheat worldwide. A microbial fungicide is a promising alternative to a chemical fungicide ...for wheat disease control. In this study, strain RB5 against R. cerealis was isolated from wheat rhizosphere soil, which was identified as Pseudomonas fluorescens according to physiological, biochemical, and 16S rRNA gene sequence analyses. For improving the antifungal activity of RB5, the response surface methodology (RSM) was used to optimize the culture conditions for strain RB5, and the optimal culture conditions are 8.7 g/L of cassava, 5.2 g/L of soybean meal, pH 6.8, a 218 r/min speed, a 31.5 °C temperature, and 54 h of culture time. The inhibition rate of the culture filtrate obtained under this culture condition was up to 79.06%. The investigation of action mechanism showed strain RB5 could produce protease, chitinase, and siderophore, and its culture filtrate disrupted the mycelial morphology and inhibited the activities of three cell-wall-degrading enzymes of R. cerealis. Furthermore, the pot experiment exhibited that RB5 significantly controlled the wheat sheath blight with an efficacy of 71.22%. The evaluation of toxicological safety on an animal indicated that the culture filtrate was safe on mice. Overall, the culture filtrate of RB5 is a very promising microbial fungicide for the control of wheat sheath blight.
Rhizoctonia cerealis is a worldwide soil-borne pathogenic fungus that significantly infects wheat and causes sharp eyespot in China. However, the biocontrol strains used for the control of ...Rhizoctonia cerealis are insufficient. In the present study, antagonistic strain B1302 from the rhizosphere of wheat were isolated and identified as Bacillus mojovensis based on their morphological, physiological, and biochemical characteristics, and their 16S rDNA sequence. Culture filtrate of strain B1302 had a broad antifungal spectrum. In order to improve the antifungal activity of B1302, response surface methodology (RSM) was used to optimize the culture conditions. The final medium composition and culture conditions were 13.2 g/L of wheat bran, 14.1 g/L of soybean meal, 224 r/min of rotation speed, 7.50 of initial pH, and 1.5 × 108 CFU/mL of inoculation amount at 35 °C for a culture duration of 72 h. B. mojavensis B1302 inhibited the hyphae growth of R.cerealis and produced hydrolytic enzymes (protease, chitinase, and glucanase), IAA, and had N-fixing potentiality and P-solubilisation capacity. It can also promote wheat seedling growth in potted plants. The disease incidence and index of wheat seedlings were consistent with the effect of commercial pesticides under treatment with culture filtrate. The biocontrol efficacy of culture filtrate was significant—up to 65.25%. An animal toxicological safety analysis suggested that culture filtrate was safe for use and could be developed into an effective microbial fungicide to control wheat sharp eyespot.
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