Efficacy, immunogenicity, and safety of a monovalent mRNA vaccine, ABO1020, in adults: A randomized, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ABO1020 is a monovalent COVID-19 mRNA vaccine. Results from a phase 1 trial showed ABO1020 was safe and well tolerated, and phase 3 trials to evaluate the efficacy, immunogenicity, and safety of ABO1020 in healthy adults are urgently needed. METHODS: We conducted a multinational, randomized, placebo-controlled, double-blind, phase 3 trial among healthy adults (ClinicalTrials.gov: NCT05636319). Participants were randomly assigned (1:1) to receive either 2 doses of ABO1020 (15 µg per dose) or placebo, administered 28 days apart. The primary endpoint was the vaccine efficacy in preventing symptomatic COVID-19 cases that occurred at least 14 days post-full vaccination. The second endpoint included the neutralizing antibody titers against Omicron BA.5 and XBB and safety assessments. FINDINGS: A total of 14,138 participants were randomly assigned to receive either vaccine or placebo (7,069 participants in each group). A total of 366 symptomatic COVID-19 cases were confirmed 14 days after the second dose among 93 participants in the ABO1020 group and 273 participants in the placebo group, yielding a vaccine efficacy of 66.18% (95% confidence interval: 57.21-73.27, p < 0.0001). A single dose or two doses of ABO1020 elicited potent neutralizing antibodies against both BA.5 and XBB.1.5. The safety profile of ABO1020 was characterized by transient, mild-to-moderate fever, pain at the injection site, and headache. CONCLUSION: ABO1020 was well tolerated and conferred 66.18% protection against symptomatic COVID-19 in adults. FUNDING: National Key Research and Development Project of China, Innovation Fund for Medical Sciences from the CAMS, National Natural Science Foundation of China.

Blood mercury mediates the associations between fish consumption and serum uric acid levels among Chinese adults: A nationally representative study.

Fish consumption can increase purine load in human body, and the enrichment of mercury in fish may affect the glomerular filtration function, both resulting in increased serum uric acid (SUA) levels. The data of blood mercury (BHg), fish consumption frequency and SUA levels of 7653 participants aged 18 years or older was from China National Human Biomonitoring (2017-2018). The associations between fish consumption frequency, ln-transformed BHg and SUA levels were explored through weighted multiple linear regressions. The mediating effect of BHg levels between fish consumption frequency and SUA levels was evaluated by mediation analysis. We found that both the fish consumption frequency and BHg were positively associated with SUA levels in both sexes. Compared to participants who had never consumed fish, participants who consumed fish once a week or more had higher SUA levels [ß (95% confidence interval, CI): 20.39 (2.16, 38.62) in males; ß (95% CI): 10.06 (0.76, 19.37) in females] and ln-transformed BHg [ß (95% CI): 0.97 (0.61, 1.34) in males; ß (95% CI): 0.84 (0.63, 1.05) in females]. Each 1-unit increase in ln-transformed BHg, the SUA levels rose by 4.78 (95% CI: 0.01, 9.54) µmol/L for males and 3.81 (95% CI: 1.60, 6.03) µmol/L for females. The association between fish consumption with SUA levels was mediated by ln-transformed BHg with the percent mediated of 34.66% in males and 26.58% in females. It revealed that BHg played mediating roles in the elevation of SUA levels caused by fish consumption. This study's findings could promote the government to intervene in mercury pollution in fish, so as to ensure the safety of fish consumption.

Flexible Substrate-Compatible and Efficiency-Improved Quantum-Dot Light-Emitting Diodes with Reduced Annealing Temperature of NiOx Hole-Injecting Layer.

The growing demand for wearable and attachable displays has sparked significant interest in flexible quantum-dot light-emitting diodes (QLEDs). However, the challenges of fabricating and operating QLEDs on flexible substrates persist due to the lack of stable and low-temperature processable charge-injection/-transporting layers with aligned energy levels. In this study, we utilized NiOx nanoparticles that are compatible with flexible substrates as a hole-injection layer (HIL). To enhance the work function of the NiOx HIL, we introduced a self-assembled dipole modifier called 4-(trifluoromethyl)benzoic acid (4-CF3-BA) onto the surface of the NiOx nanoparticles. The incorporation of the dipole molecules through adsorption treatment has significantly changed the wettability and electronic characteristics of NiOx nanoparticles, resulting in the formation of NiO(OH) at the interface and a shift in vacuum level. The alteration of surface electronic states of the NiOx nanoparticles not only improves the carrier balance by reducing the hole injection barrier but also prevents exciton quenching by passivating defects in the film. Consequently, the NiOx-based red QLEDs with interfacial modification demonstrate a maximum current efficiency of 16.1 cd/A and a peak external quantum efficiency of 10.3%. This represents a nearly twofold efficiency enhancement compared to control devices. The mild fabrication requirements and low annealing temperatures suggest potential applications of dipole molecule-modified NiOx nanoparticles in flexible optoelectronic devices.

Tolerance of Perovskite Solar Cells to Electrostatic Discharge in Martian Dust Activities.

In exploring the viability of perovskite solar cells (PSCs) for Mars missions, our study first delved into their temperature endurance in conditions mimicking the Martian climate, revealing remarkable thermal stability within the temperature range of 173-303 K. We then pioneered the examination of PSC resilience to electrostatic discharge (ESD), a critical factor given the frequent Martian dust activities. In a custom-built Martian simulation chamber, we discovered that ESD exposure dramatically reduced the power conversion efficiency of these devices by more than half (55.4%) in just 90 s. This groundbreaking research not only advances our understanding of the potential of PSCs for Mars exploration but also opens new avenues for optimizing solar technology in extreme environments.

Regulation of Glandular Size and Phytoalexin Biosynthesis by a Negative Feedback Loop in Cotton.

Plants have evolved diverse defense mechanisms encompassing physical and chemical barriers. Cotton pigment glands are known for containing various defense metabolites, but the precise regulation of gland size to modulate defense compound levels remains enigmatic. Here, it is discovered that the VQ domain-containing protein JAVL negatively regulates pigment gland size and the biosynthesis of defense compounds, while the MYC2-like transcription factor GoPGF has the opposite effect. Notably, GoPGF directly activates the expression of JAVL, whereas JAVL suppresses GoPGF transcription, establishing a negative feedback loop that maintains the expression homeostasis between GoPGF and JAVL. Furthermore, it is observed that JAVL negatively regulates jasmonate levels by inhibiting the expression of jasmonate biosynthetic genes and interacting with GoPGF to attenuate its activation effects, thereby maintaining homeostatic regulation of jasmonate levels. The increased expression ratio of GoPGF to JAVL leads to enlarged pigment glands and elevated jasmonates and defense compounds, enhancing insect and pathogen resistance in cotton. These findings unveil a new mechanism for regulating gland size and secondary metabolites biosynthesis, providing innovative strategies for strengthening plant defense.

SDPR expression in human trabecular meshwork and its potential role in racial disparities of glaucoma.

In order to identify how differential gene expression in the trabecular meshwork (TM) contributes to racial disparities of caveolar protein expression, TM dysfunction and development of primary open angle glaucoma (POAG), RNA sequencing was performed to compare TM tissue obtained from White and Black POAG surgical (trabeculectomy) specimens. Healthy donor TM tissue from White and Black donors was analyzed by PCR, qPCR, immunohistochemistry staining, and Western blot to evaluate SDPR (serum deprivation protein response; Cavin 2) and CAV1/CAV2 (Caveolin 1/Caveolin 2). Standard transmission electron microscopy (TEM) and immunogold labeled studies were performed. RNA sequencing demonstrated reduced SDPR expression in TM from Black vs White POAG patients' surgical specimens, with no significant expression differences in other caveolae-associated genes, confirmed by qPCR analysis. No racial differences in SDPR gene expression were noted in healthy donor tissue by PCR analysis, but there was greater expression as compared to specimens from patients with glaucoma. Analysis of SDPR protein expression confirmed specific expression in the TM regions, but not in adjacent tissues. TEM studies of TM specimens from healthy donors did not demonstrate any racial differences in caveolar morphology, but a significant reduction of caveolae with normal morphology and immuno-gold staining of SDPR were noted in glaucomatous TM as compared to TM from healthy donors. Linkage of SDPR expression levels in TM, POAG development, and caveolar ultrastructural morphology may provide the basis for a novel pathway of exploration of the pathologic mechanisms of glaucoma. Differential gene expression of SDPR in TM from Black vs White subjects with glaucoma may further our understanding of the important public health implications of the racial disparities of this blinding disease.

NanoMUD: Profiling of pseudouridine and N1-methylpseudouridine using Oxford Nanopore direct RNA sequencing.

Nanopore direct RNA sequencing provided a promising solution for unraveling the landscapes of modifications on single RNA molecules. Here, we proposed NanoMUD, a computational framework for predicting the RNA pseudouridine modification (Ψ) and its methylated analog N1-methylpseudouridine (m1Ψ), which have critical application in mRNA vaccination, at single-base and single-molecule resolution from direct RNA sequencing data. Electric signal features were fed into a bidirectional LSTM neural network to achieve improved accuracy and predictive capabilities. Motif-specific models (NNUNN, N = A, C, U or G) were trained based on features extracted from designed dataset and achieved superior performance on molecule-level modification prediction (Ψ models: min AUC = 0.86, max AUC = 0.99; m1Ψ models: min AUC = 0.87, max AUC = 0.99). We then aggregated read-level predictions for site stoichiometry estimation. Given the observed sequence-dependent bias in model performance, we trained regression models based on the distribution of modification probabilities for sites with known stoichiometry. The distribution-based site stoichiometry estimation method allows unbiased comparison between different contexts. To demonstrate the feasibility of our work, three case studies on both in vitro and in vivo transcribed RNAs were presented. NanoMUD will make a powerful tool to facilitate the research on modified therapeutic IVT RNAs and provides useful insight to the landscape and stoichiometry of pseudouridine and N1-pseudouridine on in vivo transcribed RNA species.

Advancing skeletal health and disease research with single-cell RNA sequencing.

Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

The proteomic landscape of fall armyworm oral secretion reveals its role in plant adaptation.

BACKGROUND: The fall armyworm (FAW, Spodoptera frugiperda (J.E. Smith)) is a polyphagous agricultural pest with rapidly evolving adaptations to host plants. We found the oral secretion (OS) of FAW from different plants influences plant defense response differentially, suggesting its role in adapting to host plants. However, the protein expression profile of FAW OS respond to different plants is largely unknown. RESULTS: Here, from the mass spectrometry assay, we identified a total of 256 proteins in the OS of FAW fed on cotton (Gossypium hirsutum L.), tobacco (Nicotiana benthamiana Domin), maize (Zea mays L.) and artificial diet. The FAW OS primarily comprise of 60 proteases, 32 esterases and 92 non-enzymatic proteins. It displays high plasticity across different diets. We found that more than half of the esterases are lipases which have been reported as insect elicitors to enhance plant defense response. The lipase accumulation in cotton-fed larvae was the highest, followed by maize-fed larvae. In the presence of lipase inhibitors, the enhanced induction on defense genes in wounded leaves by OS was attenuated. However, the putative effectors were most highly accumulated in the OS from FAW larvae fed on maize compared to those fed on other diets. We identified that one of them (VRLP4) reduces the OS-mediated induction on defense genes in wounded leaves. CONCLUSION: Together, our investigation presents the proteomic landscape of the OS of FAW influenced by different diets and reveals diet-mediated plasticity of OS is involved in FAW adaptation to host plants. © 2024 Society of Chemical Industry.

Plantaginis semen ameliorates diabetic kidney disease via targeting the sphingosine kinase 1/sphingosine-1-phosphate pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Plantaginis Semen (PS) is widely utilized as a common herb in several Asian countries, particularly China, due to its diuretic, anti-hypertensive, anti-hyperlipidemic, and anti-hyperglycemic properties. Furthermore, it is acknowledged for its ability to mitigate renal complications associated with metabolic syndrome. Despite its extensive usage, there is limited systematic literature elucidating its therapeutic mechanisms, thus emphasizing the necessity for comprehensive investigations in this field. AIM: This study aims to comprehensively evaluate the therapeutical potential of PS in treating diabetic kidney disease (DKD) and to elucidate the underlying mechanisms through in vivo and in vitro models. METHODS: The main composition of PS were characterized using the UPLC-QTOF-MS method. For the in vivo investigation, a mouse model mediated by streptozocin (STZ) associated with a high-fat diet (HFD) and unilateral renal excision was established. The mice were split into 6 groups (n = 8): control group (CON group), DKD group, low-dose of Plantago asiatica L. seed extract group (PASE-L group, 3 g/kg/d), medium-dose of PASE group (PASE-M, 6 g/kg/d), high-dose of PASE group (PASE-H, 9 g/kg/d), and positive drug group (valsartan, VAS group, 12 mg/kg/d). After 8 weeks of treatment, the damage induced by DKD was evaluated by using relevant parameters of urine and blood. Furthermore, indicators of inflammation and factors associated with the SphK1-S1P signaling pathway were investigated. For the in vitro study, the cell line HBZY-1 was stimulated by high glucose (HG), they were then co-cultured with different concentrations of PASE, and the corresponding associated inflammatory and sphingosine kinase 1/sphingosine-1-phosphate (SphK1-S1P) factors were examined. RESULTS: A total of 59 major components in PS were identified, including flavonoids, iridoids, phenylethanol glycosides, guanidine derivatives, and fatty acids. In the mouse model, PS was found to significantly improve body weight, decrease fasting blood glucose (FBG) levels, increased glucose tolerance and insulin tolerance, improved kidney-related markers compared to the DKD group, pathological changes in the kidneys also improved dramatically. These effects showed a dose-dependent relationship, with higher PASE concentrations yielding significantly better outcomes than lower concentrations. However, the effects of the low PASE concentration were not evident for some indicators. In the cellular model, the high dose of PASE suppressed high glucose (HG) stimulated renal mesangial cell proliferation, suppressed inflammatory factors and NF-κB, and decreased the levels of fibrillin-1(FN-1) and collagen IV(ColIV). CONCLUSION: Our results indicate that PS exerts favorable therapeutic effects on DKD, with the possible mechanisms including the inhibition of inflammatory pathways, suppression of mRNA levels and protein expressions of SphK1 and S1P, consequently leading to reduced overexpression of FN-1 and ColIV, thereby warranting further exploration.

Identification of hub genes in calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is a heart valve disorder characterized primarily by calcification of the aortic valve, resulting in stiffness and dysfunction of the valve. CAVD is prevalent among aging populations and is linked to factors such as hypertension, dyslipidemia, tobacco use, and genetic predisposition, and can result in becoming a growing economic and health burden. Once aortic valve calcification occurs, it will inevitably progress to aortic stenosis. At present, there are no medications available that have demonstrated effectiveness in managing or delaying the progression of the disease. In this study, we mined four publicly available microarray datasets (GSE12644 GSE51472, GSE77287, GSE233819) associated with CAVD from the GEO database with the aim of identifying hub genes associated with the occurrence of CAVD and searching for possible biological targets for the early prevention and diagnosis of CAVD. This study provides preliminary evidence for therapeutic and preventive targets for CAVD and may provide a solid foundation for subsequent biological studies.

Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.

Perovskite Single Crystals by Vacuum Evaporation Crystallization.

Perovskite single crystals have attracted tremendous attention owing to their excellent optoelectronic properties and stability compared to typical multicrystal structures. However, the growth of high-quality perovskite single crystals (PSCs) generally relies on temperature gradients or the introduction of additives to promote crystal growth. In this study, a vacuum evaporation crystallization technique is developed that allows PSCs to be grown under extremely stable conditions at constant temperature and without requiring additives to promote crystal growth. The new method enables the growth of PSCs of unprecedented quality, that is, MAPbBr3 single crystals that exhibit an ultranarrow full width at half maximum of 0.00701°, which surpasses that of all previously reported values. In addition, the MAPbBr3 single crystals deliver exceptional optoelectronic performance, including a long carrier lifetime of 1006 ns, an ultralow trap-state density of 3.67 × 109 cm-3, and an ultrahigh carrier mobility of 185.86 cm2 V-1 s-1. This method is applicable to various types of PSCs, including organic-inorganic hybrids, fully inorganic structures, and low-dimensional structures.

Identification of Treg-related prognostic molecular subtypes and individualized characteristics in clear cell renal cell carcinoma through single-cell transcriptomes and bulk RNA sequencing.

BACKGROUND: In clear cell renal cell carcinoma (ccRCC), the role of Regulatory T cells (Treg cells) as prognostic and immunotherapy response predictors is not fully explored. METHODS: Analyzing renal clear cell carcinoma datasets from TISCH, TCGA, and GEO, we focused on 8 prognostic Treg genes to study patient subtypes in ccRCC. We assessed Treg subtypes in relation to patient prognosis, tumor microenvironment, metabolism. Using Cox regression and principal component analysis, we devised Treg scores for individual patient characterization and explored the molecular role of C1QL1, a critical gene in the Treg model, through in vivo and in vitro studies. RESULTS: Eight Treg-associated prognostic genes were identified, classifying ccRCC patients into cluster A and B. Cluster A patients showed poorer prognosis with distinct clinical and molecular profiles, potentially benefiting more from immunotherapy. Low Treg scores correlated with worse outcomes and clinical progression. Low scores also suggested that patients might respond better to immunotherapy and targeted therapies. In ccRCC, C1QL1 knockdown reduced tumor proliferation and invasion via NF-kb-EMT pathways and decreased Treg cell infiltration, enhancing immune efficacy. CONCLUSIONS: The molecular subtype and Treg score in ccRCC, based on Treg cell marker genes, are crucial in personalizing ccRCC treatment and underscore C1QL1's potential as a tumor biomarker and target for immunotherapy.

Few-cycle laser pulse characterization on-target using high-harmonic generation from nano-scale solids.

We demonstrate high-harmonic generation for the time-domain observation of the electric field (HHG-TOE) and use it to measure the waveform of ultrashort mid-infrared (MIR) laser pulses interacting with ZnO thin-films or WS2 monolayers. The working principle relies on perturbing HHG in solids with a weak replica of the pump pulse. We measure the duration of few-cycle pulses at 3200 nm, in reasonable agreement with the results of established pulse characterization techniques. Our method provides a straightforward approach to accurately characterize femtosecond laser pulses used for HHG experiments right at the point of interaction.