Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

Circular RNA vaccines against SARS-CoV-2 and emerging variants.

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

Mesophilic Argonaute-Mediated Polydisperse Droplet Biosensor for Amplification-Free, One-Pot, and Multiplexed Nucleic Acid Detection Using Deep Learning.

Detection of nucleic acids from a single multiplexed and amplification-free test is critical for ensuring food safety, clinical diagnostics, and environmental monitoring. In this study, we introduced a mesophilic Argonaute protein from Clostridium butyricum (CbAgo), which exhibits nucleic acid endonuclease activity, to achieve a programmable, amplification-free system (PASS) for rapid nucleic acid quantification at ambient temperatures in one pot. By using CbAgo-mediated binding with specific guide DNA (gDNA) and subsequent targeted cleavage of wild-type target DNAs complementary to gDNA, PASS can detect multiple foodborne pathogen DNA (<102 CFU/mL) simultaneously. The fluorescence signals were then transferred to polydisperse emulsions and analyzed by using deep learning. This simplifies the process and increases the suitability of polydisperse emulsions compared to traditional digital PCR, which requires homogeneous droplets for accurate detection. We believe that PASS has the potential to become a next-generation point-of-care digital nucleic acid detection method.

Solution-Processable Large-Area Black Phosphorus/Reduced Graphene Oxide Schottky Junction for High-Temperature Broadband Photodetectors.

2D materials-based broadband photodetectors have extensive applications in security monitoring and remote sensing fields, especially in supersonic aircraft that require reliable performance under extreme high-temperature conditions. However, the integration of large-area heterostructures with 2D materials often involves high-temperature deposition methods, and also limited options and size of substrates. Herein, a liquid-phase spin-coating method is presented based on the interface engineering to prepare larger-area Van der Waals heterojunctions of black phosphorus (BP)/reduced graphene oxide (RGO) films at room temperature on arbitrary substrates of any required size. Importantly, this method avoids the common requirement of high-temperature, and prevents the curling or stacking in 2D materials during the liquid-phase film formation. The BP/RGO films-based devices exhibit a wide spectral photo-response, ranging from the visible of 532 nm to infrared range of 2200 nm. Additionally, due to Van der Waals interface of Schottky junction, the array devices provide infrared detection at temperatures up to 400 K, with an outstanding photoresponsivity (R) of 12 A W-1 and a specific detectivity (D*) of ≈2.4 × 109 Jones. This work offers an efficient approach to fabricate large-area 2D Schottky junction films by solution-coating for high-temperature infrared photodetectors.

Metal-Organic Framework Based Mucoadhesive Nanodrugs for Multifunction Helicobacter Pylori Targeted Eradication, Inflammation Regulation and Gut Flora Protection.

The prevalence of drug-resistant bacteria presents a significant challenge to the antibiotic treatment of Helicobacter pylori (H. pylori), while traditional antimicrobial agents often suffer from shortcomings such as poor gastric retention, inadequate alleviation of inflammation, and significant adverse effects on the gut microbiota. Here, a selenized chitosan (CS-Se) modified bismuth-based metal-organic framework (Bi-MOF@CS-Se) nanodrug is reported that can target mucin through the charge interaction of the outer CS-Se layer to achieve mucosal adhesion and gastric retention. Additionally, the Bi-MOF@CS-Se can respond to gastric acid and pepsin degradation, and the exposed Bi-MOF exhibits excellent antibacterial properties against standard H. pylori as well as clinical antibiotic-resistant strains. Remarkably, the Bi-MOF@CS-Se effectively alleviates inflammation and excessive oxidative stress by regulating the expression of inflammatory factors and the production of reactive oxygen species (ROS), thereby exerting therapeutic effects against H. pylori infection. Importantly, this Bi-MOF@CS-Se nanodrug does not affect the homeostasis of gut microbiota, providing a promising strategy for efficient and safe treatment of H. pylori infection.

Climate and Environmental Variables Drive Stream Biofilm Bacterial and Fungal Diversity on Tropical Mountainsides.

High mountain freshwater systems are particularly sensitive to the impacts of global warming and relevant environmental changes. Microorganisms contribute substantially to biogeochemical processes, yet their distribution patterns and driving mechanism in alpine streams remain understudied. Here, we examined the bacterial and fungal community compositions in stream biofilm along the elevational gradient of 745-1874 m on Mt. Kilimanjaro and explored their alpha and beta diversity patterns and the underlying environmental drivers. We found that the species richness and evenness monotonically increased towards higher elevations for bacteria, while were non-significant for fungi. However, both bacterial and fungal communities showed consistent elevational distance-decay relationships, i.e., the dissimilarity of assemblage composition increased with greater elevational differences. Bacterial alpha diversity patterns were mainly affected by chemical variables such as total nitrogen and phosphorus, while fungi were affected by physical variables such as riparian shading and stream width. Notably, climatic variables such as mean annual temperature strongly affected the elevational succession of bacterial and fungal community compositions. Our study is the first exploration of microbial biodiversity and their underlying driving mechanisms for stream ecosystems in tropical alpine regions. Our findings provide insights on the response patterns of tropical aquatic microbial community composition and diversity under climate change.

Association of subclinical hypothyroidism with metabolic syndrome and its components among outpatients with first-episode drug-naïve major depressive disorder: a large-scale cross-sectional study.

Both metabolic syndrome (MetS) and subclinical hypothyroidism (SCH) are prevalent in major depressive disorder (MDD) patients. However, their relationship in this population remains unknown. The study assessed the association between SCH and MetS in 1706 first-episode drug-naïve (FEDN) MDD patients. We also compared the relationship between MetS and clinical symptoms in patients with and without comorbid SCH. The Positive and Negative Syndrome Scale positive subscale, the Hamilton Anxiety Rating Scale, and the Hamilton Depression Rating Scale were used to detect clinical symptoms. Serum levels of free triiodothyronine, free thyroxine, thyroid stimulating hormone (TSH), anti-thyroglobulin, thyroid peroxidases antibody, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and fasting glucose were measured. The Area Under the Curve (AUC) was used to test the performance of serum TSH in identifying MetS patients. The prevalence of MetS and SCH was 34.5% (n = 585) and 61% (n = 1034), respectively. The presence of SCH increased the risk of MetS, hyperglycemia, hypertension, obesity, and low HDL-C by 4.91, 3.51, 3.54, 2.02, and 2.34 times, respectively. Serum TSH had a nice ability to distinguish MetS patients from non-MetS patients (AUC value = 0.77). MetS and its components exhibited a positive association with clinical profiles only in SCH patients, but not in non-SCH patients. Taken together, our study suggested SCH was closely related to MetS and might play a vital role in the relationship between MetS and clinical symptoms. Regular thyroid function checks might help early detect MetS.

Employing Bayesian analysis to establish a cut-off point and assess stigma prevalence in substance use disorder: a comprehensive study of the Chinese version of the Substance Use Stigma Mechanism Scale.

PURPOSE: In China, individuals with substance use disorders (SUD) face severe stigma, but reliable stigma assessment tool is lacking. Therefore, this study aimed to validate the Chinese version of the Substance Use Stigma Mechanism Scale (SU-SMS-C) and set its cut-off point. METHODS: We recruited 1005 individuals with SUDs from Chinese rehabilitation centers. These participants completed a battery of questionnaires that included the SU-SMS-C, The Multidimensional Scale of Perceived Social Support (MSPSS), Center for Epidemiologic Studies Depression Scale (CES-D), General Self-Efficacy Scale (GSES), and Perceived Devaluation and Discrimination (PDD). Confirmatory factor analysis was used to assess the construct validity of the scale. Additionally, the Naive Bayes classifier was used to establish the cut-off point for the SU-SMS-C. We additionally explored the correlation between patient demographic characteristics and stigma. RESULTS: A confirmatory factor analysis was utilized, revealing a second-order five-factor model. Based on the Naive Bayes classifier, the area under the receiver operating characteristic (AUCROC) of 0.746, the cut-off point for the SU-SMS-C was established at 44.5. The prevalence of stigma observed in the study population was 49.05%. Significant disparities were observed in the distribution of stigma across genders, with males experiencing more pronounced stigma than females. Moreover, patients consuming different primary substances reported diverse levels of stigma. Notably, those primarily using heroin endured a higher degree of stigma than users of other substances. CONCLUSION: The study is the first to identify a cut-off point for the SU-SMS-C by Naive Bayes classifier, bridging a major gap in stigma measurement research. SU-SMS-C may help treat and manage SUDs by reducing stigma.

Molecular and Functional Characterization of Three General Odorant-Binding Protein 2 Genes in Cydia pomonella (Lepidoptera: Tortricidae).

General odorant-binding proteins (GOBPs) play a crucial role in the detection of host plant volatiles and pheromones by lepidopterans. Previous studies identified two duplications in the GOBP2 gene in Cydia pomonella. In this study, we employed qRT-PCR, protein purification, and fluorescence competitive binding assays to investigate the functions of three GOBP2 genes in C. pomonella. Our findings reveal that CpomGOBP2a and CpomGOBP2b are specifically highly expressed in antennae, while CpomGOBP2c exhibits high specific expression in wings, suggesting a potential divergence in their functions. Recombinant proteins of CpomGOBP2a, CpomGOBP2b, and CpomGOBP2c were successfully expressed and purified, enabling an in-depth exploration of their functions. Competitive binding assays with 20 host plant volatiles and the sex pheromone (codlemone) demonstrated that CpomGOBP2a exhibits strong binding to four compounds, namely butyl octanoate, ethyl (2E,4Z)-deca-2,4-dienoate (pear ester), codlemone, and geranylacetone, with corresponding dissolution constants (Ki) of 8.59993 µM, 9.14704 µM, 22.66298 µM, and 22.86923 µM, respectively. CpomGOBP2b showed specific binding to pear ester (Ki = 17.37481 µM), while CpomGOBP2c did not exhibit binding to any tested compounds. In conclusion, our results indicate a functional divergence among CpomGOBP2a, CpomGOBP2b, and CpomGOBP2c. These findings contribute valuable insights for the development of novel prevention and control technologies and enhance our understanding of the evolutionary mechanisms of olfactory genes in C. pomonella.

Recent Advances in Metabolic Engineering for the Biosynthesis of Phosphoenol Pyruvate-Oxaloacetate-Pyruvate-Derived Amino Acids.

The phosphoenol pyruvate-oxaloacetate-pyruvate-derived amino acids (POP-AAs) comprise native intermediates in cellular metabolism, within which the phosphoenol pyruvate-oxaloacetate-pyruvate (POP) node is the switch point among the major metabolic pathways existing in most living organisms. POP-AAs have widespread applications in the nutrition, food, and pharmaceutical industries. These amino acids have been predominantly produced in Escherichia coli and Corynebacterium glutamicum through microbial fermentation. With the rapid increase in market requirements, along with the global food shortage situation, the industrial production capacity of these two bacteria has encountered two bottlenecks: low product conversion efficiency and high cost of raw materials. Aiming to push forward the update and upgrade of engineered strains with higher yield and productivity, this paper presents a comprehensive summarization of the fundamental strategy of metabolic engineering techniques around phosphoenol pyruvate-oxaloacetate-pyruvate node for POP-AA production, including L-tryptophan, L-tyrosine, L-phenylalanine, L-valine, L-lysine, L-threonine, and L-isoleucine. Novel heterologous routes and regulation methods regarding the carbon flux redistribution in the POP node and the formation of amino acids should be taken into consideration to improve POP-AA production to approach maximum theoretical values. Furthermore, an outlook for future strategies of low-cost feedstock and energy utilization for developing amino acid overproducers is proposed.