Safety, tolerability, and immunogenicity of a CpG/Alum adjuvanted SARS-CoV-2 recombinant protein vaccine (ZR202-CoV) in healthy adults: Preliminary report of a phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial.

This was a phase 1 dose-escalation study of ZR202-CoV, a recombinant protein vaccine candidate containing a pre-fusion format of the spike (S)-protein (S-trimer) combined with the dual-adjuvant system of Alum/CpG. A total of 230 participants were screened and 72 healthy adults aged 18-59 years were enrolled and randomized to receive two doses at a 28-day interval of three different ZR202-CoV formulations or normal saline. We assessed the safety for 28 days after each vaccination and collected blood samples for immunogenicity evaluation. All formulations of ZR202-CoV were well-tolerated, with no observed solicited adverse events ≥ Grade 3 within 7 days after vaccination. No unsolicited adverse events ≥ Grade 3, or serious adverse events related to vaccination occurred as determined by the investigator. After the first dose, detectable immune responses were observed in all subjects. All subjects that received ZR202-CoV seroconverted at 14 days after the second dose by S-binding IgG antibody, pseudovirus and live-virus based neutralizing antibody assays. S-binding response (GMCs: 2708.7 ~ 4050.0 BAU/mL) and neutralizing activity by pseudovirus (GMCs: 363.1 ~ 627.0 IU/mL) and live virus SARS-CoV-2 (GMT: 101.7 ~ 175.0) peaked at 14 days after the second dose of ZR202-CoV. The magnitudes of immune responses compared favorably with COVID-19 vaccines with reported protective efficacy.

LNCGM1082-mediated NLRC4 activation drives resistance to bacterial infection.

The activation of NLRC4 is a major host response against intracellular bacteria infection. However, NLRC4 activation after a host senses diverse stimuli is difficult to understand. Here, we found that the lncRNA LNCGM1082 plays a critical role in the activation of NLRC4. LNCGM1082 in macrophages affects the maturation of interleukin (IL)-1ß and pyroptotic cell death only after exposure to an NLRC4 ligand. Similar to NLRC4-/- mice, LNCGM1082-/- mice were highly sensitive to Salmonella Typhimurium (S. T) infection. LNCGM1082 deficiency in mouse or human macrophages inhibited IL-1ß maturation and pyroptosis. Mechanistically, LNCGM1082 induced the binding of PKCδ with NLRC4 in both mice and humans. In contrast, NLRC4 did not bind PKCδ in LNCGM1082-/- macrophages. The activity of the lncRNA LNCGM1082 induced by S. T may be mediated through TLR5 in the macrophages of both mice and humans. In summary, our data indicate that TLR5-mediated LNCGM1082 activity can promote the binding of PKCδ with NLRC4 to activate NLRC4 and induce resistance to bacterial infection.

FABP4 in Paneth cells regulates antimicrobial protein expression to reprogram gut microbiota.

Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4fl/flpvillinCreT mice were highly resistance to Salmonella Typhimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes (F/B) ratio in FABP4fl/flpvillinCreT mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.Abbreviations: FABP4: Fatty acid binding protein 4; S. T: Salmonella Typhimurium; HFD: High-fat diet; Defa: α-defensin; 930 HD5: Human α-defensin 5; HD6: Human α-defensin 6; F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentous bacteria; AMPs: Antimicrobial peptides; PPARγ: Peroxisome proliferator-activated receptor γ; P-PPAR: Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935 EGF: Epidermal growth factor; ENR: Noggin and R-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme 1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2, group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE: Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940 acid; GPR40: G-protein-coupled receptor; GF: Germ-free; EGF: Epidermal growth factor; LP: Lamina propria; KO: Knock out; WT: Wild-type.

Development of real-time PCR and droplet digital PCR based marker for the detection of Tilletia caries inciting common bunt of wheat.

This is the first study reporting droplet digital PCR and quantitative real time PCR for detection of Tilletia caries (syn. T. tritici), which causes common bunt of wheat and leads to yield losses of 80% in many wheat growing areas worldwide. To establish an accurate, rapid and quantifiable detection method, we tested 100 inter simple sequence repeats (ISSR) primers and obtained a species-specific fragment (515 bp) generated by ISSR 827. Then, a specific 266 bp band for the sequence characterized amplified region (SCAR) marker was produced from T. caries. The detection limit reached 50 pg/µL. Based on the SCAR marker, we further developed a higher sensitivity of quantitative real time-polymerase chain reaction (qRT-PCR) with a detection limit of 2.4 fg/µL, and droplet digital PCR (ddPCR) with a detection limit of 0.24 fg/µL. Both methods greatly improved the detection sensitivity of T. caries, which will be contribute a lot for quickly and accurately detection of T. caries, which causes wheat common bunt.

Gut microbiota-derived metabolite 3-idoleacetic acid together with LPS induces IL-35+ B cell generation.

BACKGROUND: IL-35-producing Bregs and Treg cells critically regulate chronic illnesses worldwide via mechanisms related to disrupting the gut microbiota composition. However, whether the gut microbiota regulates these IL-35+ cells remains elusive. We herein investigated the regulatory effects of the gut microbiota on IL-35+ cells by using genetically modified mouse models of obesity. RESULTS: We first found that gut Reg4 promoted resistance to high-fat diet-induced obesity. Using 16S rRNA sequencing combined with LC-MS (liquid chromatography-mass spectrometry)/MS, we demonstrated that gut Reg4 associated with bacteria such as Lactobacillus promoted the generation of IL-35+ B cells through 3-idoleacetic acid (IAA) in the presence of LPS. HuREG4IECtg mice fed a high-fat diet exhibited marked IL-35+ cell accumulation in not only their adipose tissues but also their colons, whereas decreased IL-35+ cell accumulation was observed in the adipose and colon tissues of Reg4 knockout (KO) mice. We also found that Reg4 mediated HFD-induced obesity resistance via IL-35. Lower levels of IAA were also detected in the peripheral blood of individuals with obesity compared with nonobese subjects. Mechanistically, IAA together with LPS mediated IL-35+ B cells through PXR and TLR4. KO of PXR or TLR4 impaired the generation of IL-35+ B cells. CONCLUSION: Together, IAA and LPS induce the generation of IL-35+ B cells through PXR and TLR4. Video Abstract.

[Characteristics and Ecological Risk Assessment of POPs Pollution in Sediments of Xiaoxingkai Lake in the Northeast China].

The pollution characteristics of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and phthalate esters (PAEs) in the surface sediments of Xiaoxingkai Lake were analyzed by GC-MS, and the main sources and biological toxicity risks of the pollutants were discussed. The results show that:① The content of PAHs in the sediments of xiaoxingkai lake ranged from 82.1 to 534.6 ng·g-1, and the concentration of PAHs in the northwestern port of the lake was higher. The content of OCPs and PAEs in the sediments ranged from 4.8 to 50.4 ng·g-1 and 33.3 to 401.6 ng·g-1, respectively. The concentration was higher in the southeastern lakes. ② PAHs in the sediments were dominated by 3-5-ring compounds (accounting for more than 85%), which were mainly combustion sources, among which the combustion of coal and firewood contributed 47%, the combustion of gasoline and diesel contributed 39%, and the oil product leakage contributed 14%. The OCPs were mainly HCHs (78%) from the use of new lindane and the input of a small amount of industrial HCHs. The PAEs were mainly dibutyl phthalate (DBP) and diethyl phthalate (2-ethyl hexyl) ester (DEHP; 94%), which were mainly derived from household garbage and common human articles. ③ Compared with other lakes in China, PAHs and PAEs in the sediments of Xiaoxingkai Lake are at a low pollution level, and there is no ecological risk at present, but some OCPs at some points present a moderate ecological risk.

LncRNA lncLy6C induced by microbiota metabolite butyrate promotes differentiation of Ly6Chigh to Ly6Cint/neg macrophages through lncLy6C/C/EBPß/Nr4A1 axis.

Macrophages are mainly divided into two populations, which play a different role in physiological and pathological conditions. The differentiation of these cells may be regulated by transcription factors. However, it is unclear how to modulate these transcription factors to affect differentiation of these cells. Here, we found that lncLy6C, a novel ultraconserved lncRNA, promotes differentiation of Ly6Chigh inflammatory monocytes into Ly6Clow/neg resident macrophages. We demonstrate that gut microbiota metabolites butyrate upregulates the expression of lncLy6C. LncLy6C deficient mice had markedly increased Ly6Chigh pro-inflammatory monocytes and reduced Ly6Cneg resident macrophages. LncLy6C not only bound with transcription factor C/EBPß but also bound with multiple lysine methyltransferases of H3K4me3 to specifically promote the enrichment of C/EBPß and H3K4me3 marks on the promoter region of Nr4A1, which can promote Ly6Chigh into Ly6Cneg macrophages. As a result, lncLy6C causes the upregulation of Nr4A1 to promote Ly6Chigh inflammatory monocytes to differentiate into Ly6Cint/neg resident macrophages.

Reg4 and complement factor D prevent the overgrowth of E. coli in the mouse gut.

The expansion of Enterobacteriaceae, such as E. coli is a main characteristic of gut inflammation and is related to multiple human diseases. However, how to control these E. coli overgrowth is not well understood. Here, we demonstrate that gut complement factor D (CFD) plays an important role in eliminating E. coli. Increased E. coli, which could stimulate inflammatory macrophages to induce colitis, were found in the gut of CFD deficient mice. We also showed that gut Reg4, which is expressed in gut epithelial cells, stimulated complement-mediated attack complexes to eliminate E. coli. Reg4 deficient mice also had increased E. coli. The dominant E. coli were isolated from colitis tissues of mice and found to be sensitive to both CFD- and Reg4-mediated attack complexes. Thus, gut Reg4- and CFD-mediated membrane attack complexes may maintain gut homeostasis by killing inflammatory E. coli.

Flexible Functional Surface for Efficient Water Collection.

Inspired by both the water collection strategy of desert beetles and the lubrication effect of Nepenthes pitcher plants, a new flexible functional surface for water collection is designed and can be easily fabricated. Such a functional surface consists mainly of a superhydrophobic region and a hydrophobic region with infused lubricating oil. Different functional patterns can be easily manipulated by different templates. Due to the flexibility of the surface, not only a two-dimensional surface but also a three-dimensional one can be designed. Directional water collection can be achieved. Furthermore, it is an integrative bioinspired functional surface that does not require any tailoring. Compared with existing functional surfaces, the present surface has higher water collection efficiency in fog and such a function can last 15 days. The functional degraded surfaces can also be easily reused.

Weather-Manipulated Smart Broadband Electromagnetic Metamaterials.

Smart materials and structures with tunable electromagnetic (EM) properties are highly demanded for active environmental sensitive systems. As polar molecules in the environment, in this work, water and ice are utilized as wetting and freezing conditions to manipulate the electromagnetic response behaviors in a graphene-based composite material, aiming to achieve a smart weather-manipulated EM metamaterial. Owing to the introduced polar water and ice phase in the self-assembled porous electromagnetic attenuating networks, energy consumption of EM waves is significantly altered via multiple scattering of polar induced interfaces. In frozen conditions, a wide absorption band (2-18 GHz) with efficient absorption (reflection loss < -10 dB) has been obtained. Additionally, the mechanical feature of the as-assembled metamaterials could also be manipulated via altering the weather conditions in terms of changing the phase of the introduced water. Interestingly, the mechanical properties could be massively changed while the broadband absorption capability has rarely been impacted. Implication of the results highlights an efficient method for fabricating smart EM metamaterials that are capable of being manipulated by the environment.

Constructing Repairable Meta-Structures of Ultra-Broad-Band Electromagnetic Absorption from Three-Dimensional Printed Patterned Shells.

Ultra-broad-band electromagnetic absorption materials and structures are increasingly attractive for their critical role in competing with the advanced broad-band electromagnetic detection systems. Mechanically soft and weak wax-based materials composites are known to be insufficient to serve in practical electromagnetic absorption applications. To break through such barriers, here we developed an innovative strategy to enable the wax-based composites to be robust and repairable meta-structures by employing a three-dimensional (3D) printed polymeric patterned shell. Because of the integrated merits from both the dielectric loss wax-based composites and mechanically robust 3D printed shells, the as-fabricated meta-structures enable bear mechanical collision and compression, coupled with ultra-broad-band absorption (7-40 and 75-110 GHz, reflection loss  smaller than -10 dB) approaching state-of-the-art electromagnetic absorption materials. With the assistance of experiment and simulation methods, the design advantages and mechanism of employing such 3D printed shells for substantially promoting the electromagnetic absorption performance have been demonstrated. Therefore, such universal strategy that could be widely extended to other categories of wax-based composites highlights a smart stage on which high-performance practical multifunction meta-structures with ultra-broad-band electromagnetic absorption could be envisaged.

Graphene-Based Sandwich Structures for Frequency Selectable Electromagnetic Shielding.

Due to substantial development of electronics and telecommunication techniques, materials with electromagnetic interference (EMI) shielding performance are significant in alleviating the interference impacts induced from a remarkable variety of devices. In the work, we propose novel sandwich structures for manipulating the EM wave transport, which holds unique EMI shielding features of frequency selectivity. By employing electrical and magnetic loss spacers, the resultant sandwich structures are endowed with tunable EMI shielding performance, showing substantial improvements in overall shielding effectiveness along with pronounced shielding peak shift. The mechanisms suggest that the multiple interfaces, electromagnetic loss media, and changes of representative EM wavelength could be critical roles in tailoring the EMI shielding performance. The results provide a versatile strategy that could be extended in other frequency ranges and various types of sandwich structures, promising great opportunities for designing and fabricating advanced electromagnetic attenuation materials and devices.

Effect of relative humidity on the peeling behavior of a thin film on a rigid substrate.

Inspired by gecko adhesion in humid environments, a modified Kendall's model is established in order to investigate the effect of relative humidity on the interfacial peeling behavior of a thin film adhering on a rigid substrate. When the humidity is less than 90%, a monolayer of water molecules adsorbed on the substrate surface induces a strong disjoining pressure at the interface. As a result, the steady-state peel-off force between the thin film and substrate is significantly enhanced. When the humidity is greater than 90%, water molecules condense into water droplets. Four different peeling models are established on this occasion, depending on the surface wettability of the film and substrate. It is found that the steady-state peel-off force is influenced by the water meniscus in a complicated manner, which is either enhanced or reduced by the water capillarity comparing to that predicted by the classical Kendall's model, i.e., a dry peeling model. It should be noted that, at the vicinity of the wetting transition, the peel-off force of the four models can be reduced to an identical one, which means the four peeling models can transit from one to another continuously. The present model, as an extension of the classical Kendall's one, should be useful not only for understanding gecko adhesion in humid environments, but also for analyzing interface behaviors of a film-substrate system in real applications.