The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis.

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.

Spectroscopy and efficient dual-wavelength laser performances of a Nd:GYSAG crystal.

We reported on the spectral properties and dual-wavelength laser performances of a novel, to the best of our knowledge, Nd:Gd1.8Y1.2ScAl4O12 (Nd:GYSAG) crystal for the first time. The absorption spectra, emission spectra, and fluorescence lifetime were systematically investigated. Further, a continuous-wavelength (CW) laser output power up to 5.02 W was obtained under an absorbed pump power of 9.45 W with slope and optical-to-optical efficiencies of 59.4% and 53.1%, respectively, at 1061.2 and 1063.2 nm. A stable passively Q-switched (PQS) laser employing Cr:YAG as a saturable absorber (SA) was realized. The maximum average output power of 0.756 W with a slope of near 34.4% was obtained with the pulse width, pulse energy, and peak power of 14.0 ns, 128.1 µJ, and 9.15 kW, respectively. The results indicate that the Nd:GYSAG crystal is an excellent laser medium for generating a high-efficiency dual-wavelength laser and has potential in terahertz (THz) laser generation.

Yb:GdScO3 crystal for efficient ultrashort pulse lasers.

We present, to the best of our knowledge, the first demonstration of thermal, optical, and laser properties of Yb:GdScO3 for potentially efficient ultrashort pulse lasers. The stimulated emission cross section at 1025 nm (E//c) is 0.46×10-20cm2 with the emission band width of 85 nm, even broader than the well-known Yb:CaGdAlO4. It has quite a high thermal conductivity of 5.54W/(m⋅K) at 50°C, comparable with Yb:YAG. In the continuous-wave regime, the maximum output power of 13.45 W at 1063.9 nm was generated with the optical-to-optical efficiency of 63.3%. These results suggest that the Yb:GdScO3 crystal is a promising candidate for ultrashort pulse lasers.

Regulatory T Cells: Concept, Classification, Phenotype, and Biological Characteristics.

Regulatory T cells (Treg) play an indispensable role in maintaining the body's immune nonresponse to self-antigens and suppressing the body's unwarranted and potentially harmful immune responses. Their absence, reduction, dysfunction, transformation, and instability can lead to numerous autoimmune diseases. There are several distinct subtypes of the Treg cells, although they share certain biological characteristics and have unique phenotypes with different regulatory functions, as well as mechanistic abilities. In this book chapter, we introduce the latest advances in Treg cell subtypes pertaining to classification, phenotype, biological characteristics, and mechanisms. We also highlight the relationship between Treg cells and various diseases, including autoimmune, infectious, as well as tumors and organ transplants.

Eliminating imidacloprid and its toxicity by permanganate via highly selective partial oxidation.

Imidacloprid is a widely used neonicotinoid insecticide worldwide, and has attracted great concerns due to its potential threat to human and environment. Much effort was thus spent on developing the effective way for removing imidacloprid from water, but might also produce various degradation products with unknown risks. The hypothesis was then proposed that permanganate oxidation was probably the appropriate tool for eliminating imidacloprid and its toxicity through selective oxidation of specific groups. To that end, we studied the kinetics of permanganate/imidacloprid reaction by considering the effects of pH (5.0-9.0), temperature (15-35 °C), ionization strength (0.05-0.20 M), typical anions (Cl-, Br-, I-) and humic acid. Based on the identified products from mass spectrometer, the main reaction pathway was found to be the hydroxylation of C-H bond at imidazole ring, leading to the decreased toxicity evaluated by ECOSAR program. Our results demonstrate that permanganate oxidation should be a very promising technique for controlling imidacloprid contamination by effective detoxification through highly selective partial oxidation. Moreover, this study has also paved the way toward applying permanganate oxidation for in situ chemical remediation of imidacloprid, though the corresponding standards need to be established in advance.

Power scaling of the self-frequency-doubled quasi-two-level Yb:YCOB laser with a 30% slope efficiency.

The lab-on-chip integration of photonic devices has been attracting increasing attention recently. Multifunctional materials provide natural platforms for the desirable performance by the coupling of different functionalities. The insufficient coupling efficiency of the laser and nonlinear processes in self-frequency-doubled (SFD) lasers is the limiting factor for the output power and further practical applications. Here we demonstrate a SFD Yb3+-doped calcium yttrium oxoborate (Yb:YCOB) crystal laser with an unprecedented slope efficiency of 30% and output power of 6.2 W at 513 nm. The successful realization of this laser operating in a quasi-two-level configuration is based on enhanced coupling of the laser and frequency-doubling processes using a monolithic configuration, benefiting from an ultimately small laser quantum defect, the anisotropic gain cross sections, and the high effective nonlinearity of the monoclinic YCOB outside the principal planes. Solid-state lasers in the spectral range around 510 nm are scarce, and the results not only present a significant advancement in the field of SFD lasers, but also pave the way for future applications of such green lasers, especially in areas such as medical treatment, daily life, and scientific investigations.

Output power enhancement of a self-frequency-doubled laser by selective excitation of inequivalent active centers in La2CaB10O19 (Nd:LCB) crystal.

We demonstrated the output power enhancement of a self-frequency-doubled laser with Nd3+-doped lanthanum calcium borate La2CaB10O19 (Nd:LCB) crystals by selective excitation of its inequivalent active centers. When the Nd3+ ions located in the Ca2+ sites were excited in the Nd:LCB crystal, the fundamental laser at the wavelength of 1066 nm was successfully realized, which can keep the self-frequency-doubled wavelength away from the self-absorption peak of Nd3+ ions at about 523 nm. By optimizing the key parameters, the maximum output power of 801 mW was achieved with the frequency-doubling at the wavelength of 533 nm, and the enhancement of output power was about 7.8 times compared with the results by excitation of Nd3+ ions in the La3+ sites. Up to now, this output power of the self-frequency-doubled laser represents the highest one in the Nd:LCB crystal, and the efficient emission at 533 nm should have promising applications in the visible range, such as laser displays, optical data storage, laser printing, etc. Meanwhile, the selective excitation of inequivalent active ions and the enhancement of the self-frequency-doubled laser may provide some inspiration for the investigation of multi-functional materials.

Self-frequency-doubled vibronic yellow Yb:YCOB laser at the wavelength of 570 nm.

A watt-level self-frequency-doubled yellow laser at the 570 nm wavelength was realized by taking advantage of the vibronic emission of a Yb3+ doped calcium yttrium oxoborate (Yb:YCOB) crystal cut along the optimized direction out of the principal planes with the maximum effective nonlinear coefficient. Fluorescence spectroscopic properties of Yb:YCOB were studied, which showed that it had broad and anisotropic vibronic emission with a small peak at ∼1130 nm. By suppressing the electronic emission, the polarized vibronic Yb:YCOB radiation was realized with the fundamental wavelength shifting from 1130 nm to 1140 nm. By employing the self-frequency-doubling behavior of Yb:YCOB, the self-frequency-doubled yellow laser was achieved with a maximum output power of 1.08 W at 570 nm. This work provides an unprecedented and efficient way to generate yellow lasers with a compact microchip structure that may have promising applications in some regimes including medicine, entertainment, and scientific research.

Development of a PCSK9-targeted nanoparticle vaccine to effectively decrease the hypercholesterolemia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor (LDLR) and mediates its internalization and degradation, resulting in an increase in LDL cholesterol levels. Recently, PCSK9 emerged as a therapeutic target for hypercholesterolemia and atherosclerosis. In this study, we develop a PCSK9 nanoparticle (NP) vaccine by covalently conjugating the catalytic domain (aa 153-aa 454, D374Y) of PCSK9 to self-assembled 24-mer ferritin NPs. We demonstrate that the PCSK9 NP vaccine effectively induces interfering antibodies against PCSK9 and reduces serum lipids levels in both a high-fat diet-induced hypercholesterolemia model and an adeno-associated virus-hPCSK9D374Y-induced hypercholesterolemia model. Additionally, the vaccine significantly reduces plaque lesion areas in the aorta and macrophages infiltration in an atherosclerosis mouse model. Furthermore, we discover that the vaccine's efficacy relied on T follicular help cells and LDLR. Overall, these findings suggest that the PCSK9 NP vaccine holds promise as an effective treatment for hypercholesterolemia and atherosclerosis.

Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others' works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019. IMPORTANCE: The outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.

Advances on the role of the deleted in breast cancer (DBC1) in cancer and autoimmune diseases.

DBC1 (deleted in breast cancer 1) is a human nuclear protein that modulates the activities of various proteins. Most of the research on DBC1 has focused on metabolism and epigenetics because it is a crucial endogenic inhibitor of deacetylase Sirtuin1 (SIRT1). In this review, we have discussed and summarized the new advances in DBC1 research, mostly focusing on its structure, regulatory function, and significance in cancer and autoimmune diseases.

CD19+CD24hiCD38hi regulatory B cells: a potential immune predictive marker of severity and therapeutic responsiveness of hepatitis C.

OBJECTIVES: Hepatitis C virus (HCV) infection is associated with abnormal immune responses. Since regulatory T (Tregs) and B (Bregs) cells modulate the progression of infectious diseases, this study aimed at examining how these cells are involved with the development of HCV infection. METHODS: The frequencies of circulating Bregs and Tregs were characterized using flow cytometry. Both the association and dynamic changes of these cells with related clinical parameters were analyzed after Direct-Acting Antiviral (DAA) agent treatments. Additionally, both regulatory B and T and naïve B and T cells were sorted and stimulated with healthy or HCV sera in vitro. RESULTS: Bregs frequency in HCV-infected patients increased significantly and were positively correlated with levels of sera HCV RNA load, Alanine aminotransferase (AST) and total bilirubin (TBILI). Additionally, the increased Bregs returned to normal levels after DAA treatment. However, Tregs increased markedly in patients with HCV-cirrhosis and were significantly associated with Aspartate aminotransferase to Platelet Ratio Index (APRI) and Fibrosis 4 (FIB-4) scores. Furthermore, HCV sera doesn't expand either Tregs or Bregs, however, it does induce the IL-10 expression in B cells although it fails to induce FOXP3 expression in CD4+ T cells. CONCLUSIONS: Increased Bregs not only may be associated with poor viral eradication and liver injury but also may provide a predictive marker of HCV disease therapeutic efficacy following DAA-treatment. HCV sera may selectively induce Bregs. Tregs probably do not control disease status in the early stages but may contribute to the progression of liver fibrosis in the late stages of HCV infection.

Negligible Effect of Sodium Chloride on the Development and Function of TGF-ß-Induced CD4+ Foxp3+ Regulatory T Cells.

High-salt diets inhibit the suppressive function of thymus-derived natural regulatory T cells (tTreg). Transforming growth factor ß (TGF-ß)-induced ex vivo regulatory T cells (iTreg) comprise another Treg subset that exhibits similarities and differences with tTreg. Here, we demonstrate that iTregs are completely stable and fully functional under high salt conditions. High salt does not influence the development, differentiation, and functional activities of iTreg but affects Foxp3 stability and function of tTreg in vitro and in vivo. In addition, high salt does not significantly change the transcription profiles of the iTreg signature or pro-inflammatory genes. Therefore, we conclude that iTreg, unlike tTreg, are stable and functional in the presence of high salt. Our findings provide additional evidence that iTreg may have different biological features from tTreg and suggest a greater potential for clinical utility in patients with autoimmune diseases, in which the complicated role of environmental factors, including diet, must be considered.

lncRNA-PDPK2P promotes hepatocellular carcinoma progression through the PDK1/AKT/Caspase 3 pathway.

Hepatocellular carcinoma (HCC) is a malignancy with one of the worst prognoses. Long noncoding RNA (lncRNA) are emerging as an important regulator of gene expression and function, leading to the development of cancer. The aim of this study was to determine the relationship between lncRNA and HCC and to further guide clinical therapy. lncRNA in HCC and adjacent tissues were screened, and the correlation between lncRNA-PDPK2P expression in liver tissues and the pathological characteristics and severity of HCC was assessed. The effects of PDPK2P on HCC proliferation, apoptosis, metastasis, and invasion were also systematically investigated via CCK-8 assay, flow cytometry, scratch wound healing, and transwell assay, respectively. The relationship between PDPK2P and PDK1 was verified by RNA pull-down, rescue experiments and western blot. lncRNA-PDPK2P was highly expressed in HCC tissues with a distinct positive correlation between PDPK2P and PDK1, and the upregulation was clinically associated with a larger tumor embolus, low differentiation, and poor survival. Mechanistically, lncRNA-PDPK2P interacted with PDK1 and promoted HCC progression through the PDK1/AKT/caspase 3 signaling pathway. lncRNA-PDPK2P can promote HCC progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of hepatocellular carcinoma.