Clearing Persistent Extracellular Antigen of Hepatitis B Virus: An Immunomodulatory Strategy To Reverse Tolerance for an Effective Therapeutic Vaccination

Development of therapeutic vaccines/strategies to control chronic hepatitis B virus (HBV) infection (CHB) has been challenging due to HBV-induced tolerance. In this study, we explored strategies for breaking tolerance and restoring the immune response to the HBV surface antigen in tolerant mice. We demonstrated that immune tolerance status is attributed to the level and duration of circulating HBsAg in HBV carrier models. Removal of circulating HBsAg by a monoclonal anti-HBsAg antibody in tolerant mice could gradually reduce tolerance and reestablish B cell and CD4+ T cell responses to subsequent Engerix-B vaccination, producing protective IgG. Furthermore, HBsAg-specific CD8+ T cells induced by the addition of a TLR agonist, resulted in clearance of HBV in both serum and liver. Thus, generation of protective immunity can be achieved by clearing extracellular viral antigen with neutralizing antibodies followed by vaccination

The seeds of ecological recovery in urbanization-Spatiotemporal evolution of ecological resiliency of Dianchi Lake Basin, China

As a result of years of monitoring the ecological resiliency of natural areas and cities, it has become clear that it is both important and often feasible to implement ecological and environmental restoration in conjunction with ongoing processes of landscape change development and urbanization. Ecological resiliency and spatiotemporal evolution studies can objectively reveal the resiliency of ecosystems to external disturbances. Ecological monitoring and assessment can also help planners understand regional ecological spatial differentiation patterns and provided data support for planning. In this paper we have analyzes quantitatively the interrelationships of ecological factors in Dianchi Lake Basin (DLB) over the past 30 years and explored the spatial and temporal dynamics of ecological resiliency. Based on remote sensing images and primary data in 1995, 2005, 2010, 2015, 2018, and 2022, we used the center of gravity migration and kernel density analysis to explore the spatial and temporal changes of ecological resiliency. We built the overall resiliency evaluation system using entropy weight in the TOPSIS model, and finally simulate the future changes based on CA-Markov (CA-MC) model. The results show that from 1995 to 2022, the ecological resiliency of land use and vegetation cover in DLB decreased substantially. An important finding was that the ecological resiliency of riparian buffer zone and landscape pattern were generally increasing. The distribution of barycenter movement and kernel density of different levels of ecological resiliency differed significantly and showed fluctuating changes. The extreme low resiliency and extremely resilient areas shift to the northeast, the mildly resilient areas shift to the northwest, and the highly resilient areas shift to the southeast. The overall resiliency level of DLB is predicted to slowly increase from 2022 to 2030 by deduction of the CA-MC model. Our analysis suggests that the study of the evolution of regional ecological resiliency can provide a timely understanding of regional ecological evolution patterns and propose ecological protection strategies

Tunable and absolute electromagnetic vacuum in two-dimensional photonic-band-gap Based on multiferroic materials

When multiferroic terbium manganite (TbMnO₃) crystal cylinders are periodically arranged in a square lattice, the resulting two-dimensional (2D) system exhibits photonic band gaps (PBGs). The absolute PBG originating from the Mie resonance is modulated from closed to open by applying an external static magnetic field, which is attributed to the electromagnon depression of the dielectric constant by the rearrangement of antiferromagnetic order. Tunable electromagnetic band structure may be realized by controlling the magnetic transition of manganese spins in TbMnO₃.The authors are grateful for financial support from the Outstanding Foundation of NJUST, the NJUST Research Funding (No. 2010ZDJH06), the National Natural Science Foundation of China (Grant Nos. 11004106, 50672034, 50832002, and 50901042), and the State Key Program for Basic Research of China (Grant Nos. 2009CB623303 and 2009CB929501)

QTL Detection for Kernel Size and Weight in Bread Wheat (Triticum aestivum L.) Using a High-Density SNP and SSR-Based Linkage Map

High-density genetic linkage maps are essential for precise mapping quantitative trait loci (QTL) in wheat (Triticum aestivum L.). In this study, a high-density genetic linkage map consisted of 6312 SNP and SSR markers was developed to identify QTL controlling kernel size and weight, based on a recombinant inbred line (RIL) population derived from the cross of Shixin828 and Kenong2007. Seventy-eight putative QTL for kernel length (KL), kernel width (KW), kernel diameter ratio (KDR), and thousand kernel weight (TKW) were detected over eight environments by inclusive composite interval mapping (ICIM). Of these, six stable QTL were identified in more than four environments, including two for KL (qKL-2D and qKL-6B.2), one for KW (qKW-2D.1), one for KDR (qKDR-2D.1) and two for TKW (qTKW-5A and qTKW-5B.2). Unconditional and multivariable conditional QTL mapping for TKW with respect to TKW component (TKWC) revealed that kernel dimensions played an important role in regulating the kernel weight. Seven QTL-rich genetic regions including seventeen QTL were found on chromosomes 1A (2), 2D, 3A, 4B and 5B (2) exhibiting pleiotropic effects. In particular, clusters on chromosomes 2D and 5B possessing significant QTL for kernel-related traits were highlighted. Markers tightly linked to these QTL or clusters will eventually facilitate further studies for fine mapping, candidate gene discovery and marker-assisted selection (MAS) in wheat breeding

B-Cell Receptor-Associated Protein 31 Promotes Metastasis via AKT/β-Catenin/Snail Pathway in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most lethal cancer worldwide, characterized with high heterogeneity and inclination to metastasize. Emerging evidence suggests that BAP31 gets involved in cancer progression with different kinds. It still remains unknown whether and how BAP31 plays a role in HCC metastasis. Epithelial–mesenchymal transition (EMT) has been a common feature in tumor micro-environment, whose inducer TGF-β increased BAP31 expression in this research. Elevated expression of BAP31 was positively correlated with tumor size, vascular invasion and poor prognosis in human HCC. Ectopic expression of BAP31 promoted cell migration and invasion while BAP31 knockdown markedly attenuated metastatic potential in HCC cells and mice orthotopic xenografts. BAP31 induced EMT process, and enhanced the expression level of EMT-related factor Snail and decreased contents and membrane distribution of E-cadherin. BAP31 also activated AKT/β-catenin pathway, which mediated its promotional effects on HCC metastasis. AKT inhibitor further counteracted the activated AKT/β-catenin/Snail upon BAP31 over-expression. Moreover, silencing Snail in BAP31-overexpressed cells impaired enhanced migratory and invasive abilities of HCC cells. In HCC tissues, BAP31 expression was positively associated with Snail. In conclusion, BAP31 promotes HCC metastasis by activating AKT/β-catenin/Snail pathway. Thus, our study implicates BAP31 as potential prognostic biomarker, and provides valuable information for HCC prognosis and treatment

Facile discovery of surrogate cytokine agonists

Cytokines are powerful immune modulators that initiate signaling through receptor dimerization, but natural cytokines have structural limitations as therapeutics. We present a strategy to discover cytokine surrogate agonists by using modular ligands that exploit induced proximity and receptor dimer geometry as pharmacological metrics amenable to high-throughput screening. Using VHH and scFv to human interleukin-2/15, type-I interferon, and interleukin-10 receptors, we generated combinatorial matrices of single-chain bispecific ligands that exhibited diverse spectrums of functional activities, including potent inhibition of SARS-CoV-2 by surrogate interferons. Crystal structures of IL-2R:VHH complexes revealed that variation in receptor dimer geometries resulted in functionally diverse signaling outputs. This modular platform enabled engineering of surrogate ligands that compelled assembly of an IL-2R/IL-10R heterodimer, which does not naturally exist, that signaled through pSTAT5 on T and natural killer (NK) cells. This “cytokine med-chem” approach, rooted in principles of induced proximity, is generalizable for discovery of diversified agonists for many ligand-receptor systems

Monitoring the Process and Characterizing Symptoms of Suckling Mouse Inoculation Promote Isolating Viruses from Ticks

Suckling mouse inoculation is an important method that has been used for years to isolate viruses from ticks; however, this method has usually been briefly described in the literature on a case-by-case basis upon successful isolation rather than providing extensive details. This study describes the procedure from preparation of tick homogenates to identification of virus isolation using the suckling mouse inoculation method. The transient and persistent features were characterized and the incidence of manifestations that developed in the suckling mice, especially in mice from which viruses were isolated, is reported. We identified 22 symptoms that developed in mice, including 13 transient symptoms that recovered by the end of the observation period and 7 persistent symptoms that the mice suffered from throughout the observation period. Persistent symptoms (lateral positioning and dead) and transient symptoms (malaise, emaciation, and difficulty turning over) were the main symptoms based on the high overall incidence. Moreover, we showed that mice from which viruses were isolated had a concentrated period and advanced days of disease onset. This study provides detailed information necessary for better use of suckling mouse inoculation to isolate viruses from ticks, which may benefit optimization of this method to identify, discover, and acquire tick-borne viruses

Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3

该研究论文发现蛋白磷酸酶Ppm1b 通过去磷酸化RIP3负调控程序性细胞坏死（necroptosis），阐明了RIP3磷酸化状态的精确调控对于细胞和机体在生理和病理状态下的存活至关重要。The auto-phosphorylation of murine ​receptor-interacting protein 3 (​Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how ​Rip3 phosphorylation is regulated is still largely unknown. Here we identified ​protein phosphatase 1B (​Ppm1b) as a ​Rip3 phosphatase and found that ​Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by ​Rip3 auto-phosphorylation in resting cells, and ​tumour necrosis factor-α (​TNF)-induced necroptosis in cultured cells. We revealed that ​Ppm1b selectively suppresses necroptosis through the dephosphorylation of ​Rip3, which then prevents the recruitment of ​mixed lineage kinase domain-like protein (​Mlkl) to the necrosome. We further showed that ​Ppm1b deficiency (​Ppm1bd/d) in mice enhanced ​TNF-induced death in a ​Rip3-dependent manner, and the role of ​Ppm1b in inhibiting necroptosis was evidenced by elevated ​Rip3 phosphorylation and tissue damage in the caecum of ​TNF-treated ​Ppm1bd/d mice. These data indicate that ​Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3 in vitro and in vivo