A Schistosoma japonicum chimeric protein with a novel adjuvant induced a polarized Th1 immune response and protection against liver egg burdens

<p>Abstract</p> <p>Background</p> <p>Schitosomiasis japonica is still a significant public health problem in China. A protective vaccine for human or animal use represents an important strategy for long-term control of this disease. Due to the complex life cycle of schistosomes, different vaccine design approaches may be necessary, including polyvalent subunit vaccines. In this study, we constructed four chimeric proteins (designated SjGP-1~4) via fusion of Sj26GST and four individual paramyosin fragments. We tested these four proteins as vaccine candidates, and investigated the effect of deviating immune response on protection roles in mice.</p> <p>Methods</p> <p>The immunogencity and protection efficacy of chimeric proteins were evaluated in mice. Next, the chimeric protein SjGP-3 was selected and formulated in various adjuvants, including CFA, ISA 206, IMS 1312 and ISA 70M. The titers of antigen-specific IgG, IgE and IgG subclass were measured. The effect of adjuvant on cytokine production and percentages of CD3⁺CD8^-IFN-γ⁺cells and CD3⁺CD8^-IL-4⁺cells were analyzed at different time points. Worm burdens and liver egg counts in different adjuvant groups were counted to evaluate the protection efficacy against cercarial challenge.</p> <p>Results</p> <p>Immunization of mice with chimeric proteins provided various levels of protection. Among the four proteins, SjGP-3 induced the highest level of protection, and showed enhanced protective efficacy compared with its individual component Sj26GST. Because of this, SjGP-3 was further formulated in various adjuvants to investigate the effect of adjuvant on immune deviation. The results revealed that SjGP-3 formulated in veterinary adjuvant ISA 70M induced a lasting polarized Th1 immune response, whereas the other adjuvants, including CFA, ISA 206 and IMS 1312, generated a moderate mixed Th1/Th2 response after immunization but all except for IMS 1312 shifted to Th2 response after onset of eggs. More importantly, the SjGP-3/70M formulation induced a significant reduction in liver egg deposition at 47.0–50.3% and the number of liver eggs per female at 34.5–37.2% but less effect on worm burdens at only 17.3–23.1%, whereas no effect of the formulations with other adjuvants on the number of liver eggs per female was observed.</p> <p>Conclusion</p> <p>Construction of polyvalent subunit vaccine was capable to enhance immunogenicity and protection efficacy against schistosomiasis. There was correlation of the polarized Th1 response with reduction of liver egg burdens, supporting the immune deviation strategy for schistosomiasis japonica vaccine development.</p

Unveiling A Core Linguistic Region in Large Language Models

Brain localization, which describes the association between specific regions of the brain and their corresponding functions, is widely accepted in the field of cognitive science as an objective fact. Today's large language models (LLMs) possess human-level linguistic competence and can execute complex tasks requiring abstract knowledge and reasoning. To deeply understand the inherent mechanisms of intelligence emergence in LLMs, this paper conducts an analogical research using brain localization as a prototype. We have discovered a core region in LLMs that corresponds to linguistic competence, accounting for approximately 1% of the total model parameters. This core region exhibits significant dimension dependency, and perturbations to even a single parameter on specific dimensions can lead to a loss of linguistic competence. Furthermore, we observe that an improvement in linguistic competence does not necessarily accompany an elevation in the model's knowledge level, which might imply the existence of regions of domain knowledge that are dissociated from the linguistic region. Overall, exploring the LLMs' functional regions provides insights into the foundation of their intelligence. In the future, we will continue to investigate knowledge regions within LLMs and the interactions between them.Comment: Work on progres

Relaxin in fibrotic ligament diseases: Its regulatory role and mechanism

Fibrotic ligament diseases (FLDs) are diseases caused by the pathological accumulation of periarticular fibrotic tissue, leading to functional disability around joint and poor life quality. Relaxin (RLX) has been reported to be involved in the development of fibrotic lung and liver diseases. Previous studies have shown that RLX can block pro-fibrotic process by reducing the excess extracellular matrix (ECM) formation and accelerating collagen degradation in vitro and in vivo. Recent studies have shown that RLX can attenuate connective tissue fibrosis by suppressing TGF-β/Smads signaling pathways to inhibit the activation of myofibroblasts. However, the specific roles and mechanisms of RLX in FLDs remain unclear. Therefore, in this review, we confirmed the protective effect of RLX in FLDs and summarized its mechanism including cells, key cytokines and signaling pathways involved. In this article, we outline the potential therapeutic role of RLX and look forward to the application of RLX in the clinical translation of FLDs

Faster accumulation and greater contribution of glomalin to the soil organic carbon pool than amino sugars do under tropical coastal forest restoration

Microbial metabolic products play a vital role in maintaining ecosystem multifunctionality, such as soil physical structure and soil organic carbon (SOC) preservation. Afforestation is an effective strategy to restore degraded land. Glomalin-related soil proteins (GRSP) and amino sugars are regarded as stable microbial-derived C, and their distribution within soil aggregates affects soil structure stability and SOC sequestration. However, the information about how afforestation affects the microbial contribution to SOC pools within aggregates is poorly understood. We assessed the accumulation and contribution of GRSP and amino sugars within soil aggregates along a restoration chronosequence (Bare land, Eucalyptus exserta plantation, native species mixed forest, and native forest) in tropical coastal terraces. Amino sugars and GRSP concentrations increased, whereas their contributions to the SOC pool decreased along the restoration chronosequence. Although microaggregates harbored greater microbial abundances, amino sugars and GRSP concentrations were not significantly affected by aggregate sizes. Interestingly, the contributions of amino sugars and GRSP to SOC pools decreased with decreasing aggregate size which might be associated with increased accumulation of plant-derived C. However, the relative change rate of GRSP was consistently greater in all restoration chronosequences than that of amino sugars. The accumulation of GRSP and amino sugars in SOC pools was closely associated with the dynamics of soil fertility and the microbial community. Our findings suggest that GRSP accumulates faster and contributes more to SOC pools during restoration than amino sugars did which was greatly affected by aggregate sizes. Afforestation substantially enhanced soil quality with native forest comprising species sequestering more SOC than the monoculture plantation did. Such information is invaluable for improving our mechanistic understanding of microbial control over SOC preservation during degraded ecosystem restoration. Our findings also show that plantations using arbuscular mycorrhizal plants can be an effective practice to sequester more soil carbon during restoration

Metabolic regulation by biomaterials in osteoblast

The repair of bone defects resulting from high-energy trauma, infection, or pathological fracture remains a challenge in the field of medicine. The development of biomaterials involved in the metabolic regulation provides a promising solution to this problem and has emerged as a prominent research area in regenerative engineering. While recent research on cell metabolism has advanced our knowledge of metabolic regulation in bone regeneration, the extent to which materials affect intracellular metabolic remains unclear. This review provides a detailed discussion of the mechanisms of bone regeneration, an overview of metabolic regulation in bone regeneration in osteoblasts and biomaterials involved in the metabolic regulation for bone regeneration. Furthermore, it introduces how materials, such as promoting favorable physicochemical characteristics (e.g., bioactivity, appropriate porosity, and superior mechanical properties), incorporating external stimuli (e.g., photothermal, electrical, and magnetic stimulation), and delivering metabolic regulators (e.g., metal ions, bioactive molecules like drugs and peptides, and regulatory metabolites such as alpha ketoglutarate), can affect cell metabolism and lead to changes of cell state. Considering the growing interests in cell metabolic regulation, advanced materials have the potential to help a larger population in overcoming bone defects

Investigating the role of a lncRNA (4833427F10Rik) in mouse placental development and function

[EMBARGOED UNTIL 8/1/2023] Long non-coding RNAs (lncRNAs) have traditionally been viewed as transcriptional noise. However, experimental evidence of their cell-type-specific expression, presence of functional genetic elements, along with their role in developmental disorders, including reproductive disorders such as preeclampsia and intrauterine growth restriction (IUGR) have motivated us to investigate the role of candidate lncRNAs in placental development. Our hypothesis is that lncRNAs that have placental-specific expression will be important for proper placental development and function, and if dysregulated will result in perturbed placental/fetal development. Transcriptome analysis previously performed in our laboratory had identified [greater than] 1000 lncRNAs that were differentially expressed between the embryonic and extraembryonic tissues of E7.5 mouse conceptus. Specifically, a candidate lncRNA 4833427F10Rik had expression specific to the placental lineages in conceptus during early development stage. Both RT-qPCR and in situ hybridization verified the RNA-seq results and confirmed that 4833427F10Rik had expression specific to the placental lineage as early as E7.5 conceptus and had a sustained expression in the placenta throughout gestation. In this study, RNAscope was performed to investigate the expression of 4833427F10Rik in mouse conceptus. Results showed that in the conceptus, 4833427F10Rik had expression specific to the placenta lineage tissues but not in the embryo/fetus. To investigate the function of 4833427F10Rik, knock-out mouse lines were generated by removing the proximal promoter and part of exon 1 region of this lncRNA from the mouse genome using CRISPR/Cpf1 system with two single guide RNAs (sgRNAs). Based on the results from two knock-out mouse lines (line 28 and line 32), 4833427F10Rik knock-out was not embryonic lethal and did not alter the fetal growth (as measured by weights) during the early development of the knock-out mouse lines (3-week-old to 6-week-old). However, RT-PCR and RNAscope in the knock-out line showed that the knock-out mouse line 28 still had 4833427F10Rik expression in the E12.5 mouse placenta. Our finding about lncRNA 4833427F10Rik knock-out mice, therefore, might not be conclusive. However, the proximal promoter and the exon 1 region of mouse line 28 were ablated, and compared to wild-type mice, a larger maternal decidua and a smaller fetal placenta were seen by immunostaining in the homozygous mouse line 28, but this phenotype will need to be verified by additional experimentation. The expression levels as well as the resulting phenotype in another knock-out mouse line 32 will need to be explored in the future. In addition to generating knock-out mouse lines, we attempted to generate a Credriver mouse by knocking-in the Cre into exon 1 of the lncRNA 4833427F10Rik. The resulting Cre-driver mice could be leveraged for investigating spatioxiv temporal expression of the 4833427F10Rik, and for generating placental-specific knock-out of other candidate genes. However, two missense mutations (p.Ser305Leu, p.Asn327Tyr) were identified in the knock-in Cre sequence by Sanger sequencing, which may or may not affect the Cre enzyme folding or activity. Additional experiments will be needed to be performed to validate the Cre activity in the knock-in mice line in the future.Includes bibliographical references

A Multifunctional Molecular Probe for Detecting Hg2+ and Ag+ Based on Ion-Mediated Base Mismatch

In this paper, a multifunctional biosensing platform for sensitively detecting Hg2+ and Ag+, based on ion-mediated base mismatch, fluorescent labeling, and strand displacement, is introduced. The sensor can also be used as an OR logic gate, the multifunctional design of sensors is realized. Firstly, orthogonal experiments with three factors and three levels were carried out on the designed sensor, and preliminary optimization of conditions was performed for subsequent experiments. Next, the designed sensor was tested the specificity and target selectivity under the optimized conditions, and the application to actual environmental samples further verified the feasibility. Generally, this is a convenient, fast, stable, and low-cost method that provides a variety of ideas and an experimental basis for subsequent research

An Enzyme- and Label-Free Fluorescence Aptasensor for Detection of Thrombin Based on Graphene Oxide and G-Quadruplex

An enzyme- and label-free aptamer-based assay is described for the determination of thrombin. A DNA strand (S) consisting of two parts was designed, where the first (Sa) is the thrombin-binding aptamer and the second (Se) is a G-quadruplex. In the absence of thrombin, Sa is readily adsorbed by graphene oxide (GO), which has a preference for ss-DNA rather than for ds-DNA. Upon the addition of the N-methyl-mesoporphyrin IX (NMM), its fluorescence (with excitation/emission at 399/610 nm) is quenched by GO. In contrast, in the presence of thrombin, the aptamer will bind thrombin, and thus, be separated from GO. As a result, fluorescence will be enhanced. The increase is linear in the 0.37 nM to 50 &micro;M thrombin concentration range, and the detection limit is 0.37 nM. The method is highly selective over other proteins, cost-effective, and simple. In our perception, it represents a universal detection scheme that may be applied to other targets according to the proper choice of the aptamer sequence and formation of a suitable aptamer-target pair