Involvement of Actin-Regulating Factor Cofilin in the Inclusion Body Formation and RNA Synthesis of Human Parainfluenza Virus Type 3 via Interaction With the Nucleoprotein

Human parainfluenza virus type 3 (HPIV3) is one of the primary pathogens that causing severe respiratory tract diseases in newborns and infants. It could induce inclusion bodies (IBs) in infected cells. Comprised of viral nucleoprotein (N) and phosphoprotein (P), as well as some cellular factors, HPIV3 IBs are unique platform for efficient viral synthesis. Although several studies have demonstrated the formation of IBs, little is known about cellular proteins involved in HPIV3 IBs formation. By quantitative real-time PCR assays after cytochalasin D treatment, we found actin microfilaments of the cytoskeleton were indispensible for HPIV3 RNA synthesis. Using co-immunoprecipitation and immunofluorescence assays, an actin-modulating protein, cofilin was found to involve in the IBs formation through interaction with the N protein in N–P induced IBs complex. Viral IBs formation reduced upon RNA interference knockdown of cellular cofilin, thus viral RNA synthesis and protein expression level were also suppressed. What’s more, the inactive form of cofilin, p-cofilin was increased after HPIV3 infection, and phosphorylation of cofilin was required for interacting with N–P complex and IBs formation. We further identified that the regions in cofilin interacting with N protein lies in the C-terminus. Our findings for the first time to state that cellular cofilin involves in HPIV3 IBs and interaction with N is critical for cofilin to aid IBs formation and enhancing viral RNA synthesis

Effect of Integrated Chinese and Western Medicine Treatment on Immune Factors in a Rat Model with Phlegm-heat Syndrome in Acute Exacerbation-stable Stage of Chronic Obstructive Pulmonary Disease

BackgroundSecretory immunoglobulin A (sIgA) deficiency and immune imbalance caused by T lymphocyte aggregation in lung tissue are associated with the development of chronic obstructive pulmonary disease (COPD) . Human gastrointestinal and respiratory tracts have a typical mucosal structure, which are connected with the common mucosal immune system.ObjectiveTo examine the responses of some immune factors to integrated Chinese and Western Medicine treatment in a rat model with phlegm-heat syndrome during the acute exacerbation to stable stage of COPD.MethodsA study was implemented between September 2019 and December 2020. Sixty SPF Sprague-Dawley rats were selected, and divided into five groups using the RAND function in Excel: control, COPD, acute exacerbation of COPD (AECOPD) , Western Medicine, and integrated Chinese and Western Medicine. Except the control group, other groups were exposed to cigarette smoke and heat, and received intranasal administration of lipopolysaccharide to develop COPD in acute exacerbation to stable stage with phlegm-heat syndrome. The intervention in the acute exacerbation stage lasted for 8 days, during which Western Medicine group received intragastric administration of solution containing moxifloxacin hydrochloride tablets (0.027 g·kg-1·d-1) and salbutamol sulfate tablets (0.41 mg·kg-1·d-1) , integrated Chinese and Western Medicine group received intragastric administration of solution containing Tongsai granules (7.2 g·kg-1·d-1) , moxifloxacin hydrochloride tablets (0.027 g·kg-1·d-1) , and salbutamol sulfate tablets (0.41 mg·kg-1·d-1) , the other three groups received intragastric administration of isotonic (0.9%) sodium chloride 2 ml per day. Subsequently, the intervention in the stable period lasted for 14 days, during which western medicine group received intragastric administration of salbutamol sulfate tablets 0.41 mg·kg-1·d-1, and the integrated Chinese and Western Medicine group received intragastric administration of BufeiYishen formula 4.42 g·kg-1·d-1 and salbutamol sulfate tablets 0.41 mg·kg-1·d-1. The other three groups received intragastric administration of isotonic (0.9%) sodium chloride 2 ml per day. The forced vital capacity (FVC) , forced expiratory volume during the first 300 milliseconds (FEV0.3) , FEV0.3/FVC ratio, and sIgA, as well as CD3+ and CD4+, in the lung and gut were detected after the interventions.ResultsThe FVC, FEV0.3, FEV0.3/FVC ratio, sIgA in the lung and gut, as well as expression level of CD3+ in the lung, showed a trend of successive decrease across control group, COPD group, and AECOPD group (P<0.05) . The above-mentioned parameters were lower in AECOPD group than those of Western Medicine group or integrated Chinese and Western Medicine group (P<0.05) . And they were lower in Western Medicine group than those of integrated Chinese and Western Medicine group (P<0.05) .ConclusionIntegrated Chinese and Western Medicine treatment may improve immunity of the rat model via repairing the immune barrier function of the lung and gut by increasing the expression of sIgA, CD3+, and CD4+ in the lung and gut, which provides evidence for the prevention and treatment of COPD with Chinese medicine

ANALGESIC EFFECT OF TRANSCRANIAL DIRECT CURRENT STIMULATION ON CHRONIC PAIN IN A RAT MODEL OF OSTEOARTHRITIS AND ITS MECHANISM

Objective To investigate the analgesic effect of transcranial direct current stimulation (tDCS) on chronic pain in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) and its mechanism. Methods Healthy male Sprague-Dawley rats were randomly divided into sham-operation group, MIA group, tDCS group, and sham-tDCS group, with 9 rats in each group. The rats in the sham-operation group were given intra-articular injection of normal saline into the left knee joint, and those in the MIA group, the tDCS group, and the sham-tDCS group were given MIA injection at the same site to establish a model of chronic pain in OA. On day 21 after MIA injection, the rats in the tDCS group and the sham-tDCS group were treated with real or sham tDCS, respectively, for 8 d. The pain behavioral test was performed for the rats in each group on day 1, 2, and 7 after treatment; the periaqueductal gray (PAG) of rats were collected on day 2 after treatment and Western blot was used to measure the expression of brain-derived neurotrophic factor (BDNF). Results The pain behavioral test showed that compared with the sham-tDCS group, the tDCS group had a significantly longer thermal paw withdrawal latency at each time point after treatment (F=11.25-21.48,P<0.01) and a significantly higher mechanical paw withdrawal threshold at each time point after treatment (F=54.42-186.40,P<0.01). Western blot showed that compared with the sham-tDCS group, the tDCS group had a significant reduction in the protein expression of BDNF in PAG tissue (F=24.70,P<0.01). Conclusion This study shows that tDCS can effectively alleviate chronic pain in rats with MIA-induced OA, and such therapeutic effect can last till day 7 after treatment; tDCS exerts an analgesic effect possibly by downregulating the expression of BDNF and reducing neuronal excitability in PAG tissue of rats with MIA-induced OA

A novel natural killer-related signature to effectively predict prognosis in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma (HCC) is a prevalent tumor that poses a significant threat to human health, with 80% of cases being primary HCC. At present, Early diagnosis and predict prognosis of HCC is challenging and the it is characterized by a high degree of invasiveness, both of which negatively impact patient prognosis. Natural killer cells (NK) play an important role in the development, diagnosis and prognosis of malignant tumors. The potential of NK cell-related genes for evaluating the prognosis of patients with hepatocellular carcinoma remains unexplored. This study aims to address this gap by investigating the association between NK cell-related genes and the prognosis of HCC patients, with the goal of developing a reliable model that can provide novel insights into evaluating the immunotherapy response and prognosis of these patients. This work has the potential to significantly advance our understanding of the complex interplay between immune cells and tumors, and may ultimately lead to improved clinical outcomes for HCC patients. Methods For this study, we employed transcriptome expression data from the hepatocellular carcinoma cancer genome map (TCGA-LIHC) to develop a model consisting of NK cell-related genes. To construct the NK cell-related signature (NKRLSig), we utilized a combination of univariate COX regression, Area Under Curve (AUC) LASSO COX regression, and multivariate COX regression. To validate the model, we conducted external validation using the GSE14520 cohort. Results We developed a prognostic model based on 5-NKRLSig (IL18RAP, CHP1, VAMP2, PIC3R1, PRKCD), which divided patients into high- and low-risk groups based on their risk score. The high-risk group was associated with a poor prognosis, and the risk score had good predictive ability across all clinical subgroups. The risk score and stage were found to be independent prognostic indicators for HCC patients when clinical factors were taken into account. We further created a nomogram incorporating the 5-NKRLSig and clinicopathological characteristics, which revealed that patients in the low-risk group had a better prognosis. Moreover, our analysis of immunotherapy and chemotherapy response indicated that patients in the low-risk group were more responsive to immunotherapy. Conclusion The model that we developed not only sheds light on the regulatory mechanism of NK cell-related genes in HCC, but also has the potential to advance our understanding of immunotherapy for HCC. With its strong predictive capacity, our model may prove useful in evaluating the prognosis of patients and guiding clinical decision-making for HCC patients

Continental Fragments in the South China Block: Constraints From Crustal Radial Anisotropy

The lithospheric architecture of the South China Block (SCB) is crucial to understanding the formation and evolution of this distinctive and highly reworked continental lithosphere with over 3 billion years of tectonic history. However, due to a lack of high-resolution geophysical datasets, a detailed picture of the SCB lithosphere is absent, and fundamental questions regarding its formation, assembly, and subsequent reworking processes are actively debated. Assuming that unique deformation patterns due to such tectonic processes can be mapped by seismic anisotropy, we present a new crustal radially anisotropic shear-wave velocity model along a 1500-km seismic transect that spans the major tectonic domains of the SCB to characterize the past deformation processes. The new seismic models show significant lateral variations in seismic anisotropy and velocity, suggesting that the SCB consists of several separated (micro)continental blocks or terranes that likely have different origins and have survived the prolonged deformation history since the early formation of these continental fragments. Combining available geophysical datasets, we link individual crustal domains of distinct anisotropy to constrain the multiphase deformation processes of the SCB, including the early formation of the Proto-Yangtze and Cathaysia Blocks, the assembly of the SCB, and the subsequent reactivation of the interior and extensive deformation that have formed the Basin-and-Range style tectonics in the Cathaysia Block. We suggest that relict continental fragments have played critical roles in the formation and reactivation of the SCB lithosphere

FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer

Abstract Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8. FDW028, an inhibitor specifically targeted FUT8, promotes defucosylation and consequent HSC70/LAMP2A-mediated lysosomal degradation of B7-H3, and exhibits potent anti-mCRC activities