TXNIP deficiency attenuates renal fibrosis by modulating mTORC1/TFEB-mediated autophagy in diabetic kidney disease.

Thioredoxin-interacting protein (TXNIP) is an important regulatory protein for thioredoxin (TRX) that elicits the generation of reactive oxygen species (ROS) by inhibiting the redox function of TRX. Abundant evidence suggests that TXNIP is involved in the fibrotic process of diabetic kidney disease (DKD). However, the potential mechanism of TXNIP in DKD is not yet well understood. In this study, we found that TXNIP knockout suppressed renal fibrosis and activation of mammalian target of rapamycin complex 1 (mTORC1) and restored transcription factor EB (TFEB) and autophagy activation in diabetic kidneys. Simultaneously, TXNIP interference inhibited epithelial-to-mesenchymal transformation (EMT), collagen I and fibronectin expression, and mTORC1 activation, increased TFEB nuclear translocation, and promoted autophagy restoration in HK-2 cells exposed to high glucose (HG). Rapamycin, an inhibitor of mTORC1, increased TFEB nuclear translocation and autophagy in HK-2 cells under HG conditions. Moreover, the TFEB activators, curcumin analog C1 and trehalose, effectively restored HG-induced autophagy, and abrogated HG-induced EMT and collagen I and fibronectin expression in HK-2 cells. Taken together, these findings suggest that TXNIP deficiency ameliorates renal fibrosis by regulating mTORC1/TFEB-mediated autophagy in diabetic kidney diseases.

White matter biomarker for predicting de novo Parkinson's disease using tract-based spatial statistics: a machine learning-based model.

Background: Parkinson's disease (PD) is an irreversible, chronic degenerative disease of the central nervous system, potentially associated with cerebral white matter (WM) lesions. Investigating the microstructural alterations within the WM in the early stages of PD can help to identify the disease early and enable intervention to reduce the associated serious threats to health. Methods: This study selected 227 cases from the Parkinson's Progression Markers Initiative (PPMI) database, including 152 de novo PD patients and 75 normal controls (NC). Whole-brain voxel analysis of the WM was performed using the tract-based spatial statistics (TBSS) method. The WM regions with statistically significant differences (P<0.05) between the PD and NC groups were identified and used as masks. The mask was applied to each case's fractional anisotropy (FA) image to extract voxel values as feature vectors. Geometric dimensionality reduction was then applied to eliminate redundant values in the feature vectors. Subsequently, the cases were randomly divided into a training group (158 cases, including 103 PD patients and 55 NC) and a test group (69 cases, including 49 PD patients and 20 NC). The least absolute shrinkage and selection operator (LASSO) regression algorithm was employed to extract the minimal set of relevant features, then the random forest (RF) algorithm was utilized for classification using 5-fold cross validation. The resulting model was further integrated with clinical factors to create a comprehensive prediction model. Results: In comparison to the NC group, the FA values in PD patients exhibited a statistically significant decrease (P<0.05), indicating the presence of widespread WM lesions across multiple brain regions. Moreover, the PD prediction model, constructed based on these WM lesion regions, yielded prediction accuracy (ACC) and area under the receiver operating characteristic (ROC) curve (AUC) values of 0.778 and 0.865 in the validation set, and 0.783 and 0.831 in the test set, respectively. Furthermore, the performance of the integrated model showed some improvement, with ACC and AUC values in the test set reaching 0.804 and 0.844, respectively. Conclusions: The quantitative calculation of WM lesion area on FA images using the TBSS method can serve as a neuroimaging biomarker for diagnosing and predicting early PD at the individual level. When integrated with clinical variables, the predictive performance improves.

MicroRNA-204-5p Ameliorates Renal Injury via Regulating Keap1/Nrf2 Pathway in Diabetic Kidney Disease.

Background: Diabetic kidney disease (DKD) is characterized by renal fibrosis, and the pathogenesis of renal fibrosis is still not definitely confirmed. MiR-204-5p plays an important role in the regulation of fibrosis, autophagy and oxidative stress. In this study, we aimed to investigate the role of miR-204-5p on renal damage in diabetic kidneys and the underlying mechanisms involved. Methods: In vivo, AAV-Ksp-miR-204-5p mimics were injected into mice via tail vein. In vitro, high glucose-induced HK-2 cells were treated with miR-204-5p inhibitor, miR-204-5p mimics, ATG5 siRNA, tertiary butyl hydroquinone (TBHQ), ML385, or 3-Methyladenine (3-MA). FISH and qRT-PCR were used to detect miR-204-5p expression. The expressions of protein and mRNA were detected by Western blotting, immunofluorescence, immunohistochemistry and qRT-PCR. The concentration of fibronectin in HK-2 cells culture medium was detected by ELISA. Results: The expression of miR-204-5p in diabetic kidneys was significantly inhibited than that in control group. Delivering miR-204-5p mimics increased miR-204-5p expression, improved renal function, inhibited renal fibrosis and oxidative stress, and restored autophagy in db/db mice. In vitro, the expression of miR-204-5p was inhibited by HG treatment in HK-2 cells. MiR-204-5p mimics effectively increased miR-204-5p expression and reduced fibronectin and collagen I expression, restored autophagy dysfunction, and increased Nrf2 expression, whereas these alterations were abrogated by Nrf2 inhibitor ML385, autophagy inhibitor 3-methyladenine (3-MA, 5 mM) treatment or ATG5 siRNA transfection in HG-induced HK-2 cells. In addition, miR-204-5p inhibitor significantly inhibited miR-204-5p expression and aggravated HG-induced fibronectin and collagen I expression, autophagy dysfunction, and decreased Nrf2 expression, while these alterations were abolished by Nrf2 activator TBHQ. Furthermore, the binding of miR-204-5p with Keap1 was confirmed by luciferase reporter assay and miR-204-5p negatively regulated Keap1 expression, resulting in the activation of Nrf2 pathway. Conclusion: MicroRNA-204-5p protects against the progression of diabetic renal fibrosis by restoring autophagy via regulating Keap1/Nrf2 pathway.

Effects of evidence-based nursing on surgical site wound infections in patients undergoing surgery for liver cancer: A meta-analysis.

This study aimed to systematically evaluate the impact of evidence-based nursing (EBN) on perioperative wound infections and postoperative complications in patients undergoing surgery for liver hepatocellular carcinoma (LIHC). Randomised controlled trials (RCTs) on the application of EBN on patients receiving LIHC surgery were searched in PubMed, Web of Science, Cochrane Library, Embase, Wanfang, China Biomedical Literature Database and China National Knowledge Infrastructure from the inception of each database to September 2023. Studies were screened and evaluated by two investigators based on inclusion and exclusion criteria, and data were extracted from the final included literature. RevMan 4.0 was used for data analysis. Overall, 15 RCTs involving 1374 patients with LIHC were included, with 687 in the EBN group and 687 in the conventional care group. The analysis revealed that the incidence of wound infections (odds ratio [OR] = 0.32, 95% confidence interval [CI]: 0.18-0.56, p < 0.001) and postoperative complications (OR = 0.22, 95% CI: 0.15-0.31, p < 0.001) was significantly lower in the EBN group than in the conventional care group. The available evidence suggests that nursing strategies for EBN applied in the perioperative period in patients with LIHC receiving surgery can effectively reduce the incidence of wound infections and postoperative complications and promote postoperative recovery.

The Potential of Berberine to Target Telocytes in Rabbit Heart.

A brand-new class of interstitial cells, called telocytes, has been detected in the heart. Telocytes can connect and transmit signals to almost all cardiomyocytes; this is highly interrelated with the occurrence and development of heart diseases. Modern studies have shown that berberine has a therapeutic effect on cardiovascular health. However, berberine's mechanism of action on the cardiovascular system through cardiac telocytes is unclear. Interestingly, 5 µm of berberine remarkably decreased the concentration of intracellular calcium and membrane depolarization in cultured telocytes, upregulated the expression of CX43 and ß-catenin, and downregulated the expressions of TRPV4 and TRPV1. Here, telocytes were identified in the vascular adventitia and intima, endocardium, myocardium, adventitia, and heart valves. Moreover, telocytes were broadly dispersed around cardiac vessels and interacted directly through gap junctions and indirectly through extracellular vesicles. Together, cardiac telocytes interact with berberine and then deliver drug information to the heart. Telocytes may be an essential cellular target for drug therapy of the cardiovascular system.

Tembusu virus induced apoptosis in vacuolate spermatogenic cells is mediated by Cytc-mediated mitochondrial apoptotic signaling pathway.

Duck Tembusu virus (DTMUV) is an emerging mosquito-borne flavivirus that infects mainly poultry and has caused huge economic losses to the poultry farming industry in China. Also known as duck hemorrhagic ovarian disease, DTMUV principally destroys ovarian tissue in ducks, causing a dramatic drop in egg production. and can also invade the male reproductive system causing lesions. Currently, little research has been done to reveal the underlying mechanisms of reproductive dysfunction in ducks caused by DTMUV infection. In this study, histopathological analysis and electron microscopy of testes of ducks infected with DTMUV showed that DTMUV caused testicular atrophy and cytoplasmic vacuolation in ducks. Terminal Deoxynucleotidyl Transferase-Mediated Nick-End Labeling (TUNEL) staining and real-time quantitative PCR(RT-qPCR) results further indicated that DTMUV induced spermatogenic cells apoptosis. After DTMUV infection, a large amount of cytochrome c(Cytc) was released from the mitochondrial matrix into the cytoplasm, activating downstream target proteins and causing apoptosis. To sum up, DTMUV induces spermatogenic cell apoptosis through the Cytc-induced mitochondrial apoptosis pathway, our study provides evidence for DTMUV infection-induced male reproductive disorders.

The Cellular Mechanism of Acupuncture for Ulcerative Colitis based on the Communication of Telocytes.

Acupuncture can ameliorate or treat diseases according to the meridian theory in traditional Chinese medicine (TCM); however, its mechanism has not been scientifically clarified. On the other hand, telocytes (TCs) are morphologically in accordance with the meridian system, which needs further cytological investigations and acupuncture confirmation. The present study showed that acupuncture could activate TCs in several ways, alleviating rabbit ulcerative colitis. TCs could cytologically communicate the acupoints, the acupuncture sites in skin with their corresponding large intestine by TC homo-cellular junctions, exosomes around TCs, and TC-mediated nerves or blood vessels. TCs expressed transient receptor potential vanilloid type 4, the mechanosensitive channel protein that can transduce the mechanical stimulation of acupuncture into biochemical signals transferring along the extremely thin and long TCs. Collectively, a cellular mechanism diagram of acupuncture was concluded based on TC characteristics. Those results also confirmed the viewpoint that TCs were the key cells of meridian essence in TCM.

Recyclable soft photonic crystal film with overall improved circularly polarized luminescence.

Existing circularly polarized luminescence materials can hardly satisfy the requirements of both large luminescence dissymmetry factor and high luminescent quantum yield, which hinders their practical applications. Here, we present a soft photonic crystal film embedded with chiral nanopores that possesses excellent circularly polarized luminescence performance with a high luminescence dissymmetry factor as well as a large luminescent quantum yield when loaded with various luminescent dyes. Benefitting from the retention of chiral nanopores imprinted from a chiral liquid crystal arrangement, the chiral soft photonic crystal film can not only endow dyes with chiral properties, but also effectively avoid severe aggregation of guest dye molecules. More importantly, the soft photonic crystal film can be recycled many times by loading and eluting guest dye molecules while retaining good stability as well as circularly polarized luminescence performance, enabling various applications, including smart windows, multi-color circularly polarized luminescence and anticounterfeiting.

Predicting Lymph Node Metastasis From Primary Cervical Squamous Cell Carcinoma Based on Deep Learning in Histopathologic Images.

We developed a deep learning framework to accurately predict the lymph node status of patients with cervical cancer based on hematoxylin and eosin-stained pathological sections of the primary tumor. In total, 1524 hematoxylin and eosin-stained whole slide images (WSIs) of primary cervical tumors from 564 patients were used in this retrospective, proof-of-concept study. Primary tumor sections (1161 WSIs) were obtained from 405 patients who underwent radical cervical cancer surgery at the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014; 165 and 240 patients were negative and positive for lymph node metastasis, respectively (including 166 with positive pelvic lymph nodes alone and 74 with positive pelvic and para-aortic lymph nodes). We constructed and trained a multi-instance deep convolutional neural network based on a multiscale attention mechanism, in which an internal independent test set (100 patients, 228 WSIs) from the FUSCC cohort and an external independent test set (159 patients, 363 WSIs) from the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program database were used to evaluate the predictive performance of the network. In predicting the occurrence of lymph node metastasis, our network achieved areas under the receiver operating characteristic curve of 0.87 in the cross-validation set, 0.84 in the internal independent test set of the FUSCC cohort, and 0.75 in the external test set of the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program. For patients with positive pelvic lymph node metastases, we retrained the network to predict whether they also had para-aortic lymph node metastases. Our network achieved areas under the receiver operating characteristic curve of 0.91 in the cross-validation set and 0.88 in the test set of the FUSCC cohort. Deep learning analysis based on pathological images of primary foci is very likely to provide new ideas for preoperatively assessing cervical cancer lymph node status; its true value must be validated with cervical biopsy specimens and large multicenter datasets.

Cellular Evidence for Telocytes Mediating Electroacupuncture to Ameliorate Obesity in Mice.

Electroacupuncture has been generally applied to target obesity, the principle of which is based on the meridian in traditional Chinese medicine. Although Telocytes (TCs) have been reported as the potential essence of meridians, their specific role in the electroacupuncture treatment of obesity remains unclear. Thus, we investigated the cellular evidence for TC-mediated electroacupuncture to alleviate obesity. Mice were divided into three groups as follows: electroacupuncture group (EA), control group (CG), and normal group (NG). The present study showed that the weight of perirenal white adipose tissue (rWAT), the serum level of total cholesterol, and the low-density lipoprotein cholesterol were all significantly decreased after electroacupuncture. Ultrastructurally, the prolongations (telopodes, Tps) of TCs were in direct contact with adipocytes, and lipid droplets were distributed on the surface of Tps. The proportions of double-positive fluorescent areas of TCs (CD34 and PDGFRα) were significantly elevated with concomitant elongated Tps in EA mice, as compared to those in CG mice. The expression of Cx43 and CD63 (gap junction and exosome markers) was significantly enhanced. These characteristics facilitated the transmission of electroacupuncture stimulation from skin to rWAT. We conclude that electroacupuncture relieved obesity by activating TCs morphologically, upregulating the gap junctions between TCs, and increasing the exosomes around TCs.

Segmentation of Portal Vein in Multiphase CTA Image Based on Unsupervised Domain Transfer and Pseudo Label.

BACKGROUND: Clinically, physicians diagnose portal vein diseases on abdominal CT angiography (CTA) images scanned in the hepatic arterial phase (H-phase), portal vein phase (P-phase) and equilibrium phase (E-phase) simultaneously. However, existing studies typically segment the portal vein on P-phase images without considering other phase images. METHOD: We propose a method for segmenting portal veins on multiphase images based on unsupervised domain transfer and pseudo labels by using annotated P-phase images. Firstly, unsupervised domain transfer is performed to make the H-phase and E-phase images of the same patient approach the P-phase image in style, reducing the image differences caused by contrast media. Secondly, the H-phase (or E-phase) image and its style transferred image are input into the segmentation module together with the P-phase image. Under the constraints of pseudo labels, accurate prediction results are obtained. RESULTS: This method was evaluated on the multiphase CTA images of 169 patients. The portal vein segmented from the H-phase and E-phase images achieved DSC values of 0.76 and 0.86 and Jaccard values of 0.61 and 0.76, respectively. CONCLUSION: The method can automatically segment the portal vein on H-phase and E-phase images when only the portal vein on the P-phase CTA image is annotated, which greatly assists in clinical diagnosis.

Comparison of endocytosis pathways of Duck Tembusu virus in BHK-21 and duck embryo fibroblasts.

The Duck Tembusu virus (DTMUV) is a zoonotic flavivirus characterized by nonsuppurative encephalitis and decreasing egg production that has adversely affected the poultry industry. While the way of invasion of DTMUV into different host cells, especially primary cells, remains elusive. In the present study, the ultrastructural pathological characteristics showed that DTMUV underwent a typical maturation and replication process: progeny virus particles gathered in rough endoplasmic reticulum (RER) cisternae, reached the cell membrane via Golgi body's endocrine channel, then were released in the infected baby hamster kidney-21 (BHK-21) and duck embryo fibroblast (DEF). Endoplasmic reticulum vesicles in BHK-21 were short rods and densely arranged like honeycombs, whereas vesicles in DEF were round and dispersed. Further study showed that the virus replication peak in mammalian BHK-21 cells was at 48 hpi, whereas in avian DEF cells was at 24 hpi. DTMUV entry into BHK-21 and DEF cells was blocked by clathrin inhibitor, chlorpromazine (CPZ), indicating that the flavivirus DTMUV enters BHK-21 and DEF both via a clathrin-mediated endocytosis (CME) pathway rather than caveola-mediated endocytosis or micropinocytosis. The endocytic difference in DTMUV entry into BHK-21 and DEF cells might provide insight into understanding the underlying virulence difference between passaged cells and cultured cells.

Irisin Ameliorates Renal Tubulointerstitial Fibrosis by Regulating the Smad4/ß-Catenin Pathway in Diabetic Mice.

Background: The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. Methods: The purpose of this article is to examine irisin's function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-ß1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. Results: In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and ß-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/ß-catenin signaling pathway. Conclusion: The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/ß-catenin pathway.

Segmentation of multi-regional skeletal muscle in abdominal CT image for cirrhotic sarcopenia diagnosis.

Background: Sarcopenia is generally diagnosed by the total area of skeletal muscle in the CT axial slice located in the third lumbar (L3) vertebra. However, patients with severe liver cirrhosis cannot accurately obtain the corresponding total skeletal muscle because their abdominal muscles are squeezed, which affects the diagnosis of sarcopenia. Purpose: This study proposes a novel lumbar skeletal muscle network to automatically segment multi-regional skeletal muscle from CT images, and explores the relationship between cirrhotic sarcopenia and each skeletal muscle region. Methods: This study utilizes the skeletal muscle characteristics of different spatial regions to improve the 2.5D U-Net enhanced by residual structure. Specifically, a 3D texture attention enhancement block is proposed to tackle the issue of blurred edges with similar intensities and poor segmentation between different skeletal muscle regions, which contains skeletal muscle shape and muscle fibre texture to spatially constrain the integrity of skeletal muscle region and alleviate the difficulty of identifying muscle boundaries in axial slices. Subsequentially, a 3D encoding branch is constructed in conjunction with a 2.5D U-Net, which segments the lumbar skeletal muscle in multiple L3-related axial CT slices into four regions. Furthermore, the diagnostic cut-off values of the L3 skeletal muscle index (L3SMI) are investigated for identifying cirrhotic sarcopenia in four muscle regions segmented from CT images of 98 patients with liver cirrhosis. Results: Our method is evaluated on 317 CT images using the five-fold cross-validation method. For the four skeletal muscle regions segmented in the images from the independent test set, the avg. DSC is 0.937 and the avg. surface distance is 0.558 mm. For sarcopenia diagnosis in 98 patients with liver cirrhosis, the cut-off values of Rectus Abdominis, Right Psoas, Left Psoas, and Paravertebral are 16.67, 4.14, 3.76, and 13.20 cm2/m2 in females, and 22.51, 5.84, 6.10, and 17.28 cm2/m2 in males, respectively. Conclusion: The proposed method can segment four skeletal muscle regions related to the L3 vertebra with high accuracy. Furthermore, the analysis shows that the Rectus Abdominis region can be used to assist in the diagnosis of sarcopenia when the total muscle is not available.

NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-κB and TGF-ß/Smad signaling pathways in diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy (DN) is one of the main complications of diabetes, and inflammation and fibrosis play an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and damage caused by toxic quinones. In the present study, we aimed to investigate the protective effects of NQO1 against diabetes-induced renal inflammation and fibrosis and the underlying mechanisms. METHODS: In vivo, the kidneys of type 2 diabetes model db/db mice were infected with adeno-associated virus vectors to induce NQO1 overexpression. In vitro, human renal tubular epithelial (HK-2) cells transfected with NQO1 pcDNA3.1(+) were cultured under high-glucose (HG) conditions. Gene and protein expression was assessed by quantitative real-time PCR, Western blotting, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species (ROS) were detected with MitoSOX Red. RESULT: Our study revealed that the expression of NQO1 was markedly downregulated and that Toll-like receptor (TLR)4 and TGF-ß1 expression was upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed proinflammatory cytokine (IL-6, TNF-α, MCP-1) secretion, extracellular matrix (ECM) (collagen IV, fibronectin) accumulation and epithelial-mesenchymal transition (EMT) (α-SMA, E-cadherin) in the db/db mouse kidneys and HG-cultured HK-2 cells. Furthermore, NQO1 overexpression ameliorated HG-induced TLR4/NF-κB and TGF-ß/Smad pathways activation. Mechanistic studies demonstrated that a TLR4 inhibitor (TAK-242) suppressed the TLR4/NF-κB signaling pathway, proinflammatory cytokine secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that the antioxidants N-acetylcysteine (NAC) and tempol increased the expression of NQO1 and decreased the expression of TLR4, TGF-ß1, Nox1, and Nox4 and ROS production in HK-2 cells cultured under HG conditions. CONCLUSIONS: These data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating the TLR4/NF-κB and TGF-ß/Smad signaling pathways.

Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo.

Introduction: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials. Methods: The effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo. Results: Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro. It also enhanced p38 and NFKB1 phosphorylation while lowering STAT3 phosphorylation in CLL cells activated with TLR-7/8 agonists and IL-2. Among the cytokines made by activated CLL cells, high levels of IL-10 contributed strongly to STAT3 phosphorylation and inhibited TLR7 activity. Ruxolitinib limited TLR-mediated IL10 transcription and markedly reduced IL-10 production in vitro. It also decreased blood levels of IL-10 while increasing TNFα along with phospho-p38 expression and gene sets associated with TLR-activation in CLL cells in vivo. The bruton's tyrosine kinase inhibitor ibrutinib decreased IL-10 production in vitro but, in contrast to ruxolitinib, blocked initial IL10 transcription induced by TLR-signaling in vitro, decreased TNFα production, and deactivates CLL cells in vivo. Discussion: These findings suggest the possible benefits of inhibiting growth factors with JAK inhibitors in CLL are outweighed by negative effects on potential tumor suppressors such as IL-10 that allow unrestrained activation of NFκB by drivers such as TLRs. Specific inhibition of growth-promoting cytokines with blocking antibodies or infusing suppressive cytokines like IL-10 might be better strategies to manipulate cytokines in CLL.

Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy.

Background: The study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis. Methods: GSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients. Results: A total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. "chemokine signaling pathway" and "cell adhesion molecules" were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap. Conclusions: CCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.

Ultrastructural study of the duck brain infected with duck Tembusu virus.

Duck Tembusu virus (DTMUV) is an emerging avian flavivirus characterized by causing severe ovaritis and neurological symptoms in ducks. The pathology of the central nervous system (CNS) caused by DTMUV is rarely studied. This study aimed to systematically investigate the ultrastructural pathology of the CNS of ducklings and adult ducks infected with DTMUV via transmission electron microscopy technology at a cytopathological level. The results showed that DTMUV caused extensive lesions in the brain parenchyma of ducklings and slight damage in adult ducks. The neuron was the target cell of DTMUV, and virions were mainly observed in their cisternae of rough endoplasmic reticulum and the saccules of Golgi apparatus. The neuron perikaryon showed degenerative changes where the membranous organelles gradually decomposed and disappeared with DTMUV infection. Besides neurons, DTMUV infection induced marked swelling in astrocytic foot processes in ducklings and evident myelin lesions in ducklings and adult ducks. The activated microglia were observed phagocytizing injured neurons, neuroglia cells, nerve fibers, and capillaries after the DTMUV infection. Affected brain microvascular endothelial cells were surrounded by edema and had increased pinocytotic vesicles and cytoplasmic lesions. In conclusion, the above results systematically describe the subcellular morphological changes of the CNS after DTMUV infection, providing an ultrastructural pathological research basis for DTMUV-induced neuropathy.