Attributed Multi-order Graph Convolutional Network for Heterogeneous Graphs

Heterogeneous graph neural networks aim to discover discriminative node embeddings and relations from multi-relational networks.One challenge of heterogeneous graph learning is the design of learnable meta-paths, which significantly influences the quality of learned embeddings.Thus, in this paper, we propose an Attributed Multi-Order Graph Convolutional Network (AMOGCN), which automatically studies meta-paths containing multi-hop neighbors from an adaptive aggregation of multi-order adjacency matrices. The proposed model first builds different orders of adjacency matrices from manually designed node connections. After that, an intact multi-order adjacency matrix is attached from the automatic fusion of various orders of adjacency matrices. This process is supervised by the node semantic information, which is extracted from the node homophily evaluated by attributes. Eventually, we utilize a one-layer simplifying graph convolutional network with the learned multi-order adjacency matrix, which is equivalent to the cross-hop node information propagation with multi-layer graph neural networks. Substantial experiments reveal that AMOGCN gains superior semi-supervised classification performance compared with state-of-the-art competitors

Evolution of kinematic transformation from the Altyn Tagh fault to the Qilian Shan in the northern Tibetan Plateau: from early Cenozoic initiation to mid-Miocene extrusion

The Altyn Tagh fault has been a crucial tectonic boundary of the Tibetan Plateau during the Cenozoic India-Eurasia collision. However, issues have not been addressed regarding the Cenozoic evolution of the kinematic transformation from the eastern Altyn Tagh fault to the Qilian Shan. Here we focus on the kinematics at a crucial point, the Subei triple junction, along the Altyn Tagh fault, which was recorded by faulting in the Suganhu basin to the south of the junction. We reconstructed the structural pattern of faults and thickness distribution of the Cenozoic strata in the Suganhu basin by integrating seismic profiles, well logging, and topographic data. We inferred that only crustal shortening and thickening in the Danghenan Shan, a prominent topographic high, absorbed the strike-slip displacement along the Altyn Tagh fault during the early Cenozoic. Since the mid-Miocene, strike-slip fault belts within the Suganhu basin were initiated, based on the fault geometry and uneven thickness distribution across the fault belts. We thus proposed a mid-Miocene kinematic transformation realized by blocks extruding southeastward, as well as the crustal shortening and thickening in the entire Qilian Shan. Those blocks are bounded by preexisting weaknesses with lateral movements, and lithospheric heterogeneity played an essential role in the block-scale extrusion

Helper T Cell (CD4(+)) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4(+)) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation

Elevated Serum IL-21 Levels Are Associated With Stable Immune Status in Kidney Transplant Recipients and a Mouse Model of Kidney Transplantation

Allograft rejection after renal transplantation remains a challenge to overcome. Interleukin (IL)-21, a cytokine with pleiotropic effects, maintains immune homeostasis post-transplantation. Here, we report higher levels of IL-21 in kidney transplant recipients with non-rejection (NR) than in recipients with T cell-mediated rejection (TCMR, P \u3c 0.001) and antibody-mediated rejection (ABMR, P = 0.005). We observed a negative correlation between IL-21 and creatinine (Cr) levels (P = 0.016). The receiving operating characteristic (ROC) curve showed a promising diagnostic value of IL-21 to identify acute rejection with an area under the curve (AUC) of 0.822 (P \u3c 0.001). In contrast, exogenous administration of IL-21 accelerated acute rejection in a comparative translational kidney transplant (KT) mouse model. Reduced IL-21 levels in the peripheral blood were observed in KT mice after IL-21 injection. Further analysis revealed that increased IL-21 levels in the spleen induced proliferation of CD4+ T cells and CD19+ B cells after IL-21 treatment. Our findings suggest a critical function of IL-21 in kidney transplantation and the potential involvement of the IL-21/IL-21R pathway in acute rejection management

Identification of microtubule-associated biomarkers in diffuse large B-cell lymphoma and prognosis prediction

Background: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with a complicated prognosis. Even though various prognostic evaluations have been applied currently, they usually only use the clinical factors that overlook the molecular underlying DLBCL progression. Therefore, more accurate prognostic assessment needs further exploration. In the present study, we constructed a novel prognostic model based on microtubule associated genes (MAGs).Methods: A total of 33 normal controls and 1360 DLBCL samples containing gene-expression from the Gene Expression Omnibus (GEO) database were included. Subsequently, the univariate Cox, the least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were used to select the best prognosis related genes into the MAGs model. To validate the model, Kaplan-Meier curve, and nomogram were analyzed.Results: A risk score model based on fourteen candidate MAGs (CCDC78, CD300LG, CTAG2, DYNLL2, MAPKAPK2, MREG, NME8, PGK2, RALBP1, SIGLEC1, SLC1A1, SLC39A12, TMEM63A, and WRAP73) was established. The K-M curve presented that the high-risk patients had a significantly inferior overall survival (OS) time compared to low-risk patients in training and validation datasets. Furthermore, knocking-out TMEM63A, a key gene belonging to the MAGs model, inhibited cell proliferation noticeably.Conclusion: The novel MAGs prognostic model has a well predictive capability, which may as a supplement for the current assessments. Furthermore, candidate TMEM63A gene has therapeutic target potentially in DLBCL

The Effects of Digital Transformation on Firm Performance: Evidence from China’s Manufacturing Sector

With vast potentials in improving operations and stimulating growth, digital transformation has aroused much attention from firms across the world. However, the high costs associated with the transformation can not be ignored. Limited research has looked into the organizational performance effects of digital transformation. After examining the benefits and costs of digital transformation, this research makes an empirical study on the impact of digital transformation on firm operational and financial performance. The panel data from 2010 to 2020 of 2254 manufacturing companies in China suggests that the intensity of digital transformation is in positive correlation with the process-based operating performance, and in the U-shaped correlation with the profit-oriented financial performance. Further, we find that digital transformation has a much more lasting impact on operating performance than on financial performance. The conditions required (i.e., policy and innovation environment) to improve the operating performance via digital transformation are more easing. This research shows the differentiated effect of digital transformation on different dimensions of organizational performance and provides guidance for companies to set the goals for digital transformation

Efficacy and safety of SGLT2 inhibitors in nondiabetic patients with CKD: a review of recent evidence

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents in patients with type-2 diabetes. However, available data from clinical trials and meta-analyses suggest that SGLT2i have pleiotropic benefits in reducing mortality and delaying the progression of chronic kidney disease (CKD) in both diabetic and nondiabetic patients. Thus, we herein review the current evidence regarding the efficacy and safety of SGLT2i in patients with nondiabetic CKD, and appraise the recently reported clinical trials that might facilitate the management of CKD in routine clinical practice. Summary: The benefits of SGLT2i on nondiabetic CKD are multifactorial and is mediated by a combination of mechanisms. The landmark DAPA-CKD trial revealed that dapagliflozin administered with renin-angiotensin system blockade drugs reduced the risk of a sustained decline (at least 50%) in the estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), or death from cardio-renal causes. The recent EMPA-KIDNEY trial showed that empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes. These benefits were consistent in patients with and without diabetes. Moreover, a meta-analysis of DAPA-HF and EMPEROR-Reduced trials confirmed reductions in the combined risk of cardiovascular death or worsening heart failure including composite renal endpoint. Key Messages: Considering the robust data available from DAPA-CKD, EMPA-KIDNEY and other trials such as EMPEROR-Preserved, DIAMOND that included nondiabetic patients, it may be necessary to update current guidelines to include SGLT2i as a first-line therapy for CKD and re-evaluate current CKD therapeutic approaches

Structural and Functional Sensing of Bio-Tissues Based on Compressive Sensing Spectral Domain Optical Coherence Tomography

In this paper, a full depth 2D CS-SDOCT approach is proposed, which combines two-dimensional (2D) compressive sensing spectral-domain optical coherence tomography (CS-SDOCT) and dispersion encoding (ED) technologies, and its applications in structural imaging and functional sensing of bio-tissues are studied. Specifically, by introducing a large dispersion mismatch between the reference arm and sample arm in SD-OCT system, the reconstruction of the under-sampled A-scan data and the removal of the conjugated images can be achieved simultaneously by only two iterations. The under-sampled B-scan data is then reconstructed using the classic CS reconstruction algorithm. For a 5 mm × 3.2 mm fish-eye image, the conjugated image was reduced by 31.4 dB using 50% × 50% sampled data (250 depth scans and 480 spectral sampling points per depth scan), and all A-scan data was reconstructed in only 1.2 s. In addition, we analyze the application performance of the CS-SDOCT in functional sensing of locally homogeneous tissue. Simulation and experimental results show that this method can correctly reconstruct the extinction coefficient spectrum under reasonable iteration times. When 8 iterations were used to reconstruct the A-scan data in the imaging experiment of fisheye, the extinction coefficient spectrum calculated using 50% × 50% data was approximately consistent with that obtained with 100% data