The maladies of Chinese public administration

We conducted field research in China in 2010-2016 to diagnose the fundamental problems of Chinese public administration as a field of study (hereafter CPA). Our research question was ‘What are the obstacles that impede the genuine progress of CPA?’; our study shows that CPA lacks philosophical and intellectual underpinnings to justify its existence. Moreover, salvation is difficult as CPA has been suffering from three maladies, namely, reductionism, traditionalism, and conservatism, which together reinforce mediocrity. Furthermore, in order to become an indispensable field of study, scholars must strive to transform themselves so as to transform CPA. The implications for transformation of such practical examples as historical analysis and ‘optimal governance’ are discussed.</p

Unsupervised machine learning framework for discriminating major variants of concern during COVID-19

Due to high mutation rates, COVID-19 evolved rapidly, and several variants such as Alpha, Gamma, Delta, Beta, and Omicron emerged with altered viral properties like the severity of the disease caused, transmission rates, etc. These variants burdened the medical systems worldwide and created a massive impact on the world economy as each had to be studied and dealt with in its specific ways. Unsupervised machine learning methods have the ability to compress, characterize, and visualize unlabelled data. In this paper, we present a framework that utilizes unsupervised machine learning methods to discriminate and visualize the associations between major COVID-19 variants based on their genome sequences. These methods comprise a combination of selected dimensionality reduction and clustering techniques. The framework processes the RNA sequences by performing a k-mer analysis on the data and then compares the results from different dimensionality reduction methods including: Principal Component Analysis (PCA), t-Distributed Stochastic Neighbour Embedding (t-SNE), and Uniform Manifold Approximation Projection (UMAP). Our framework also employs agglomerative hierarchical clustering to visualize the mutational differences among major variants of concern and country-wise mutational differences for a particular variant (Delta and Omicron) using dendrograms. We also provide country-wise mutational differences for selected variants via dendrograms. We conclude that the proposed framework can effectively distinguish between the major variants and hence can be used for the identification of emerging variants in the future

Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

SummaryNeuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an “optimal” level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect

AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo

Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/Nneu transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (≥24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells

Substance P Induces Rapid and Transient Membrane Blebbing in U373MG Cells in a p21-Activated Kinase-Dependent Manner

U373MG astrocytoma cells endogenously express the full-length neurokinin 1 receptor (NK1R). Substance P (SP), the natural ligand for NK1R, triggers rapid and transient membrane blebbing and we report that these morphological changes have different dynamics and intracellular signaling as compared to the changes that we have previously described in HEK293-NK1R cells. In both cell lines, the SP-induced morphological changes are Gq-independent, and they require the Rho, Rho-associated coiled-coil kinase (ROCK) signaling pathway. Using confocal microscopy we have demonstrated that tubulin is phosphorylated subsequent to cell stimulation with SP and that tubulin accumulates inside the blebs. Colchicine, a tubulin polymerization inhibitor, blocked SP-induced blebbing in U373MG but not in HEK293-NK1R cells. Although p21-activated kinase (PAK) is expressed in both cell lines, SP induced rapid phosphorylation of PAK in U373MG, but failed to phosphorylate PAK in HEK293-NK1R cells. The cell-permeable Rho inhibitor C3 transferase inhibited SP-induced PAK phosphorylation, but the ROCK inhibitor Y27632 had no effect on PAK phosphorylation, suggesting that Rho activates PAK in a ROCK-independent manner. Our study demonstrates that SP triggers rapid changes in cell morphology mediated by distinct intracellular signaling mechanisms in U373MG versus HEK293-NK1R cells

Analysis of Bearing Capacity of Suction Bucket Foundation Subjected to Horizontal and Moment Loadings

Abstract: The suction bucket foundation is not only supporting the vertical loading such as the sea platform and weight itself, but also subjecting to horizontal and moment loading due to wind and wave. The response of bucket foundation to combined Horizontal (H) and Moment (M) loading has been studied using 3D finite element analysis Then the proposed method is numerically implemented in the framework of the general-purpose FEM software ABAQUS. Relationship curve between the coefficient of ultimate bearing capacity and displacement is obtained by the application of load-displacement controlled method in homogeneous soft foundation the failure envelope of foundation in the M-H is obtained by the application of swipe testing. The behavior is explained using upper bound plasticity mechanisms suggested by the soil deformation mechanisms observed in the finite element analysis. The numerical results computed by the proposed method will be helpful in engineering practices